US Pharmacist 04 2010

www.uspharmacist.
com
Op Foc
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H EALTH S YS TEMS EDITION
U.S. Pharmacist Health Systems Edition Vol. 35, No. 4 April 2010
AP
R I L 20 1 0
T H E J O U R N A L F O R P H A R M A C I S T S E D U C AT I O N
2 CE Credits
Overview of Glaucoma
Management
Cataract and LASIK Surgery
Ocular Manifestations
of Systemic Diseases
Age-Related Macular Degeneration
Reporting Adverse Drug Events
New Products in This Issue:
Authorized Generics / Greenstone LLC Brimonidine / Falcon
Pharmaceuticals, Ltd. Dexilant / Takeda Pharmaceuticals
North America, Inc. Humalog / Eli Lilly and Company
Imiquimod Cream / Fougera Injectables / Pfizer Injectables
F OR FR EE C E, GO TO:
www.uspharmacist.com
A J O B S O N P U B L I C AT I O N
00 USP APR COV 4_1sc.indd CV2
4/1/10 1:13 PM
The name
KAPIDEX (dexlansoprazole)
has changed to
Ordering Information
NDC#
PRODUCT
STRENGTH
SIZE
64764-171-30
DEXILANT
30 mg
30 ct
64764-175-30
DEXILANT
60 mg
30 ct
64764-175-90
DEXILANT
60 mg
90 ct
DEXILANT and KAPIDEX are trademarks of Takeda Pharmaceuticals North America, Inc.,
and are used under license by Takeda Pharmaceuticals America, Inc.
2010 Takeda Pharmaceuticals North America, Inc. LPD-01383 4/10 Printed in U.S.A.
Straight Talk
Its Dj vu All Over Again

or pharmacists who want to
get a sneak preview of what
pharmacy in the U.S. might
look like under any new health
care reform, maybe they should
set their sights on our neighbors
to the north in Ontario, Canada.
As everyone in the U.S. knows,
Canadas citizens have been living
with government-provided health
care for many years. And while it
probably isnt fair to compare our
current or future health care system with that of Canadas, there are arguably pros
and cons to both. There are also some similarities
between the countries programs, particularly as they
relate to retail pharmacy. Unlike most drugstores in
Europe and other continents, the pharmacies in Canada more closely resemble the kinds of stores we have
in the U.S. Aside from some different products or
the same products sporting different names, for the
most part when you walk into a drugstore in Canada, youd be hard-pressed to realize you are in a different country. And as in the U.S., Canadas pharmacists and pharmacy owners struggle with many of the
same professional issues.
A recent article that appeared in the The Globe
and Mail, a well-respected Canadian newspaper,
spoke about many pharmacists in the province of
Ontario complaining of being treated like clerks
instead of pharmacists. Sound familiar? And while
other Canadian provinces such as British Columbia,
Quebec, Alberta, and New Brunswick have been
more progressive in allowing pharmacists to step
beyond their current professional responsibility of
filling prescriptions, Ontario had notuntil now.
According to the article, Ontario pharmacists had
been making most of their profits through rebates
paid by generic drug manufacturers in return for
stocking their products. Recognizing that the practice
might be perceived as unethical or questionable, the
government tried to ban the rebates altogether, but it
quickly figured out that following that route would
just drive costs up. A number of other alternatives
were investigated, but in the end Canadian govern-
ment officials turned their attention to the possibility of paying

pharmacists for performing new
professional counseling services,
like medication therapy management. As Yankee hero Yogi Berra
is fond of saying, Its dj vu all
over again.
One interesting twist in Canadas medication management plan
is also to pay pharmacists for not
filling prescriptions in cases where
the pharmacist feels it would be
unsafe to do so. But as in the U.S., the government is
going to have to do some heavy selling to physician
groups on this concept, as doctors see pharmacist consultation infringing on their turf. And pharmaceutical
companies cant be happy about pharmacists refusing
to fill, or refill, prescriptions; after all, the companies
are in business to sell more drugs, not less. Despite
this, there are already signs that Ontario pharmacists
have embraced their new-found professional freedom,
and pharmacy schools are scrambling to reinvent their
curriculums to include courses that will help pharmacists succeed in the more communicative world of
retail pharmacy in Ontario after they graduate.
Our government will be facing much of the same
uphill battle should it adopt a similar consultative
role for pharmacists in which they would get paid for
their valuable consultative services. In many ways,
the U.S. is ahead of Canada in that it has already
proven in many therapeutic areas that medication
therapy management actually works to lower the
nations overall health care bill by keeping patients
more compliant, out of emergency rooms, and in
hospitals for fewer days. Only time will tell whether
pharmacists get that opportunity, because even Yogi
would agree, It aint over till its over.
Harold E. Cohen, RPh

Editor-in-Chief
hcohen@uspharmacist.com
1
U.S. Pharmacist April 2010 www.uspharmacist.com
01 Straight Talk 4_1rdsc.indd 1
4/1/10 11:36 AM
Vol. 35 No. 4
PATIENT TEACHING AID
Laser beam reshapes

the internal cornea
PERFORATION
A suction ring
is applied to the
numbed eye
TEAR ALONG
HEALTH SYSTEMS EDITION
LASIK Ey
e
Surgery
A thin flap is made

in
the cornea and
reflected
APR
IL 2010
Corrective Pro
cedure
to Improve Visi
on
The Journal for Pharmacists Education
MEDICAL ILLUSTRATI
ON: KRISTEN
WEINANDT
MARZEJON 2010
U.S. Pharmacist is a Peer-Reviewed Journal
LASIK (laser-as
sisted
(myopia), farsighte in situ keratomileusis) is a type
dness (hyperopia),
of eye surgery designed
are all the result
to treat nearsigh
of an out-of-focus and astigmatism. These condition
LASIK surgery
s, known as refractio tedness
works by changing image when light is reflected through
n errors,
correctly, the eye
the shape of the
the cornea onto
can
cornea using a
the retina.
laser.
performed on millionsfocus more clearly and vision
improves. The LASIK Once the cornea is shaped
of Americans since
lar procedure with
surgical procedur
its FDA approval
patients who want
e has been
in 1998, and it
LASIK is an outpatie
to improve their
continues to be
vision.
a popunt surgery that takes
eye drops, and the
less
than 30 minutes.
eyelid is held open
The eye
lift, flatten, and
by an instrume
hold the cornea
nt while a suction is numbed using anesthetic
steady. A small
allowing the laser
ring
is placed on the
flap is cut
access to shape the
eye to
into place without
corneal tissue underne from the corneal tissue and
folded back,
stitches. After LASIK
ath.
protect the cornea
surgery is complete The flap of tissue is then pressed
during the healing
d, an eye shield
back
LASIK eye surgery
period.
is placed over the
is
not
eye to
for
everyone. There
including those
are
with chronic dry
eyes, thin corneas, many people who should not undergo
error (very poor
vision). Patients
LASIK,
considering LASIK changing refractions, and significa
complications, as
well as the typical
surgery must understa
nt refraction
reduce the need
nd the risks and
for glasses or contact results of a successful procedur
potential
e. For
who achieve 20/20
lenses, but it does
not guarantee perfect many, LASIK surgery can
they had expected vision with LASIK as measured
vision.
Even
those patients
. In addition, LASIK
on the eye chart
from aging and
may not see the
cannot correct
requires
sharp images
they require a retreatm reading glasses. Many patients presbyopia, the change in vision
that results
who undergo LASIK
ent (second surgery)
to achieve better
surgery also find
vision.
that
Copyright Jobson
Medical Informati
on LLC, 2010
cont inue d
PTA1004 LASIK
2_12bo.indd
2/16/10 3:49
PM
COVER IMAGE:
FEATURES
Senior Care
Illustration: 2010 Elaine Kurie
Kaposis Sarcoma: Prognosis

Varies With Form . . . . . . . . . . . . . . . 20
The classic form of this disease, which is usually not
fatal, occurs most often in men over 60 years old.
Mary Ann E. Zagaria, PharmD, MS, CGP
Age-Related Macular
Degeneration . . . . . . . . . . . . . . . . . . 26
This ocular disorder is the most common cause of
blindness in the developed world.
Suzanne Albrecht, PharmD, MSLIS
www.ekurie.com
In glaucoma, elevation in intraocular
pressure exerts force posteriorly to cause
both structural and functional damage
to the optic disc of the eye.
THIS MONTH
Treatment Options for

Dry Eye Disease. . . . . . . . . . . . . . . . 34
Keratoconjunctivitis sicca is a frequent cause of
patient visits to pharmacies for OTC treatment.
Emily M. Ambizas, PharmD, CGP, and
Priti N. Patel, PharmD, BCPS
Editorial Focus: Ophthalmology

NEXT MONTH
Managing Common Eye

Conditions in the Pharmacy . . . . . . 42
LASIK Eye Surgery. See page 17
Pharmacists should be prepared to distinguish

when to recommend nonprescription therapies
and when a referral may be necessary.
Kiran Panesar, BPharmS (Hons), MRPharmS, RPh, CPh
2 CE Credits
An Overview of Glaucoma
Management for Pharmacists . . . . 52
This chronic disease of the eye is
characterized by progressive neuropathy
of the optic nerve that can lead to
irreversible blindness if untreated or
inadequately treated.
Karen K. OBrien, BS Pharm, PharmD; Alan W. Y.
Chock, PharmD; and Catherine A. Opere, PhD
Pharmacy Law
Steroid Marketing Convictions. . 64

The illegal distribution of anabolic steroids
and human growth hormone can cost
pharmacists their licenses and more.
Jesse C. Vivian, RPh, JD
Editorial Focus: Pain Management

View the Digital Edition of this issue and
earn additional CE credits online at:
www.uspharmacist.com
HEALTH S Y S TE M S E DI TI ON
Ocular Manifestations of Systemic Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . HS-2
Diabetes, hypertension, and autoimmune disorders may have a secondary ocular component.
Nicholas Beyda, PharmD; David Cluck, PharmD; Katia E. Taba, MD, PhD; and Mark Middlebrooks, PharmD
CUSTOMER SERVICE
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Cataract Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HS-9

Assessing whether a decrease in vision has affected daily activities is vital to determining when to operate.
Brenda Wood, BSPharm, PharmD
Reporting Adverse Drug Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HS-15

Timely and accurate reporting is an essential element of monitoring and improving patient safety.
Mark H. Mayer, PharmD, MBA; Sherie A. Dowsett, PhD; Kalpana Brahmavar, PharmD;
Kenneth Hornbuckle, DVM, PhD; and William P. Brookfield, MS, RPh
LASIK Refractive Eye Surgery in the 21st Century . . . . . . . . . . . . . . . . . . . . . HS-20

During this procedure, the stroma of the cornea is treated with an excimer laser in order to correct vision.
Mea A. Weinberg, DMD, MSD, RPh, and Michael S. Insler, MD
U.S. PHARMACIST (ISSN 01484818; USPS No. 333-490) is published monthly by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY 10013-1678. Periodicals postage
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2
02 TOC APR 4_1bosc.indd 5
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Q. Which Global Generic Companys Transdermal

Patches Were Most Dispensed in the U.S.
Last Year?
A.
Mylan Pharmaceuticals.*
With one of the most advanced transdermal development and manufacturing facilities in the
United Statesbrand or genericMylan is well-recognized as an innovator in transdermal
drug delivery technology. In fact, last year 65% of all generic patches dispensed in the U.S.
carried the Mylan name.*
We have developed more generic transdermal patches than any company in the U.S. and all
of our patches are designed with patient safety in mind. None have a bulky, liquid, gel-filled
reservoir, which eliminates any concern about the dangers associated with leakage, and
none have aluminum or other metals in their backing, which may cause potential burns in
MRI patients. So when you need generic transdermal patchesthink Mylan.
*IMS National Prescription Audit. 12 months ending December 2008.
2009 Mylan Pharmaceuticals Inc.
MYNMKT308
Vol. 35 No. 4
U.S. Pharmacist
A Jobson Publication
Senior Vice PresidentEditor-in-Chief
APR
IL 2010
Executive Editor
The Journal for Pharmacists Education
U.S. Pharmacist is a Peer-Reviewed Journal
Robert Davidson
Senior Editor
Bonnie Ostrowski
Senior Associate Editor
Marjorie Borden
Consulting Clinical Editor
Mary Gurnee, PharmD, RPh

Senior Vice PresidentPublisher
Harold E. Cohen, RPh (201) 623-0982

Associate Publisher
Jack McAleer (201) 623-0987

East Coast Regional Sales Manager
Mark Hildebrand (201) 623-0984

Midwest/West Regional Sales Manager
Megan Conley (773) 450-7339

Sales & Marketing Assistant
Deborah Mortara (201) 623-0990

Classified Advertising Sales
Heather Brennan (800) 983-7737 x106

Design Director
Sharyl Sand Carow
DEPARTMENTS
Straight Talk
Its Dj vu All Over Again . . . . . . 1

Pharmacists should look to Canada
for a preview of what pharmacy
in the U.S. might look like under
health care reform.
Production Manager
Dina Romano (201) 623-0942
Whats News . . . . . . . . . . . . . . . . . 6
Corporate Production Director
Pharmaceutical industry updates.
John Anthony Caggiano

Director, Continuing Education Processing
Regina Combs (800) 825-4696

Vice President, Circulation Director
Emelda Barea
Vice President,
Creative Services and Production
Monica Tettamanzi
Consult Your Pharmacist
The Pharmacist and

Contact Lenses . . . . . . . . . . . . . . 11
Contemporary
Compounding
Estradiol 0.1 mg/g

Vaginal Solution . . . . . . . . . . . . . 48
Menopausal symptoms and some female
hormonal disorders can benefit from
treatment with this preparation.
Loyd V. Allen, Jr, PhD
Generic Trends . . . . . . . . . . . . . . 50
Generic drug industry news.
Classified Advertising. . . . . . . . . 62
With many types of lenses and solutions

available, it is critical to prevent
infection and ensure safe lens wear.
Comorbid Conditions Among Visually Impaired People Aged 65 years

Skeletal
system 18%
W. Steven Pray, PhD, DPh

TrendWatch
Mental
health 29%
Visual Impairment
in Adults . . . . . . . . . . . . . . . . . . . 24
CEO, Information Services Division
Marc Ferrara
Senior Vice President, Operations
Jeff Levitz
Vision problems are among the

top 10 disabilities in people older
than 70 years.
Somnath Pal, BS (Pharm), MBA, PhD
Severe
condition 2%
Cardiovascular
system 17%
Auditory
system 15%
Circulatory
system 11%
Mild
condition
16%
Nonrisky
condition
11%
Cerebrovascular
system 4%
Endocrine
system 6%
THINKSTOCK
Vice President, Human Resources
Lorraine Orlando
U.S. Pharmacist
160 Chubb Avenue, Suite 306
Lyndhurst, NJ 07071
Phone: (201) 623-0999
Fax: (201) 623-0991
E-mail: editor@uspharmacist.com
Web: www.uspharmacist.com
Printed on paper containing an
average of 96 percent post-consumer
recycled waste.
New Products in This Issue

Authorized Generics / Greenstone LLC Brimonidine / Falcon Pharmaceuticals, Ltd.
Dexilant / Takeda Pharmaceuticals North America, Inc. Imiquimod Cream / Fougera
Health Systems Edition: Humalog / Eli Lilly and Company Injectables / Pfizer Injectables
4
02 TOC APR 4_1bosc.indd 4
4/1/10 1:18 PM
Im
here.
Fougera is proud to introduce Imiquimod Cream 5%. Another first approval in our
more than 160-year history of firsts. Available in unit-of-use foilpacs the innovative
packaging that helped make Fougera a leader in the industry. Imiquimod is just
one more example of how Fougera is dedicated to bringing patients the highest
quality in prescription generic topicals.
IMIQUIMOD CREAM 5%
AB Rated to Aldara *
0168-0432-24
24 single-use foilpacs
For complete product information, please see package insert. Copies of the
package insert can be obtained at www.fougera.com/ImHere or requested
by calling 1-800-645-9833.
* Aldara is a registered trademark of Graceway Pharmaceuticals, LLC
E. FOUGERA & CO., A division of Nycomed U.S. Inc.,

Melville, New York 11747
www.fougera.com 2010 Fougera. All rights reserved.
ISS 2/10
Whats News
U.S. Pharmacist
Editorial Board of Advisors
Joseph Bova, RPh
Community Pharmacy Owner,
Carys Pharmacy,
Dobbs Ferry, New York;
Member, NYS Board of Pharmacy
Carmen Catizone, RPh
Executive Director, National Association
of Boards of Pharmacy
John M. Coster, PhD, RPh
Senior VP of Government Affairs,
National Community Pharmacists Assoc.
Hewitt (Ted) W. Matthews, PhD
Dean, Southern School of Pharmacy,
Mercer University, Atlanta
David G. Miller, RPh
Pharmacy Affairs, Merck & Co., Inc.,
West Point, Pennsylvania
Mario F. Sylvestri, PharmD, PhD
Senior Director, Medical Science Liaisons,
Amylin Pharmaceuticals
Ray A. Wolf, PharmD
Medical Education, Sanofi Aventis
Mary Ann E. Zagaria,
PharmD, MS, CGP
Senior Care Consultant and
President, MZ Associates, Inc.,
Norwich, New York
Contributing Editors
Loyd V. Allen, Jr., PhD
Connie Barnes, PharmD
Bruce Berger, PhD
R. Keith Campbell, RPh, CDE
Patrick N. Catania, PhD, RPh
R. Rebecca Couris, PhD, RPh
Ed DeSimone, PhD, RPh
Ronald W. Maddox, PharmD
M. Saljoughian, PharmD, PhD
Jesse C. Vivian, BS Pharm, JD
Send your comments via

E D I T O R @ U S P H A R M A C I S T. C O M
Mail: 160 Chubb Avenue, Suite 306

Lyndhurst, NJ 07071
Telephone: (201) 623-0999
Editorial Dept. Fax: (201) 623-0991
Internet: www.uspharmacist.com
Health Care Reform Signed Into Law

Washington, DC Following months of debate in Congress, President Obama
signed the $938 billion Patient Protection and Affordable Care Act into law on
March 23, 2010. It contains extensive legislation that will be implemented throughout the next decade and will have significant impact on individuals, businesses, and
health care professionals. Included among the many provisions are the creation of
Health Benefit Exchanges to purchase insurance; requirements for large companies to
provide health insurance to their full-time employees or face penalties; amendments
to the Social Security Act; new taxes on pharmaceutical and device manufacturers;
and the expansion of Medicare and Medicaid. Pharmacy provisions include improvements to the Medicare Part D medication therapy management (MTM) benefit,
reductions in the cuts to Medicaid pharmacy reimbursement under the average manufacturer price (AMP) model, and a conditional exemption for pharmacies from the
durable medical equipment (DME) Medicare accreditation requirements. The health
care reform law is considered the most sweeping overhaul of the U.S. health care system since the creation of Medicare and Medicaid in 1965.
Name Change for Heartburn Drug
Silver Spring, MD The FDA has approved a name change for Kapidex (dexlansoprazole) to avoid confusion with two other medications. Effective in late April 2010,
Takeda Pharmaceuticals North America Inc. will market Kapidex under the new
name Dexilant. Since Kapidex was approved in January 2009, there have been
reports of dispensing errors due to confusion with the drugs Casodex (bicalutamide)
and Kadian (morphine sulfate), which have very different uses. Kapidex is a proton
pump inhibitor used to treat heartburn; Casodex, marketed by AstraZeneca, is used
to treat advanced prostate cancer; and Kadian, distributed by Actavis Kadian LLC, is
an opioid analgesic used to treat pain. There will be no changes made to Kapidex
other than its name.
Surprising Relationship Between Coffee and Heart Rhythm
San Francisco, CA In a study presented in March at the American Heart Associations 50th Annual Conference on Cardiovascular Disease Epidemiology and Prevention in San Francisco, new research suggests that coffee drinkers may be less likely to
be hospitalized for heart rhythm disturbances. Researchers at Kaiser Permanente Division of Research in Oakland, California, followed 130,054 men and women and
found that those who reported drinking four or more cups of coffee each day had an
18% lower risk of hospitalization for heart rhythm disturbances, compared to a 7%
reduction in risk in those drinking one to three cups per day. While not proof that
people should drink coffee to prevent arrhythmias, this report supports the idea that
those who are at risk for or have rhythm problems do not necessarily need to abstain
from drinking caffeinated coffee.
NCPA CEO to Step Down
Alexandria, VA The National Community Pharmacists Association (NCPA) has
announced that Executive Vice President and CEO Bruce T. Roberts, RPh, will leave
the organization as of June 25, 2010. After nearly nine years at the helm of NCPA,
the time seems right to turn over the reins of the association, Roberts said. He will
join BeneCard PBF, a prescription benefit facilitator, as president and CEO. Until a
replacement is named, NCPA Senior Vice President and Chief Operating Officer B.
Douglas Hoey, MBA, RPh, will serve as acting executive vice president and CEO.
6
06 Whats News 3_30bosc.indd 6
3/31/10 1:39 PM
See the effect of LEXAPRO

Proven efcacy in MDD in adolescents aged
12 to 17, and in MDD and GAD in adults1-5
In adults with MDD and Generalized
Anxiety Disorder (GAD)1
In adolescents aged 12 to 17 with
Major Depressive Disorder (MDD)*1
Signicantly improved MDD symptoms in adolescents2

Signicantly higher rates of response and remission vs placebo in MDD and GAD in adults4,5
There is no generic available for LEXAPRO
*LEXAPRO is indicated as an integral part of a total treatment program for MDD. Drug treatment may not be indicated for all adolescents
with this syndrome.
WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and
young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
Lexapro or any other antidepressant in a child, adolescent or young adult must balance this risk with the clinical need. Short-term
studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was
a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric
disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy
should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and
caregivers should be advised of the need for close observation and communication with the prescriber. Lexapro is not approved for use
in pediatric patients less than 12 years of age.
Contraindications
Lexapro is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). There have been reports of serious, sometimes
fatal, reactions with some cases resembling neuroleptic malignant syndrome (NMS) and serotonin syndrome. Features may include
hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid uctuations of vital signs, and mental status changes
that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have
recently discontinued SSRI treatment and have been started on an MAOI. Serotonin syndrome was reported for two patients who
were concomitantly receiving linezolid, an antibiotic which has MAOI activity. Lexapro should not be used in combination with an
MAOI or within 14 days of discontinuing an MAOI. MAOIs should not be initiated within 14 days of discontinuing Lexapro.
Lexapro is contraindicated in patients taking pimozide or with hypersensitivity to
escitalopram or citalopram.
Please see additional Important Safety Information on adjacent page.
2010 Forest Laboratories, Inc.
Printed in U.S.A.
41-1017217rR2 3/10
Visit the LEXAPRO website at www.lexapro.com
LEXAPRO: Proven efcacy in MDD

in adolescents aged 12 to 17, and
in MDD and GAD in adults1-5
Lexapro (escitalopram oxalate) is indicated for the acute and maintenance treatment of major depressive disorder (MDD) in adults
and adolescents aged 12-17 years. Lexapro is also indicated for the acute treatment of generalized anxiety disorder (GAD) in adults.
IMPORTANT SAFETY INFORMATION

Warnings and Precautions
All patients treated with antidepressants should be monitored appropriately and observed closely for clinical worsening,
suicidality and unusual changes in behavior, especially within the rst few months of treatment or when changing the dose.
Consideration should be given to changing the therapeutic regimen, including discontinuing medication, in patients whose
depression is persistently worse, who are experiencing emergent suicidality or symptoms that might be precursors to worsening
depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patients presenting
symptoms. Families and caregivers of patients treated with antidepressants should be alerted about the need to monitor patients
daily for the emergence of agitation, irritability, unusual changes in behavior, or the emergence of suicidality, and report such
symptoms immediately. Prescriptions for Lexapro should be written for the smallest quantity of tablets, consistent with good
patient management, in order to reduce the risk of overdose.
A major depressive episode may be the initial presentation of bipolar disorder. In patients at risk for bipolar disorder, treating
such an episode with an antidepressant alone may increase the likelihood of precipitating a mixed/manic episode. Prior to
initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar
disorder. Lexapro should be used cautiously in patients with a history of mania or seizure disorder. Lexapro is not approved for
use in treating bipolar depression.
The concomitant use of Lexapro with other SSRIs, SNRIs, triptans, tryptophan, antipsychotics or other dopamine antagonists
is not recommended due to potential development of life-threatening serotonin syndrome or neuroleptic malignant syndrome
(NMS)-like reactions. Reactions have been reported with SNRIs and SSRIs alone, including Lexapro, but particularly with drugs
that impair metabolism of serotonin (including MAOIs). Management of these events should include immediate discontinuation
of Lexapro and the concomitant agent and continued monitoring.
Patients should be monitored for adverse reactions when discontinuing treatment with Lexapro. During marketing of Lexapro and
other SSRIs and SNRIs, there have been spontaneous reports of adverse events occurring upon discontinuation, including dysphoric
mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias), anxiety, confusion, headache, lethargy, emotional
lability, insomnia and hypomania. A gradual dose reduction rather than abrupt cessation is recommended whenever possible.
SSRIs and SNRIs have been associated with clinically signicant hyponatremia. Elderly patients and patients taking diuretics or
who are otherwise volume-depleted appear to be at a greater risk. Discontinuation of Lexapro should be considered in patients
with symptomatic hyponatremia and appropriate medical intervention should be instituted.
SSRIs (including Lexapro) and SNRIs may increase the risk of bleeding. Patients should be cautioned that concomitant use of
aspirin, NSAIDs, warfarin or other anticoagulants may add to the risk.
Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain
that Lexapro does not affect their ability to engage in such activities.
Lexapro should be used with caution in patients with severe renal impairment or with diseases or conditions that alter metabolism
or hemodynamic responses. In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma
concentrations were increased. The recommended dose of Lexapro in hepatically impaired patients is 10 mg/day.
For pregnant or nursing mothers, Lexapro should be used only if the potential benet justies the potential risk to the fetus or child.
Adverse Reactions
In clinical trials of MDD, the most common adverse reactions in adults treated with Lexapro (approximately 5% or greater
and at least twice the incidence of placebo) were nausea (15% vs 7%), insomnia (9% vs 4%), ejaculation disorder (9%
vs <1%), fatigue (5% vs 2%), somnolence (6% vs 2%), and increased sweating (5% vs 2%). In pediatric patients, the overall
prole of adverse reactions was similar to that seen in adults; however, the following additional adverse reactions were
reported at an incidence of at least 2% for Lexapro and greater than placebo: back pain, urinary tract infection, vomiting, and
nasal congestion.
In clinical trials of GAD, the most common adverse reactions in adults treated with Lexapro (approximately 5% or greater and at
least twice the incidence of placebo) were nausea (18% vs 8%), ejaculation disorder (14% vs 2%), insomnia (12% vs 6%), fatigue
(8% vs 2%), decreased libido (7% vs 2%) and anorgasmia (6% vs <1%).
References: 1. LEXAPRO [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2009. 2. Emslie GJ, Ventura D, Korotzer A,
Tourkodimitris S. Escitalopram in the treatment of adolescent depression: a randomized placebo-controlled multisite trial.
J Am Acad Child Adolesc Psychiatry. 2009;48:721-729. 3. Burke WJ, Gergel I, Bose A. Fixed-dose trial of the single isomer
SSRI escitalopram in depressed outpatients. J Clin Psychiatry. 2002;63:331-336. 4. Davidson JRT, Bose A, Korotzer A, Zheng H.
Escitalopram in the treatment of generalized anxiety disorder: double-blind, placebo controlled, exible-dose study.
Depress Anxiety. 2004;19:234-240. 5. Wade A, Lemming OM, Hedegaard KB. Escitalopram 10 mg/day is effective and well
tolerated in a placebo-controlled study in depression in primary care. Int Clin Psychopharmacol. 2002;17:95-102.
Please see Boxed Warning and Contraindications on adjacent page.

Please see accompanying brief summary of Prescribing Information for LEXAPRO.
LEXAPRO (escitalopram oxalate) TABLETS/ORAL SOLUTION

Brief Summary: For complete details, please see full Prescribing Information for Lexapro.
Rx Only
WARNINGS: SUICIDALITY AND ANTIDEPRESSANT DRUGS

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and
young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of
Lexapro or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term
studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was
a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric
disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant
therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior.
Families and caregivers should be advised of the need for close observation and communication with the prescriber. Lexapro is not
approved for use in pediatric patients less than 12 years of age. [See Warnings and Precautions: Clinical Worsening and Suicide Risk,
Patient Counseling Information: Information for Patients, and Used in Specific Populations: Pediatric Use].
INDICATIONS AND USAGE: Major Depressive Disorder-Lexapro (escitalopram) is indicated for the acute and maintenance treatment of major
depressive disorder in adults and in adolescents 12 to 17 years of age [see Clinical Studies]. A major depressive episode (DSM-IV) implies a
prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight
and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed
thinking or impaired concentration, a suicide attempt or suicidal ideation. Generalized Anxiety Disorder-Lexapro is indicated for the acute
treatment of Generalized Anxiety Disorder (GAD) in adults [see Clinical Studies]. Generalized Anxiety Disorder (DSM-IV) is characterized by
excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It
must be associated with at least 3 of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty
concentrating or mind going blank, irritability, muscle tension, and sleep disturbance.
CONTRAINDICATIONS: Monoamine oxidase inhibitors (MAOIs)-Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is
contraindicated [see Warnings and Precautions]. Pimozide-Concomitant use in patients taking pimozide is contraindicated [see Drug
Interactions]. Hypersensitivity to escitalopram or citalopram-Lexapro is contraindicated in patients with a hypersensitivity to escitalopram or
citalopram or any of the inactive ingredients in Lexapro.
WARNINGS AND PRECAUTIONS: Clinical Worsening and Suicide Risk-Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in
behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a
known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There
has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of
suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant
drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and
young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase
in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive
compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients.
The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials
(median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among
drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of
suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively
stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per
1000 patients treated) are provided in Table 1.
TABLE 1
Age Range
Drug-Placebo Difference in Number of Cases
of Suicidality per 1000 Patients Treated
Increases Compared to Placebo
<18
14 additional cases
18-24
5 additional cases
Decreases Compared to Placebo
25-64
1 fewer case
65
6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However,
there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the
recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed
closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy,
or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric
patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should
be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently
worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially
if these symptoms are severe, abrupt in onset, or were not part of the patients presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with
certain symptoms [see Dosage and Administration]. Families and caregivers of patients being treated with antidepressants for major depressive
disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of
agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report
such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers [see also
Patient Counseling Information]. Prescriptions for Lexapro should be written for the smallest quantity of tablets consistent with good patient
management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder-A major depressive episode may be the initial
presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of
the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients
with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a
detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Lexapro is not approved
for use in treating bipolar depression. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions-The development of a
potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and
SSRIs alone, including Lexapro treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which
impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may
include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of
serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Lexapro with MAOIs intended to treat depression is contraindicated. If concomitant treatment of Lexapro with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of
the patient is advised, particularly during treatment initiation and dose increases. The concomitant use of Lexapro with serotonin precursors
(such as tryptophan) is not recommended. Treatment with Lexapro and any concomitant serotonergic or antidopaminergic agents, including
antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Discontinuation of Treatment with Lexapro-During marketing of Lexapro and other SSRIs and SNRIs (serotonin and norepinephrine reuptake
inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt,
including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there
have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with
Lexapro. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur
following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.
Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration]. Seizures-Although
anticonvulsant effects of racemic citalopram have been observed in animal studies, Lexapro has not been systematically evaluated in patients
with a seizure disorder. These patients were excluded from clinical studies during the products premarketing testing. In clinical trials of Lexapro,
cases of convulsion have been reported in association with Lexapro treatment. Like other drugs effective in the treatment of major depressive
disorder, Lexapro should be introduced with care in patients with a history of seizure disorder. Activation of Mania/Hypomania-In placebocontrolled trials of Lexapro in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with
Lexapro and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with Lexapro
treatment. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with
racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder. As with all drugs effective in the treatment
of major depressive disorder, Lexapro should be used cautiously in patients with a history of mania. Hyponatremia-Hyponatremia may occur as
a result of treatment with SSRIs and SNRIs, including Lexapro. In many cases, this hyponatremia appears to be the result of the syndrome of
inappropriate antidiuretic hormone secretion (SIADH), and was reversible when Lexapro was discontinued. Cases with serum sodium lower than
110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Geriatric Use]. Discontinuation of Lexapro should be considered
in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia
include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Abnormal Bleeding-SSRIs and SNRIs, including Lexapro, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal
anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk. Case reports and epidemiological studies (case-control and
cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to
life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Lexapro and
NSAIDs, aspirin, or other drugs that affect coagulation. Interference with Cognitive and Motor Performance-In a study in normal volunteers,
Lexapro 10 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair
judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until
they are reasonably certain that Lexapro therapy does not affect their ability to engage in such activities. Use in Patients with Concomitant
Illness-Clinical experience with Lexapro in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using Lexapro
in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. Lexapro has not been systematically
evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the products premarketing testing. In subjects with hepatic impairment, clearance of racemic citalopram was
decreased and plasma concentrations were increased. The recommended dose of Lexapro in hepatically impaired patients is 10 mg/day [see
Dosage and Administration]. Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with Lexapro, however, it
should be used with caution in such patients [see Dosage and Administration]. Potential for Interaction with Monoamine Oxidase InhibitorsIn patients receiving serotonin reuptake inhibitor drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of
serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital
signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in
patients who have recently discontinued SSRI treatment and have been started on an MAOI. Some cases presented with features resembling
neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of SSRIs and MAOIs suggest that these drugs
may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that Lexapro should not be used
in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after
stopping Lexapro before starting an MAOI. Serotonin syndrome has been reported in two patients who were concomitantly receiving linezolid,
an antibiotic which is a reversible non-selective MAOI.
ADVERSE REACTIONS: Clinical Trials Experience-Because clinical studies are conducted under widely varying conditions, adverse reaction
rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect
the rates observed in practice. Clinical Trial Data Sources; Pediatrics (6 -17 years)-Adverse events were collected in 576 pediatric patients
(286 Lexapro, 290 placebo) with major depressive disorder in double-blind placebo-controlled studies. Safety and effectiveness of Lexapro in
pediatric patients less than 12 years of age has not been established. Adults-Adverse events information for Lexapro was collected from 715
patients with major depressive disorder who were exposed to escitalopram and from 592 patients who were exposed to placebo in double-blind,
placebo-controlled trials. An additional 284 patients with major depressive disorder were newly exposed to escitalopram in open-label trials. The
adverse event information for Lexapro in patients with GAD was collected from 429 patients exposed to escitalopram and from 427 patients
exposed to placebo in double-blind, placebo-controlled trials. Adverse events during exposure were obtained primarily by general inquiry and
recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of
the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized
event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify
reported adverse events. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a
treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened
while receiving therapy following baseline evaluation. Adverse Events Associated with Discontinuation of Treatment; Major Depressive
Disorder; Pediatrics (6 -17 years)-Adverse events were associated with discontinuation of 3.5% of 286 patients receiving Lexapro and 1% of
290 patients receiving placebo. The most common adverse event (incidence at least 1% for Lexapro and greater than placebo) associated with
discontinuation was insomnia (1% Lexapro, 0% placebo). Adults-Among the 715 depressed patients who received Lexapro in placebo-controlled
trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies,
the rate of discontinuation for adverse events in patients receiving 10 mg/day Lexapro was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of
20 mg/day Lexapro was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day
Lexapro (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with Lexapro,
and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients). Generalized Anxiety
Disorder; Adults-Among the 429 GAD patients who received Lexapro 10-20 mg/day in placebo-controlled trials, 8% discontinued treatment due
to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associated with the discontinuation of at
least 1% of patients treated with Lexapro, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and
fatigue (1%). Incidence of Adverse Reactions in Placebo-Controlled Clinical Trials; Major Depressive Disorder; Pediatrics (6 -17 years)-The
overall profile of adverse reactions in pediatric patients was generally similar to that seen in adult studies, as shown in Table 2. However, the
following adverse reactions (excluding those which appear in Table 2 and those for which the coded terms were uninformative or misleading)
were reported at an incidence of at least 2% for Lexapro and greater than placebo: back pain, urinary tract infection, vomiting, and nasal
congestion. Adults-The most commonly observed adverse reactions in Lexapro patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased,
fatigue, and somnolence. Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred
among 715 depressed patients who received Lexapro at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Events included are
those occurring in 2% or more of patients treated with Lexapro and for which the incidence in patients treated with Lexapro was greater than
the incidence in placebo-treated patients.
TABLE 2
Treatment-Emergent Adverse Reactions Observed with a Frequency of 2%
and Greater Than Placebo for Major Depressive Disorder
Adverse Reaction
Autonomic Nervous System Disorders
Dry Mouth
Sweating Increased
Central & Peripheral Nervous System Disorders
Dizziness
Gastrointestinal Disorders
Nausea
Diarrhea
Constipation
Indigestion
Abdominal Pain
General
Influenza-like Symptoms
Fatigue
Psychiatric Disorders
Insomnia
Somnolence
Appetite Decreased
Libido Decreased
Respiratory System Disorders
Rhinitis
Sinusitis
Urogenital
Ejaculation Disorder1,2
Impotence2
Anorgasmia3
Lexapro
(N=715)
Placebo
(N=592)
6%
5%
5%
2%
5%
3%
15%
8%
3%
3%
2%
7%
5%
1%
1%
1%
5%
5%
4%
2%
9%
6%
3%
3%
4%
2%
1%
1%
5%
3%
4%
2%
9%
3%
2%
<1%
<1%
<1%
1Primarily ejaculatory delay.

2Denominator used was for males only (N=225 Lexapro; N=188 placebo).
3Denominator used was for females only (N=490 Lexapro; N=404 placebo).
Generalized Anxiety Disorder; Adults-The most commonly observed adverse reactions in Lexapro patients (incidence of approximately 5% or
greater and approximately twice the incidence in placebo patients) were nausea, ejaculation disorder (primarily ejaculatory delay), insomnia,
fatigue, decreased libido, and anorgasmia. Table 3 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse
events that occurred among 429 GAD patients who received Lexapro 10 to 20 mg/day in placebo-controlled trials. Events included are those
occurring in 2% or more of patients treated with Lexapro and for which the incidence in patients treated with Lexapro was greater than the
incidence in placebo-treated patients.
TABLE 3
and Greater Than Placebo for Generalized Anxiety Disorder
Lexapro
Placebo
Adverse Reactions
(N=429)
(N=427)
Autonomic Nervous System Disorders
Dry Mouth
9%
5%
Sweating Increased
4%
1%
Central & Peripheral Nervous System Disorders
Headache
24%
17%
Paresthesia
2%
1%
Gastrointestinal Disorders
Nausea
18%
8%
Diarrhea
8%
6%
Constipation
5%
4%
Indigestion
3%
2%
Vomiting
3%
1%
Abdominal Pain
2%
1%
Flatulence
2%
1%
Toothache
2%
0%
General
Fatigue
8%
2%
Influenza-like Symptoms
5%
4%
Musculoskeletal System Disorder
Neck/Shoulder Pain
3%
1%
Psychiatric Disorders
Somnolence
13%
7%
Insomnia
12%
6%
Libido Decreased
7%
2%
Dreaming Abnormal
3%
2%
Appetite Decreased
3%
1%
Lethargy
3%
1%
Adverse Reactions
TABLE 3
and Greater Than Placebo for Generalized Anxiety Disorder (continued)
Lexapro
(N=429)
Respiratory System Disorders

Yawning
Urogenital
Ejaculation Disorder1,2
Anorgasmia3
Menstrual Disorder
Placebo
(N=427)
2%
1%
14%
6%
2%
2%
<1%
1%
1Primarily ejaculatory delay.

2Denominator used was for males only (N=182 Lexapro; N=195 placebo).
3Denominator used was for females only (N=247 Lexapro; N=232 placebo).
Dose Dependency of Adverse Reactions-The potential dose dependency of common adverse reactions (defined as an incidence rate of 5% in
either the 10 mg or 20 mg Lexapro groups) was examined on the basis of the combined incidence of adverse events in two fixed-dose trials.
The overall incidence rates of adverse events in 10 mg Lexapro-treated patients (66%) was similar to that of the placebo-treated patients (61%),
while the incidence rate in 20 mg/day Lexapro-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in
the 20 mg/day Lexapro group with an incidence that was approximately twice that of the 10 mg/day Lexapro group and approximately twice that
of the placebo group.
Adverse Reaction
Insomnia
Diarrhea
Dry Mouth
Somnolence
Dizziness
Sweating Increased
Constipation
Fatigue
Indigestion
TABLE 4
Incidence of Common Adverse Reactions in Patients with Major
Depressive Disorder
Placebo
10 mg/day
(N=311)
Lexapro
(N=310)
4%
7%
5%
6%
3%
4%
1%
4%
2%
4%
<1%
3%
1%
3%
2%
2%
1%
2%
20 mg/day
Lexapro
(N=125)
14%
14%
9%
9%
7%
8%
6%
6%
6%
Male and Female Sexual Dysfunction with SSRIs-Although changes in sexual desire, sexual performance, and sexual satisfaction often occur
as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests
that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving
sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss
them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence.
Adverse Event
Ejaculation Disorder
(primarily ejaculatory delay)
Libido Decreased
Impotence
TABLE 5
Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials
Lexapro
In Males Only
(N=407)
12%
6%
2%
Placebo
(N=383)
1%
2%
<1%
In Females Only
Libido Decreased
Anorgasmia
(N=737)
3%
3%
(N=636)
1%
<1%
There are no adequately designed studies examining sexual dysfunction with escitalopram treatment. Priapism has been reported with all SSRIs.
While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about
such possible side effects. Vital Sign Changes-Lexapro and placebo groups were compared with respect to (1) mean change from baseline in
vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated
with Lexapro treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving Lexapro indicated that
Lexapro treatment is not associated with orthostatic changes. Weight Changes-Patients treated with Lexapro in controlled trials did not differ
from placebo-treated patients with regard to clinically important change in body weight. Laboratory Changes-Lexapro and placebo groups were
compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence
of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically
important changes in laboratory test parameters associated with Lexapro treatment. ECG Changes-Electrocardiograms from Lexapro (N=625),
racemic citalopram (N=351), and placebo (N=527) groups were compared with respect to (1) mean change from baseline in various ECG
parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These
analyses revealed (1) a decrease in heart rate of 2.2 bpm for Lexapro and 2.7 bpm for racemic citalopram, compared to an increase of 0.3 bpm
for placebo and (2) an increase in QTc interval of 3.9 msec for Lexapro and 3.7 msec for racemic citalopram, compared to 0.5 msec for
placebo. Neither Lexapro nor racemic citalopram were associated with the development of clinically significant ECG abnormalities. Other
Reactions Observed During the Premarketing Evaluation of Lexapro-Following is a list of treatment-emergent adverse events, as defined in the
introduction to the ADVERSE REACTIONS section, reported by the 1428 patients treated with Lexapro for periods of up to one year in doubleblind or open-label clinical trials during its premarketing evaluation. The listing does not include those events already listed in Tables 2 & 3, those
events for which a drug cause was remote and at a rate less than 1% or lower than placebo, those events which were so general as to be
uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Events are
categorized by body system. Events of major clinical importance are described in the Warnings and Precautions section. Cardiovascular - hypertension, palpitation. Central and Peripheral Nervous System Disorders - light-headed feeling, migraine. Gastrointestinal Disorders - abdominal
cramp, heartburn, gastroenteritis. General - allergy, chest pain, fever, hot flushes, pain in limb. Metabolic and Nutritional Disorders - increased
weight. Musculoskeletal System Disorders - arthralgia, myalgia jaw stiffness. Psychiatric Disorders - appetite increased, concentration impaired,
irritability. Reproductive Disorders/Female - menstrual cramps, menstrual disorder. Respiratory System Disorders - bronchitis, coughing, nasal
congestion, sinus congestion, sinus headache. Skin and Appendages Disorders - rash. Special Senses - vision blurred, tinnitus. Urinary System
Disorders - urinary frequency, urinary tract infection. Post-Marketing Experience; Adverse Reactions Reported Subsequent to the Marketing
of Escitalopram-The following additional adverse reactions have been identified from spontaneous reports of escitalopram received worldwide.
These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal
connection to escitalopram and have not been listed elsewhere in labeling. However, because these adverse reactions were reported voluntarily
from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure. These events include: Blood and Lymphatic System Disorders: anemia, agranulocytis, aplastic anemia, hemolytic anemia, idiopathic
thrombocytopenia purpura, leukopenia, thrombocytopenia. Cardiac Disorders: atrial fibrillation, bradycardia, cardiac failure, myocardial
infarction, tachycardia, torsade de pointes, ventricular arrhythmia, ventricular tachycardia. Ear and Labyrinth Disorders: vertigo Endocrine
Disorders: diabetes mellitus, hyperprolactinemia, SIADH. Eye Disorders: diplopia, glaucoma, mydriasis, visual disturbance. Gastrointestinal
Disorders: dysphagia, gastrointestinal hemorrhage, gastroesophageal reflux, pancreatitis, rectal hemorrhage. General Disorders and
Administration Site Conditions: abnormal gait, asthenia, edema, fall, feeling abnormal, malaise. Hepatobiliary Disorders: fulminant hepatitis,
hepatic failure, hepatic necrosis, hepatitis. Immune System Disorders: allergic reaction, anaphylaxis. Investigations: bilirubin increased,
decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INR increased, prothrombin
decreased. Metabolism and Nutrition Disorders: hyperglycemia, hypoglycemia, hypokalemia, hyponatremia. Musculoskeletal and Connective
Tissue Disorders: muscle cramp, muscle stiffness, muscle weakness, rhabdomyolysis. Nervous System Disorders: akathisia, amnesia, ataxia,
choreoathetosis, cerebrovascular accident, dysarthria, dyskinesia, dystonia, extrapyramidal disorders, grand mal seizures (or convulsions),
hypoaesthesia, myoclonus, nystagmus, Parkinsonism, restless legs, seizures, syncope, tardive dyskinesia, tremor. Pregnancy, Puerperium and
Perinatal Conditions: spontaneous abortion. Psychiatric Disorders: acute psychosis, aggression, agitation, anger, anxiety, apathy, completed
suicide, confusion, depersonalization, depression aggravated, delirium, delusion, disorientation, feeling unreal, hallucinations (visual and
auditory), mood swings, nervousness, nightmare, panic reaction, paranoia, restlessness, self-harm or thoughts of self-harm, suicide attempt,
suicidal ideation, suicidal tendency. Renal and Urinary Disorders: acute renal failure, dysuria, urinary retention. Reproductive System and Breast
Disorders: menorrhagia, priapism. Respiratory, Thoracic and Mediastinal Disorders: dyspnea, epistaxis, pulmonary embolism, pulmonary
hypertension of the newborn. Skin and Subcutaneous Tissue Disorders: alopecia, angioedema, dermatitis, ecchymosis, erythema multiforme,
photosensitivity reaction, Stevens Johnson Syndrome, toxic epidermal necrolysis, urticaria. Vascular Disorders: deep vein thrombosis, flushing,
hypertensive crisis, hypotension, orthostatic hypotension, phlebitis, thrombosis.
DRUG INTERACTIONS: Serotonergic Drugs-Based on the mechanism of action of SNRIs and SSRIs including Lexapro, and the potential
for serotonin syndrome, caution is advised when Lexapro is coadministered with other drugs that may affect the serotonergic neurotransmitter
systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. Johns Wort [see Warnings
and Precautions]. The concomitant use of Lexapro with other SSRIs, SNRIs or tryptophan is not recommended. Triptans-There have been rare
postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Lexapro with a triptan is clinically
warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and
Precautions]. CNS Drugs- Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other
centrally acting drugs. Alcohol-Although Lexapro did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other
psychotropic medications, the use of alcohol by patients taking Lexapro is not recommended. Monoamine Oxidase Inhibitors (MAOIs)-[see
Contraindications and Warnings and Precautions]. Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)-Serotonin release
by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an
association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have
also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased
bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully
monitored when Lexapro is initiated or discontinued. Cimetidine-In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The
clinical significance of these findings is unknown. Digoxin-In subjects who had received 21 days of 40 mg/day racemic citalopram, combined
administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.
Lithium-Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the
pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium
dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of escitalopram, caution should
be exercised when Lexapro and lithium are coadministered. Pimozide and Celexa-In a controlled study, a single dose of pimozide 2 mg coadministered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately
10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or Cmax of pimozide. The mechanism of this
pharmacodynamic interaction is not known. Sumatriptan-There have been rare postmarketing reports describing patients with weakness,
hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g.,
fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted, appropriate observation of the patient is advised.
Theophylline-Combined administration of racemic citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose
of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not
evaluated. Warfarin-Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown. Carbamazepine-Combined administration of
racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing
properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two
drugs are coadministered. Triazolam-Combined administration of racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4
substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam. KetoconazoleCombined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the Cmax and AUC of
ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram. Ritonavir-Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect
the pharmacokinetics of either ritonavir or escitalopram. CYP3A4 and -2C19 Inhibitors-In vitro studies indicated that CYP3A4 and -2C19 are the
primary enzymes involved in the metabolism of escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a
potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram. Because escitalopram is metabolized by multiple
enzyme systems, inhibition of a single enzyme may not appreciably decrease escitalopram clearance. Drugs Metabolized by Cytochrome
P4502D6-In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram
were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram,
suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration
of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted
in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution
is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6. Metoprolol-Administration of 20 mg/day Lexapro for
21 days in healthy volunteers resulted in a 50% increase in Cmax and 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a
single dose of 100 mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of Lexapro
and metoprolol had no clinically significant effects on blood pressure or heart rate. Electroconvulsive Therapy (ECT)-There are no clinical
studies of the combined use of ECT and escitalopram.
USE IN SPECIFIC POPULATIONS: Pregnancy; Pregnancy Category C-In a rat embryo/fetal development study, oral administration of
escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and
associated delays in ossification at the two higher doses (approximately 56 times the maximum recommended human dose [MRHD] of
20 mg/day on a body surface area [mg/m2] basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild
at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 28 times the MRHD on a
mg/m2 basis. No teratogenicity was observed at any of the doses tested (as high as 75 times the MRHD on a mg/m2 basis). When female rats
were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and
growth retardation were noted at 48 mg/kg/day which is approximately 24 times the MRHD on a mg/m2 basis. Slight maternal toxicity (clinical
signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was also seen at
24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD on a mg/m2 basis. In animal reproduction
studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects,
when administered at doses greater than human therapeutic doses. In two rat embryo/fetal development studies, oral administration of racemic
citalopram (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and
survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also
associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. In a rabbit
study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. Thus, teratogenic
effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit. When female rats were
treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first
4 days after birth and persistent offspring growth retardation were observed at the highest dose. The no-effect dose was 12.8 mg/kg/day. Similar
effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses 24 mg/kg/day.
A no-effect dose was not determined in that study. There are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy-Nonteratogenic Effects
Neonates exposed to Lexapro and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included
respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia,
hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs
or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome
[see Warnings and Precautions]. Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension
of the newborn (PPHN). PPHN occurs in 1-2 per 1000 live births in the general population and is associated with substantial neonatal
morbidity and mortality. In a retrospective, case-control study of 377 women whose infants were born with PPHN and 836 women whose infants
were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation
compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the
risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include
enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. When treating a pregnant woman
with Lexapro during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment [see Dosage
and Administration]. Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were
euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience
a relapse of major depression than women who continued antidepressant medication. Labor and Delivery-The effect of Lexapro on labor and
delivery in humans is unknown. Nursing Mothers-Escitalopram is excreted in human breast milk. Limited data from women taking 10-20 mg
escitalopram showed that exclusively breast-fed infants receive approximately 3.9% of the maternal weight-adjusted dose of escitalopram and
1.7% of the maternal weight-adjusted dose of desmethylcitalopram. There were two reports of infants experiencing excessive somnolence,
decreased feeding, and weight loss in association with breastfeeding from a racemic citalopram-treated mother; in one case, the infant was
reported to recover completely upon discontinuation of racemic citalopram by its mother and, in the second case, no follow-up information was
available. Caution should be exercised and breastfeeding infants should be observed for adverse reactions when Lexapro is administered to a
nursing woman. Pediatric Use-Safety and effectiveness of Lexapro has not been established in pediatric patients (less than 12 years of age) with
Major Depressive Disorder. Safety and effectiveness of Lexapro has been established in adolescents (12 to 17 years of age) for the treatment of
major depressive disorder [see Clinical Studies]. Although maintenance efficacy in adolescent patients with Major Depressive Disorder has not
been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients. Safety and effectiveness of Lexapro has not been established in pediatric patients less than
18 years of age with Generalized Anxiety Disorder. Geriatric Use-Approximately 6% of the 1144 patients receiving escitalopram in controlled
trials of Lexapro in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of
Lexapro between 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess for possible differential
efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of Lexapro cannot
be ruled out. SSRIs and SNRIs, including Lexapro, have been associated with cases of clinically significant hyponatremia in elderly patients,
who may be at greater risk for this adverse event [see Hyponatremia]. In two pharmacokinetic studies, escitalopram half-life was increased by
approximately 50% in elderly subjects as compared to young subjects and Cmax was unchanged [see Clinical Pharmacology]. 10 mg/day is the
recommended dose for elderly patients [see Dosage and Administration]. Of 4422 patients in clinical studies of racemic citalopram, 1357 were
60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these
subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger
patients, but again, greater sensitivity of some elderly individuals cannot be ruled out.
DRUG ABUSE AND DEPENDENCE: Abuse and Dependence; Physical and Psychological Dependence-Animal studies suggest that the abuse
liability of racemic citalopram is low. Lexapro has not been systematically studied in humans for its potential for abuse, tolerance, or physical
dependence. The premarketing clinical experience with Lexapro did not reveal any drug-seeking behavior. However, these observations were not
systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate Lexapro patients for history of drug abuse and follow such
patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
OVERDOSAGE: Human Experience-In clinical trials of escitalopram, there were reports of escitalopram overdose, including overdoses of up
to 600 mg, with no associated fatalities. During the postmarketing evaluation of escitalopram, Lexapro overdoses involving overdoses of over
1000 mg have been reported. As with other SSRIs, a fatal outcome in a patient who has taken an overdose of escitalopram has been rarely
reported. Symptoms most often accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included
convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes (including QT
prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose. Management
of Overdose-Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of
activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general
symptomatic and supportive care. Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, hemoperfusion, and exchange
transfusion are unlikely to be of benefit. There are no specific antidotes for Lexapro. In managing overdosage, consider the possibility of
multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any
overdose.
Forest Pharmaceuticals, Inc.
Subsidiary of Forest Laboratories, Inc.
St. Louis, MO 63045 USA
Licensed from H. Lundbeck A/S
2009 Forest Laboratories, Inc.
Rev. 05/09
The Pharmacist and Contact Lenses

harmacists occasionally field
meability allows the cornea to
and sharper than with soft lenses.
patients questions about
receive oxygen, unlike the older hard Most visual problems can be corcontact lenses. There are
lenses that were prevalent in the
rected using RGP lenses. They may
numerous types of lenses and solu1970s. Patients usually adjust to
be better for certain patient populations, and pharmacists should not
daily wear soft lenses within several
tions, such as those with presbyopia
hesitate to refer patients to an eye
days, and these lenses are considered or astigmatism. However, RGP
care practitioner whenever
lenses slip off the center of the
they do not feel comfortable
eye more easily than other
answering these questions.
types. Debris can collect under
Contact lenses have
the lenses, and patients require
important advantages comoffice visits for follow-up care.
pared to eyeglasses.1,2 They
Extended-Wear Reusable
move with the eye, allow the
patient to have a natural field
Lenses: Lenses known as
extended wear are most often
of view, do not have frames
soft plastic lenses, although
that obstruct vision, and
occasionally RGPs may be
reduce visual distortions
approved for overnight wear.
caused by eyeglass lenses.
Soft extended wear lenses may
Glasses fog up with temperabe worn overnight, continuture and humidity changes,
ously for 1 to 6 nights or up to
and they can be spotted with
In order to maximize comfort and avoid infection, contact
30 days.1,2 The maximum time
rain; contacts do not share
lenses must be properly stored, cleaned, and handled.
of wear is determined by the
these drawbacks. Contacts are
prescriber for each patient based on
to be more comfortable and more
better for active sports, and they
the specific lens and the patients tolgenerally provide better sight when difficult to dislodge than RGP
lenses. More recent materials include erance for extended use. These lenses
compared to eyeglasses.
silicone hydrogel plastics that further cannot correct all visual problems,
Categories of Contact Lenses
and patients require regular office
increase corneal oxygenation. Daily
Contact lenses fall into one of two
visits for follow-up care.
wear soft lenses are available in
general categories: soft and rigid gas
tinted and bifocal versions, but they
Extended-Wear Disposable Lenses:
permeable (RGP) lenses. There are
cannot correct all visual problems.
These soft lenses are worn for 1 to 6
also several other ways to categorize
Patients must make regular office
them, including as decorative convisits for follow-up care. These lenses days before disposal. They require
little or no cleaning.1,2 If the patient
tacts. Approximately 34 million peo- soil and must then be replaced to
follows directions, they present miniple in the United States wear contact ensure decent vision.
mal risk of infection. Vision may be
lenses, with soft lenses being the
3
RGP Lenses: RGP lenses have sigless sharp than with RGPs. Handling
most common type (87%).
nificant advantages and disadvanmay be more complicated, and they
Daily Wear Soft Contact Lenses:
tages when compared to soft lenses.
cannot correct all visual problems.
These lenses are composed of soft,
It may take a few weeks to become
Planned Replacement Lenses:
flexible plastic.1,2 Their oxygen peradapted to them due to greater disThese lenses are daily wear soft
comfort.1,2 However, RGPs are less
likely to tear, are more durable, and
lenses that are replaced according to
Bernhardt Professor, Nonprescription
generally last longer. They are more
a planned schedule, such as every 2
Products and Devices, College of Pharmacy
resistant to buildup of deposits, and
weeks, each month, or once every 3
Southwestern Oklahoma State University
the visual acuity achieved is clearer
months (quarterly).1,2 Cleaning and
Weatherford, Oklahoma
THINKSTOCK
11
11 Consult 3_30sc.indd 11
3/31/10 1:40 PM
PATIENT INFORMATION
Common Questions About Contact Lenses
When you need vision correction,

there are several choices, such as
eyeglasses or LASIK surgery.
However, many people choose
contact lenses, for which a prescription is required.
What Do I Need to Know

to Wear My Lenses Safely?
You must follow the recommended wearing schedule. Be
sure to wash your hands thoroughly before inserting your
lenses. This will reduce the risk
of infection. Never expose your
contacts to nonsterile water such
as tap water, bottled water, distilled water, or ocean water. If
you fail to follow this vital precaution, you may get an organism
known as Acanthamoeba in your
eyes. This and other organisms
found in nonsterile water can
cause blindness, so avoidance is
the best advice. Lenses should
never be placed in the mouth, as
saliva is full of bacteria.
your lenses and lens care products

are some of the most confusing
and detailed. When there is any
question, call or visit your prescriber. Only use the lens solutions that your eye care professional has recommended. Do not
substitute another trade name,
simply guessing that it will be the
same as the product that was recommended to you.
Use only your own products.
You should not trust others to
pay sufficiently careful attention
to the sterility and care of their
products. Never use any product
or lens solution if the tamperproof seal has been violated, or if
it has expired.
Sterile saline solutions are only
to be used for rinsing lenses.
They are never to be used as
cleaning or disinfecting solutions.
Rub and rinse your lenses as recommended by your prescriber.
Cleaning and disinfecting should
THINKSTOCK
When you are first prescribed contact lenses,

numerous questions will arise. The answers can
be critical to prevent infection and ensure safe
lens wear. There are many types of lenses, and
the advice below should not replace a discussion
with the eye care professional who prescribed
your lenses.
follow all instructions exactly.
Never top off the contact solutions in your case. Any leftover
solution should be discarded after
each use. Lens solutions should
never be reused.
Each time you remove your
lenses, clean, rinse, and air-dry
the case. Allow excess solution to
drain out of your lens case by
turning it upsidedown. Bacteria
may grow in the case if this is not
done properly.
When you travel, keep your
lens solutions in their original
bottles. Never transfer them to
smaller containers for travel, as
this can introduce infection by
contaminating them. Further, the
new containers will not have the
appropriate labels. As a result,
you may mix them up, or you
may even mistakenly use another
liquid that you keep in a similar
container (e.g., shampoo).
PHARMACY STAMP
What Do I Need
to Know About
Cleaning My Lenses?
You should recall and follow strictly all instructions
given to you by your prescriber. Those relating to
When Should I See

My Prescriber?
If your eyes become red or
irritated, or if you experience changes in vision, you
should remove your lenses
immediately and make an
appointment with an eye
care professional.
Remember, if you have questions, Consult Your Pharmacist.

12
4/1/10 1:03 PM
Simply illuminating.
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or visit us at www.actavis.us
disinfection are simpler,

although vision may not be
as sharp as with RGPs.
A Look at Decorative Lenses

The FDA and FTC are vitally concerned about decorative lenses
that are sold to unsuspecting consumers as nonprescription
products that may result in serious injury. Some Web sites,
often providing products from outside the U.S., offer an array of
startling lenses at the click of a cursor, with no medical intervention.24 They include cosmetic, theatrical, and custom lenses
that make the entire eye appear black, white, or blood red, and
allow purchasers to cover the iris with dozens of strange and
radical decorations (e.g., cyclops, demon, dragon, gargoyle,
goblin).The FTC stresses that all contact lenses, even those that
are cosmetic, require a prescription, leaving the very legality of
these products open to question.7 Pharmacists should advise
against such lenses to ensure their patients eye safety.
Risks of Wearing
Contact Lenses
Patients may ask pharmacists
about certain types of ocular
discomfort, each of which
may indicate irritation or
infection.4 These include discomfort, itching, burning,
pain, or swelling; a foreign
body sensation with a feeling
of grittiness; excessive tears or any
other ophthalmic discharge; extreme
sensitivity to light; unusual redness;
or blurred vision. If untreated, these
symptoms can lead to corneal ulceration, worsening of infection, and
blindness. Patients with these problems should be referred to their eye
care professional.
Preventing Contact Lens Problems

Pharmacists can give patients several
commonsense bits of advice to prevent problems.5 To reduce the risk of
infection and irritation, patients
should not sleep in daily wear lenses.
They should only purchase lenses
after a visit to an eye care professional and after receiving a prescription. The FDA alerts patients against
purchasing contact lenses from gas
stations, convenience stores, video
stores, and other vendors who sell
them illegally. It is risky to swap
lenses with another person, as crosscontamination may occur. In addition, wearing lenses fitted for
another person can result in permanent ocular injury or blindness.
Patients should be advised to cease
smoking, as smokers experience an
enhanced risk of adverse reactions.
Patients should not swim while
wearing lenses, since water in pools,
hot tubs, lakes, and oceans is not

sterile. Contact wearers often ask
about concomitant use of ophthalmic drops for dry eye, red eye, and
allergic conjunctivitis. Although
OTC eye drops for use with contact
lenses are available, it is vital for
patients to contact their prescribers
before using any products, to confirm whether the drops are compatible with their specific lens type.
The Contact Lens Prescription

A prescription for contact lenses is a
legal document issued following an
examination by a legitimate prescriber
(e.g., ophthalmologist, optometrist).
The prescription may be filled by the
issuer, an optician, or an online vendor (e.g., VisionDirect.com).6,7 Prescriptions contain such data as date
of the examination, expiration date
of the prescription, power of the
lenses, the material and/or manufacturer of the prescribed lenses, the
diameter of the lenses, and the base
curve of the lenses. The Federal
Trade Commission (FTC) enforces a
legal requirement that patients be
given a copy of their prescriptions.6
This law is meant to make the transaction portable. Patients should be
urged to keep a copy of their prescription with other medical records.
When the patient chooses a

lens provider who was not
the original prescriber, the
seller is required to verify
each prescription with the
eye care provider before filling.7 It may be necessary for
the patient to fax or send
the prescription to such sellers to speed the process of
procuring their lenses.
Safe Use of
Contact Lens Solutions
The sheer complexity of the contact
lens solution market defies discussion of individual products here.
However, both the FDA and CDC
provide several practical pieces of
advice that must be followed.8,9
Patients must understand that their
contact lens case can become a
breeding ground for infection if not
cleaned properly. They must empty
the solution out after every use.
Remaining solution is contaminated
and has reduced disinfectant capability. Each time lenses are removed
from the case, the patient should
clean and rinse the case, inverting it
to allow fluid to drain, and then
allow it to air-dry. Cases should be
replaced every 3 to 6 months.
In addition, patients should
understand that cleaning via rubbing and rinsing is superior to rinsing alone (i.e., the no rub method)
for cleaning lenses.10-12 To properly
rub and rinse, the wearer places
the disinfectant solution on the lens
while it lies in the palm. The solution is rubbed over the lens surface
for 5 to 10 seconds with the index
finger of the other hand. The lens is
then turned over and the process
repeated. A strong stream of disinfectant solution is sprayed over both
sides of the lens to remove debris,
14
3/31/10 1:40 PM
such as bacteria, proteins, and other

deposits. Patients must never use
saline solution or rewetting solution
as a contact disinfectant, as neither is
effective for that purpose.9
within the cornea grow slowly but

can cause severe pain leading to corneal ulcer and blindness.10,16 They
are highly resistant to therapy. A
protozoan of the genus Acanthamoeba is a rare cause of contact
lensrelated infection, with about 1
to 2 cases per million lens wearers.13,17,18 Risk factors include
improper lens storage and handling
or improper disinfection (e.g., using
homemade solutions or tap water);
wearing lenses while swimming,
using a hot tub, or showering; contacting infected water; and having a
history of corneal trauma.17,19 The
organism can also cause blindness.
Lens-Related Infections
Pharmacists may suspect infection
when patients complain of discomfort, itching, burning, severe pain,
photophobia, excessive tearing,
mucus discharge, blurred vision,
decreased visual acuity, swelling,
unusual redness, or a foreign body
sensation.8,13 The symptoms may be
confined to one eye only. This helps
differentiate infection from allergic
rhinitis, in which the eyes are pruritic, the discharge is watery, and
both eyes are affected equally due to
common allergen exposure.8
Bacterial infections are the most
common type in contact lens wearers. They include those caused by
Clostridium species (spp), Peptostreptococcus, Propionibacterium spp, and
Fusobacterium spp.14 In particular,
Pseudomonas infection is liable to be
a rapidly progressing condition causing the development of corneal
ulcers and blindness within 24 hours
if left untreated.10,15 Fungal infections (e.g., from Fusarium spp)
sold illegally at beauty shops, flea

markets, convenience stores, record/
video stores, and from the Internet.20
Use of lenses without a fitting by an
eye care practitioner can lead to corneal ulcer, which can progress to
internal ocular infection, corneal
scarring, visual impairment, blindness, and loss of the eye.8
Future Uses for Contact Lenses

The future of contact lenses and
their potential to help patients with
medical problems is unknown.
Researchers project that they may
deliver medications to the eye
through creation of a lens known as
a drug-eluting lens.21 Prototype lenses
were tested for their ability to release
ciprofloxacin in a controlled,
extended manner.22 The lenses were
able to do so over a 4-week period
during in vitro experiments.
Contact lenses may also be used
to help manage diabetes. Researchers
have developed lenses embedded
with nanoparticles capable of reacting with glucose molecules in tears.
The reaction results in a chemical
change that alters the lens color.
Using this innovative technology,
patients with diabetes may eventually
be able to eliminate fingersticks.23
Dangers of Decorative Lenses

FDA personnel experience great
apprehension with the approach of
Halloween each year.8,20 The reason
is the desire of some people to alter
the appearance of their eyes for decorative purposes. Decorative lenses
change eye colors and give the eyes a
strange, startling look, such as cat
eyes. The lenses are also known as
zero-powered, plano, or noncorrective
lenses. The FDA regulates such decorative lenses, and legislation does not
allow marketing them as nonprescription items. Nevertheless, they are
REFERENCES
1. Types of contact lenses. FDA. www.fda.gov/MedicalDevices/
ProductsandMedicalProcedures/HomeHealthandConsumer/
ConsumerProducts/ContactLenses/ucm062319.htm. Accessed
February 8, 2010.
2. Advantages and disadvantages of various types of contact lenses.
American Optometric Association. www.aoa.org/x5234.xml.
Accessed February 8, 2010.
3. Contact lens statistics and trends. The Optical Vision Site.
http://theopticalvisionsite.com/contact-lenses/contact-lens-statisticsand-trends/. Accessed March 26, 2010.
4. Contact lenses. Risks. FDA. www.fda.gov/MedicalDevices/
February 8, 2010.
5. Contact lenses. Everyday eye care. FDA.
www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/
HomeHealthandConsumer/ConsumerProducts/ContactLenses/
ucm062594.htm. Accessed February 8, 2010.
6. Contact lens prescription. FDA. www.fda.gov/MedicalDevices/
February 8, 2010.
7. The eyes have itget your prescription. FTC. www2.ftc.gov/bcp/

edu/pubs/consumer/alerts/alt143.shtm. Accessed February 8, 2010.
8. Decorative, non-corrective contact lenses. FDA. www.fda.gov/
MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071572.htm. Accessed February 8, 2010.
9. Acanthamoeba prevention. CDC. www.cdc.gov/acanthamoeba/
prevention.html. Accessed March 26, 2010.
10. Ensuring safe use of contact lens solution. FDA. www.fda.gov/
ForConsumers/ConsumerUpdates/ucm164197.htm. Accessed
February 8, 2010.
11. Patel A, Hammersmith K. Contact lens-related microbial keratitis: recent outbreaks. Curr Opin Ophthalmol. 2008;19:302-306.
12. Butcko V, McMahon TT, Joslin CE, et al. Microbial keratitis
and the role of rub and rinsing. Eye Contact Lens. 2007;33:421-425.
13. Acanthamoeba keratitis fact sheet [health professionals]. CDC.
www.cdc.gov/acanthamoeba/health_professionals/acanthamoeba_
keratitis_hcp.html. Accessed March 26, 2010.
14. Brook I. Ocular infections due to anaerobic bacteria in children. J Pediatr Ophthalmol Strabismus. 2008;45:78-84.
15. Mena KD, Gerba CP. Risk assessment of Pseudomonas aeruginosa in water. Rev Environ Contam Toxicol. 2009;201:71-115.
16. Hu S, Fan VC, Koonapareddy C, et al. Contact lens-related
Fusarium infection: case series experience in New York City and
review of fungal keratitis. Eye Contact Lens. 2007;33:322-328.

17. Epidemiology and risk factors. CDC. www.cdc.gov/ncidod/
dpd/parasites/acanthamoeba/epidemiology_acanthamoeba.htm.
18. Dart JK, Saw VP, Kilvington S. Acanthamoeba keratitis: diagnosis
and treatment update 2009. Am J Ophthalmol. 2009;148:487-499.
19. Anger C, Lally JM. Acanthamoeba: a review of its potential to
cause keratitis, current lens care solution disinfection standards
and methodologies, and strategies to reduce patient risk.
Eye Contact Lens. 2008;34:247-253.
20. Improper use of decorative contact lenses may haunt you.
FDA. www.fda.gov/ForConsumers/ConsumerUpdates/
ucm048902.htm. Accessed February 8, 2010.
21. Ciolino JB, Dohlman CH, Kohane DS. Contact lenses for
drug delivery. Semin Ophthalmol. 2009;24:156-160.
22. Ciolino JB, Hoare TR, Iwata NG, et al. A drug-eluting contact lens. Invest Ophthalmol Vis Sci. 2009;50:3346-3352.
23. Soon, contact lenses to help manage diabetes. American Diabetes Association. www.diabetes.org/news-research/news/diabetesin-the-news/soon-contact-lenses-to-help-manage-diabetes.html.
24. Consumer protection warning. Non-FDA approved contact
lenses. www.dangerous-contact-lenses.com. Accessed March 30, 2010.
15
3/31/10 1:40 PM
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SDZ0049
01DR10004

LASIK Eye
Surgery
Laser beam reshapes
the internal cornea
TEAR ALONG PERFORATION
A suction ring
is applied to the
numbed eye
A thin flap is made in

the cornea and reflected
MEDICAL ILLUSTRATION: KRISTEN WEINANDT MARZEJON 2010
Corrective Procedure
to Improve Vision
PTA1004 LASIK 2_12bo.indd 1
LASIK (laser-assisted in situ keratomileusis) is a type of eye surgery designed to treat nearsightedness
(myopia), farsightedness (hyperopia), and astigmatism. These conditions, known as refraction errors,
are all the result of an out-of-focus image when light is reflected through the cornea onto the retina.
LASIK surgery works by changing the shape of the cornea using a laser. Once the cornea is shaped
correctly, the eye can focus more clearly and vision improves. The LASIK surgical procedure has been
performed on millions of Americans since its FDA approval in 1998, and it continues to be a popular procedure with patients who want to improve their vision.
LASIK is an outpatient surgery that takes less than 30 minutes. The eye is numbed using anesthetic
eye drops, and the eyelid is held open by an instrument while a suction ring is placed on the eye to
lift, flatten, and hold the cornea steady. A small flap is cut from the corneal tissue and folded back,
allowing the laser access to shape the corneal tissue underneath. The flap of tissue is then pressed back
into place without stitches. After LASIK surgery is completed, an eye shield is placed over the eye to
protect the cornea during the healing period.
LASIK eye surgery is not for everyone. There are many people who should not undergo LASIK,
including those with chronic dry eyes, thin corneas, changing refractions, and significant refraction
error (very poor vision). Patients considering LASIK surgery must understand the risks and potential
complications, as well as the typical results of a successful procedure. For many, LASIK surgery can
reduce the need for glasses or contact lenses, but it does not guarantee perfect vision. Even those patients
who achieve 20/20 vision with LASIK as measured on the eye chart may not see the sharp images
they had expected. In addition, LASIK cannot correct presbyopia, the change in vision that results
from aging and requires reading glasses. Many patients who undergo LASIK surgery also find that
they require a retreatment (second surgery) to achieve better vision.
Copyright Jobson Medical Information LLC, 2010
continued
2/16/10 3:49 PM

Reduces the Need for
Glasses or Contact Lenses
Millions of people in the United States have undergone LASIK
surgery to improve their vision and become less dependent
on corrective lenses (contacts or glasses). Although the majority of patients are pleased with the results, some are disappointed in their visual improvement or suffer permanent side
effects or complications from the surgery. It is important to
learn about the procedure and identify a surgeon who is skilled During the LASIK procedure, a laser
in the technique and can determine whether the candidate is is used to reshape the underlying
corneal tissue.
likely to benefit from LASIK. Eye doctors who advertise that
their patients will never need glasses again or make similar promises should be avoided. There
are financial considerations as well, since many insurance companies do not reimburse the cost.
Candidates for Surgery: Often people are able to eliminate glasses or contact lenses for
everyday tasks after LASIK surgery, although their vision may not be perfect or even as clear
as it would be with corrective lenses. The majority of people who have LASIK surgery will
have 20/20 to 20/40 vision without glasses or contact lenses. Patients over 40 years of age
with presbyopia (problems focusing) will still require reading glasses after LASIK unless they
are corrected in one eye for close vision and one eye for distant vision, which is known as
monovision. Not all patients adjust well to monovision, so those considering this procedure
can try out this correction with a different-strength contact in each eye or different lenses in a
pair of glasses.
Some people have conditions that make them ineligible or poor candidates for success with
LASIK eye surgery. People with chronically dry eyes, inflammation of the eyelids, thin or damaged corneas, changing refractions, and significant refraction error (very poor vision) are not
good candidates for LASIK. Large pupils may also be a problem since halos and glare, two common complaints after LASIK surgery, may be more likely to occur. Pregnant or nursing women
or those people taking certain drugs that cause changes in refraction should not undergo LASIK.
People with diseases that affect the immune system (e.g., HIV/AIDS, diabetes, lupus) may have
trouble with corneal healing after surgery. LASIK is not a good choice for younger people with
changing refractions, especially those under age 18 to 21 years.
It is recommended that people considering LASIK discuss their daily work and leisure
activities with an eye surgeon when making the decision to undergo surgery. People who need
very sharp vision for detailed work or who drive frequently at night may not be satisfied with
the results. There is a significant waiting period before vision after LASIK is stable, usually up
to 6 months. There are also various waiting periods before wearing eye makeup, swimming, and
sports activities can be resumed.
Possible Side Effects: Common complaints after LASIK surgery include scratchy or dry eyes,
hazy vision, sensitivity to light, halos or glare, and problems seeing clearly at night. Many of
these effects improve over time, although in some people these are permanent. Less typical are
problems with visual correction or with the corneal flap that may require a second surgery.
Inflammation and infection can occur, but they are usually prevented by the use of prescription
eye drops. Rarely, vision is poorer after LASIK, and permanent loss of vision has occurred.
After LASIK surgery, eye drops are prescribed to prevent infection, decrease inflammation
and swelling, and soothe dryness. These eye drops must be used as prescribed by the eye surgeon
to prevent complications. Several follow-up appointments will be necessary to confirm that the
cornea is healing properly and vision is improving. If you have questions about using these eye
drops, ask your pharmacist.
PTA1004 LASIK 2_12bo.indd 2
2/16/10 3:49 PM
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THINKSTOCK
H E A LT H S YS T E M S E D I T I O N
Ocular Manifestations
of Systemic Diseases
any systemic diseases often have an ocular component that manifests secondarily. Patients with
ocular manifestations may first present in the
emergency department with relatively nonspecific symptoms
such as visual disturbance or eye pain. Unfortunately, many
ocular symptoms overlap in terms of the disease state they
may be attributed to. In some cases, however, the information obtained from an ocular examination may aid in the
differential diagnosis and appropriate management of the
underlying disease. While there are a significant number of
diseases known to present with ocular involvement, the aim
of this article is to provide a general overview of the commonly encountered ocular manifestations of systemic disease
in clinical practice and to review how they should be
approached therapeutically.
PDR (TABLE 1 and FIGURE 1). Macular edema is often treated

with laser photocoagulation.4,5 (See FIGURE 1.)
PDR is characterized by neovascularization (new vessel
formation), which is a response to continued retinal ischemia.5 Neovascularization can cause vision loss due to vitreous hemorrhages and tractional retinal detachment, which
can be treated by nonincisional surgery (laser photocoagulation) or incisional surgery (vitrectomy).4,5 There are two
types of laser photocoagulation: focal and panretinal. Focal
photocoagulation, which is used to treat macular edema,
has been shown to reduce the risk of moderate vision loss
by 50% to 70%.6 Panretinal photocoagulation, used to treat
PDR, works by creating thousands of laser burns in areas
of the retina away from the macula, causing abnormal vessels to shrink and thereby preventing them from hemorrhaging. This surgery can reduce the risk of moderate and
Diabetic Retinopathy and Macular Edema
severe vision loss by 50% in patients with PDR.6
Diabetic retinopathy (DR), one of the leading causes of
For patients already diagnosed with diabetes, follow-up
blindness worldwide among adults aged 20 to 74 years, is with annual retinal screenings and prompt treatment are
the most common microvascular complication of diabetes.1 key components of patient care (see TABLES 1 and 2 for
It has been estimated that nearly all patients with type 1 screening and follow-up recommendations).7,8 Adequate
diabetes and 60% of those with type 2 diabetes will develop blood sugar control is paramount for preventing and consome form of retinopathy within 20 years of disease onset trolling the progression of DR.
regardless of their level of diabetic control.2 In patients with
Several randomized, controlled clinical trials found that
type 1 diabetes, retinopathy typically does not develop until the combination of tight glycemic and blood-pressure
3 to 5 years after disease onset. In contrast, retinopathy may control with laser photocoagulation therapy significantly
be the presenting manifestation of type 2 diabetes. Some prevents the progression of DR.7,9-11 The Diabetes Control
studies estimate that 20% to 30% of patients with type 2 and Complications Trial, which examined the effects of
diabetes have evident retinopathy at the time of diagnosis.2 tight glycemic control on the incidence of DR, nephropaRetinopathy can precede nephropathy, making the early thy, and neuropathy in type 1 diabetic patients, concluded
detection of ocular manifestations of diabetes essential. DR that intensive glycemic control was associated with a 76%
can be nonproliferative DR (NPDR) or proliferative (PDR), mean reduction in risk of retinopathy in patients with no
which is more advanced. DR is graded according to sever- retinopathy at baseline and with a 54% mean reduction in
ity (mild, moderate, or severe). When observed during those with minimal-to-moderate NPDR at 36 months.10
simple fundoscopic examination, mild NPDR is generally The UK Prospective Diabetes Study (UKPDS) confirmed
the protective effects of tight glycemic
characterized by microaneurysms and
Nicholas Beyda, PharmD
control in type 2 diabetic patients, findsmall hemorrhages.1,3 In moderate-toPharmacy Practice Resident
severe NPDR, increased vascular permeing a 25% reduction in microvascular
David Cluck, PharmD
ability, hard exudates, venous bleeding,
complications in the intensive-therapy
Pharmacy Practice Resident
and intraretinal microvascular anomalies
group.11 The UKPDS also found that
Katia E. Taba, MD, PhD
Department of Ophthalmology
every percentage-point decrease in glyare noted; these are caused by retinal
Mark Middlebrooks, PharmD
cosylated hemoglobin was associated
ischemia. Macular edema is the princiDirector of Pharmacy
with a 35% reduction in the risk of
pal mechanism of vision loss in DR, and
Louisiana State University Health Sciences
CenterShreveport, Shreveport, Louisiana
microvascular complications.11
it may be present in both NPDR and
HS-2
HS02 OcularManifest 3_31mb.indd HS-2
3/31/10 1:44 PM
OCULAR MANIFESTATIONS
Source: Courtesy of Katia E. Taba, MD, PhD.
ing or modifying antihypertensive therapy. As with DR,

disease-state control is of utmost importance in preventing
and controlling progression of the ocular manifestations of
hypertension. Blood pressure control, achieved through
systemic pharmacotherapy and lifestyle modifications, is
guided by the patients primary care provider.13
HIV/AIDS
Approximately 33 million people are infected with HIV
worldwide.16 Opportunistic infections typically coincide
with the patients CD4 count; thus, they often present when
the CD4 count is 200 cells/mm3 or when the patient is
unaware of HIV infection.16 Therefore, CD4 count remains
the greatest predictor of ocular manifestations in HIV
patients. It is not uncommon for an HIV patient to experience an ocular complication at some point in his or her
lifetime. HIV infection places patients at risk for both infectious and noninfectious complications. The ocular manifestations of opportunistic infections are categorized based
on anatomical origin (orbital/adnexal manifestations [external] versus anterior/posterior segment manifestations [internal]) or nonspecific systemic infection.
A myriad of infections are associated with the adnexa of
the eye, including herpes zoster ophthalmicus (attributable
to reactivation of varicella-zoster virus [VZV] infection in
the first division of the fifth cranial nerve) and conjunctival
microvascular disease, which affects up to 75% to 80% of
patients.16 The most common manifestation is molluscum
contagiosum, a viral infection of the skin. Lastly, up to 20%
of patients who develop Kaposis sarcoma have ocular
manifestations, usually with adnexal involvement.16
As many as 20% of patients may experience damage to
the accessory and major lacrimal glands, resulting in keratoconjunctivitis sicca (dry eye).16 It should be noted that
dry eye is a relatively nonspecific symptom and can have a
number of causes, of which HIV is thought to be paramount.
Anterior segment manifestations are often attributable to
an infectious process, including infectious keratitis (bacterial,
fungal, or protozoal in nature) and iridocyclitis (associated
with cytomegalovirus [CMV] or VZV). Up to 50% of
Hypertension
Hypertension, which occurs in approximately 50 million
people in the United States, remains a significant cause of
morbidity and a leading cause of cardiovascular mortality.12,13
Hypertension affects the eye in a multitude of ways, including vascular injury and increased risk of embolic events (e.g.,
central retinal vein and branch retinal artery occlusion).
The ocular manifestations of hypertension are commonly
classified as acute changes or chronic changes associated
with long-term systemic hypertension.13 The perpetual
increased pressure in the vasculature initiates a cascade of
events resulting in a change in the physiology of the eye.
This sequence of events, often collectively referred to as
hypertensive retinopathy, is the most common manifestation.14
The differences in the composition of the vasculature and
in anatomical location result in a different physiologic
response to increased blood pressure. In the acute phase,
hypertension predominantly affects the terminal arterioles;
in chronic hypertension, the observed circulatory changes
primarily involve the main retinal arterioles. Early manifestations include retinal hemorrhage, capillary obliteration,
and macular edema attributable to hypertensive choroidopathy. Long-standing hypertension can result in the development of compensatory shunt vessels and arteriovenous
nicking (impeded circulation in the retina).13
Hypertension also acts indirectly as a risk factor for
other ocular diseases. These include retinal vein occlusion,
retinal emboli, macroaneurysm, and optic neuropathy.
Hypertensive retinopathy is considered a reliable prognostic indicator of systemic disease. Perhaps the strongest
correlation is between hypertensive retinopathy and risk of
stroke. A study revealed that hypertensive retinopathy
increased stroke risk two- to fourfold when patients with
this condition were compared with patients who had no
retinopathy.15 Studies also suggest that hypertensive retinopathy can be used to predict incident congestive heart
failure, left ventricular hypertrophy, and renal impairment.13
The benefits of a fundoscopic examination are its ability
to predict underlying systemic disease (typically cardiovascular in nature) and its ability to assess the need for initiat-
Figure 1. A 45-year-old patient presented with severe vision loss due to diabetic macular edema. Reabsorption of hard exudates and
intraretinal hemorrhages was observed over 18 months. Treatment consisted of focal macular laser photocoagulation, intravitreal steroid
injection, improvement of glycemic control, and smoking cessation. Visual acuity improved from 20/200 to 20/40.
HS-3
3/31/10 1:44 PM
Most manifestations of ocular disorders

attributable to a viral infection respond
to the appropriate antiviral (e.g., acyclovir, cidofovir, ganciclovir, valganciPatient Group
Recommended 1st Exam Routine Follow-Up
clovir).18 These patients are often manType 1 diabetes
Within 5 y after onset
1y
Type 2 diabetes
Shortly after diagnosis
1y
aged by a physician specializing in
Pregnant women with Before conception and
At physicians discretion pending
infectious disease. Therapy is usually
preexisting diabetes
during 1st trimester
results of 1st-trimester exam
selected based on a global assessment
Source: Reference 9.
of the patient that includes immune
status and renal function. While a
patients experience anterior uveitis, which may be caused number of antivirals are available, use of these agents is not
by a number of different pathogens, including Treponema, without systemic consequence, with the kidneys being most
VZV, and herpes simplex virus.16
at risk for drug-induced harm. Herpesviruses usually are
Thirty percent to 50% of patients with decreased CD4 treated with acyclovir or the valine ester valacyclovir. Other
counts experience posterior segment manifestations, with agents, such as cidofovir, foscarnet, and ganciclovir, are
the most common abnormalities being attributable to CMV typically reserved for cases of CMV retinitis or refractory
and retinal microvasculopathy.16 CMV is the most common herpes infections.18
intraocular infection in AIDS patients. Ocular syphilis
should be included in any differential diagnosis, as it mim- Rheumatoid Arthritis
It is estimated that approximately 25% of patients with
rheumatoid arthritis (RA) present with ocular manifestaTable 2. Follow-Up
tions.19 The most common external manifestation is keraRecommendations by DR Stage
toconjunctivitis sicca, which can be diagnosed using SchirmStage of DR
Recommended Follow-Up
ers test. The test evaluates the functionality of the lacrimal
Mild NPDR
Every 9 mo
gland by measuring the amount of tear production through
Moderate NPDR
Every 6 mo
the placement of a Schirmer strip into the lower conjuncSevere NPDR or PDR
Every 2-4 mo
tival cul-de-sac.
CSME
Every 2-4 mo
Episcleritis (superficial inflammation of the sclera) and
CSME: clinically significant macular edema; DR: diabetic retiscleritis (deeper inflammation of the sclera) are common
nopathy; NPDR: nonproliferative DR; PDR: proliferative DR.
ocular manifestations of RA, occurring in up to 25% and
10% of RA patients, respectively.19 Corneal disease is comics several diseases. Ocular syphilis in HIV-infected patients monly associated with dry eye or with a form of anterior
may present earlier and in an accelerated form.
scleritis; it can include the presence of keratitis, sclerosing
Lastly, systemic infections such as cryptococcal menin- keratitis, and ulcerative keratitis. A combination of steroids,
gitis or toxoplasmosis can have ophthalmic involvement. immunosuppressive therapy, and surgery often is necessary
These types of infections, despite the eye not being the to prevent perforation of the cornea and permanent vision
source of the infection, often result in nonspecific symptoms loss. Scleritis and episcleritis are distinguished based on
such as visual-field loss.17
anatomy and appearance. While the symptoms may be
Treatment is largely specific to the causative pathogen. similar, pain is typically more severe in patients with scle-
Table 1. Screening and Follow-Up

Recommendations by Diabetes Type
Table 3. Ocular Manifestations of SLE

Condition
Symptoms
Treatment
Keratoconjunctivitis
sicca
Dry eye, blurry vision, pain, itching,

foreign-body sensation, crusting of eyelid
Tear substitute, humidifier, sunglasses, punctal

plug, surgery, topical cyclosporine
Keratitis
Pain with photophobia, foreign-body

sensation, red eye, decreased vision, tearing
NSAIDs, topical/oral/IV steroids, immunosuppressive

therapy (cyclosporine), surgery
Episcleritis
Sudden onset with no blurry vision; mild pain

radiating into cheek, eyebrows, temple; photophobia
NSAIDs, topical/oral steroids
Scleritis
Gradual onset with blurry vision; deep pain

radiating into cheek, eyebrows, temple; photophobia
NSAIDs, topical/oral/IV steroids, immunosuppressive

therapy (cyclosporine), surgery
NSAIDs: nonsteroidal anti-inflammatory drugs; SLE: systemic lupus erythematosus.

HS-4
3/31/10 1:44 PM
Fentanyl transdermal system should

ONLY be used in patients who are already
receiving opioid therapy, who have
demonstrated opioid tolerance, and
who require a total daily dose at least
equivalent to fentanyl transdermal system
25 mcg/hr. Patients who are considered
opioid-tolerant are those who have been
taking, for a week or longer, at least 60 mg
of morphine daily, or at least 30 mg of oral
oxycodone daily, or at least 8 mg of oral
hydromorphone daily or an equianalgesic
dose of another opioid.
Because serious or life-threatening
hypoventilation could occur, fentanyl
transdermal system is contraindicated:
in patients who are not opioid-tolerant
in the management of acute pain or in
patients who require opioid analgesia
for a short period of time
in the management of postoperative
pain, including use after out patient
or day surgeries (e.g., tonsillectomies)
in the management of mild pain
in the management of intermittent
pain [e.g., use on an as needed basis
(prn)]
The safety of fentanyl transdermal system
has not been established in children under
2 years of age. Fentanyl transdermal
system should be administered to children
only if they are opioid-tolerant and 2 years
of age or older (see PRECAUTIONS:
Pediatric Use).
Patients using fentanyl transdermal system
should avoid exposure to external heat
sources, such as heating pads, hot tubs,
long hot baths, and sunbathing. An increase
in body temperature may result in a sudden
and possible dangerous rise in their body
fentanyl level. Fentanyl transdermal
system may cause death from overdosage;
therefore, it is important for healthcare
professionals, patients and caregivers to
know the signs of fentanyl overdose, which
can include trouble breathing and extreme
sleepiness. Fentanyl transdermal system
should be stored in a safe place and
kept out of the reach of children. Used,
unneeded or defective fentanyl patches
should be safely disposed of by folding
the sticky side of the patch together
(until it sticks to itself) and flushing it
down the toilet.
The most common adverse events reported
in clinical trials were fever, nausea, vomiting,
constipation, dry mouth, somnolence,
confusion, asthenia, and sweating.
Please see adjacent Brief Summary
of Prescribing Information, including
BOXED WARNING.
In the management of persistent, moderate to severe chronic pain that requires

continuous, around-the-clock opioid administration for
an extended period of time and cannot be managed by other means*
Why Take A Chance With

Other Fentanyl Patches?
One patch can cause burns.
This matrix patch contains aluminum in its backing, which can
overheat during a magnetic resonance imaging (MRI) scan and
burn the patient who is wearing it.
Other patches can leak.

They contain a reservoir of fentanyl gel that can leak and cause
potentially life-threatening complications.
Mylan FENTANYL is the first marketed

fentanyl patch designed to avoid the
risks associated with burns and leaks.
The Mylan FENTANYL TRANSDERMAL
SYSTEM CII has no aluminum or other
metals in its backing. Also important
to patient safety, Mylan Fentanyl has a
proprietary matrix design without a
liquid, gel-filled reservoir that can leak.
It is an innovative solution in transdermal
drug delivery.
*Other means include non-steroidal analgesics, opioid combination products, or immediate-release opioids.
2009 Mylan Pharmaceuticals Inc. MYNFEN031
No metal. No burns. No leaks.
FENTANYL TRANSDERMAL SYSTEM

BRIEF SUMMARY: Please see package insert for full prescribing information.
FOR USE IN OPIOID-TOLERANT PATIENTS ONLY
Fentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl.
Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, and
oxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratory
depression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in the
patches (fentanyl transdermal system) may be a particular target for abuse and diversion.
Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that:
requires continuous, around-the-clock opioid administration for an extended period of time, and
cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or
immediate-release opioids
Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who
have demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system 25 mcg/hr. Patients who are considered opioid-tolerant are those who have been taking, for a
week or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg of
oral hydromorphone daily or an equianalgesic dose of another opioid.
Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated:
in the management of acute pain or in patients who require opioid analgesia for a short period of time
in the management of postoperative pain, including use after out patient or day surgeries (e.g., tonsillectomies)
in the management of intermittent pain [e.g., use on an as needed basis (prn)]
(See CONTRAINDICATIONS for further information.)
Since the peak fentanyl levels occur between 24 and 72 hours of treatment, prescribers should be aware that
serious or life-threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial application period.
The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such as
ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone,
amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil)
may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug
effects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal
system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosage
adjustments should be made if warranted (see CLINICAL PHARMACOLOGY: Drug Interactions, WARNINGS,
PRECAUTIONS and DOSAGE AND ADMINISTRATION in full prescribing information for further information). The
safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl
transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or
older (see PRECAUTIONS: Pediatric Use in full prescribing information).
Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparable potency. Use in non-opioid-tolerant patients may lead to fatal respiratory depression. Overestimating the
fentanyl transdermal system dose when converting patients from another opioid medication can result in fatal
overdose with the first dose. Due to the mean elimination half-life of 17 hours of fentanyl transdermal system,
patients who are thought to have had a serious adverse event, including overdose, will require monitoring and
treatment for at least 24 hours.
Fentanyl transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. This
risk should be considered when administering, prescribing, or dispensing fentanyl transdermal system in
situations where the healthcare professional is concerned about increased risk of misuse, abuse or diversion.
Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse
(including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should be
assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patients
receiving opioids should be routinely monitored for signs of misuse, abuse and addiction. Patients at
increased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations;
however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction.
Fentanyl transdermal system patches are intended for transdermal use (on intact skin) only. Do not use a
fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.
Avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heat
sources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated water
beds, while wearing the system. Avoid taking hot baths or sunbathing. There is a potential for temperaturedependent increases in fentanyl released from the system resulting in possible overdose and death. Patients
wearing fentanyl transdermal systems who develop fever or increased core body temperature due to
strenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system dose
should be adjusted if necessary.
INDICATIONS AND USAGE: Fentanyl transdermal system is indicated for management of persistent, moderate to severe
chronic pain that:
requires continuous, around-the-clock opioid administration for an extended period of time, and
cannot be managed by other means such as non-steroidal analgesics, opioid combination products, or
immediate-release opioids
Fentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who have
demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system
25 mcg/hr (see DOSAGE AND ADMINISTRATION in full prescribing information). Patients who are considered
opioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least
30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.
Because serious or life-threatening hypoventilation could result, fentanyl transdermal system is contraindicated
for use on an as needed basis (i.e., prn), for the management of postoperative or acute pain, or in patients who are not
opioid-tolerant or who require opioid analgesia for a short period of time (see BOX WARNING and CONTRAINDICATIONS).
An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable prior
to initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case,
initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidal
anti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the World
Health Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy,
or the American Pain Society.
Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.
Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons at
increased risk for opioid abuse include those with a personal or family history of substance abuse (including drug or
alcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still be
appropriately treated with modified-release opioid formulations; however these patients will require intensive
monitoring for signs of misuse, abuse, or addiction.
CONTRAINDICATIONS: Because serious or life-threatening hypoventilation could occur, fentanyl transdermal
system is contraindicated:
in the management of acute pain or in patients who require opioid analgesia for a short period of time
in the management of postoperative pain, including use after out-patient or day surgeries (e.g., tonsillectomies)
in the management of intermittent pain [e.g., use on an as needed basis (prn)]

in situations of significant respiratory depression, especially in unmonitored settings where there is a lack
of resuscitative equipment
in patients who have acute or severe bronchial asthma
Fentanyl transdermal system is contraindicated in patients who have or are suspected of having paralytic ileus.
Fentanyl transdermal system is contraindicated in patients with known hypersensitivity to fentanyl or any
components of this product.
WARNINGS:
Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do not use a fentanyl
transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.
The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyl
transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older
(see PRECAUTIONS: Pediatric Use in full prescribing information).
Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of
comparable potency. Use in non-opioid-tolerant patients may lead to fatal respiratory depression.
Overestimating the fentanyl transdermal system dose when converting patients from another opioid medication
can result in fatal overdose with the first dose. The mean elimination half-life of fentanyl transdermal system
is 17 hours. Therefore, patients who have experienced serious adverse events, including overdose, will require
monitoring for at least 24 hours after fentanyl transdermal system removal since serum fentanyl concentrations
decline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal.
Fentanyl transdermal system should be prescribed only by persons knowledgeable in the continuous
administration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, and
in the detection and management of hypoventilation including the use of opioid antagonists.
All patients and their caregivers should be advised to avoid exposing the fentanyl transdermal system
application site and surrounding area to direct external heat sources, such as heating pads or electric blankets,
heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients should
be advised against taking hot baths or sunbathing. There is a potential for temperature-dependent increases in
fentanyl released from the system resulting in possible overdose and death.
Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximately
one-third for patients with a body temperature of 40C (104F) due to temperature-dependent increases in fentanyl
released from the system and increased skin permeability. Patients wearing fentanyl transdermal systems who
develop fever or increased core body temperature due to strenuous exertion should be monitored for opioid side
effects and the fentanyl transdermal system dose should be adjusted if necessary.
Death and other serious medical problems have occurred when people were accidentally exposed to fentanyl
transdermal system. Examples of accidental exposure include transfer of a fentanyl transdermal system from an
adults body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregivers
skin to the medication in the patch while the caregiver was applying or removing the patch.
Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other than
indicated may cause choking or overdose that could result in death.
Misuse, Abuse and Diversion of Opioids
Fentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people with
addiction disorders and are subject to criminal diversion.
Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered when
prescribing or dispensing fentanyl transdermal system in situations where the physician or pharmacist is concerned
about an increased risk of misuse, abuse or diversion.
Fentanyl transdermal system has been reported as being abused by other methods and routes of administration.
These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that could
result in overdose and deaths (see WARNINGS and DRUG ABUSE AND ADDICTION).
Concerns about abuse, addiction and diversion should not prevent the proper management of pain. However,
all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid
analgesic products carries the risk of addiction even under appropriate medical use.
Healthcare professionals should contact their state professional licensing board or state controlled substances
authority for information on how to prevent and detect abuse or diversion of this product.
Hypoventilation (Respiratory Depression): Serious or life-threatening hypoventilation may occur at any time during
the use of fentanyl transdermal system especially during the initial 24 to 72 hours following initiation of therapy and
following increases in dose.
Because significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch is
removed, hypoventilation may persist beyond the removal of fentanyl transdermal system. Consequently, patients
with hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored until
respiration has stabilized.
The use of concomitant CNS active drugs requires special patient care and observation.
Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in fentanyl
transdermal system. Respiratory depression is more likely to occur in elderly or debilitated patients, usually following
large initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depress
respiration.
Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration, often associated with the sighing pattern of breathing (deep breaths separated by abnormally long pauses).
Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
This makes overdoses involving drugs with sedative properties and opioids especially dangerous.
Fentanyl transdermal system should be used with extreme caution in patients with significant chronic obstructive
pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia,
hypercapnia, or preexisting respiratory depression. In such patients, even usual therapeutic doses of fentanyl
transdermal system may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioid
analgesics should be considered, and opioids should be employed only under careful medical supervision at the
lowest effective dose.
Chronic Pulmonary Disease: Because potent opioids can cause serious or life-threatening hypoventilation, fentanyl
transdermal system should be administered with caution to patients with preexisting medical conditions predisposing
them to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive to
the point of respiratory failure.
Head Injuries and Increased Intracranial Pressure: Fentanyl transdermal system should not be used in patients who
may be particularly susceptible to the intracranial effects of CO2 retention such as those with evidence of increased
intracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with head
injury. Fentanyl transdermal system should be used with caution in patients with brain tumors.
Interactions with other CNS Depressants: The concomitant use of fentanyl transdermal system with other central
nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g.,
benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause
respiratory depression, hypotension, and profound sedation or potentially result in coma. When such combined
therapy is contemplated, the dose of one or both agents should be significantly reduced.
Interactions with Alcohol and Drugs of Abuse: Fentanyl may be expected to have additive CNS depressant effects
when used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.
Interactions with CYP3A4 Inhibitors: The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (such
as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone,
amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) may
result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and
may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4
inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be made
if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY: Drug Interactions in full prescribing information,
PRECAUTIONS, and DOSAGE AND ADMINISTRATION in full prescribing information for further information).
PRECAUTIONS: General: Fentanyl transdermal system should not be used to initiate opioid therapy in patients who
are not opioid-tolerant. Children converting to fentanyl transdermal system should be opioid-tolerant and 2 years of
age or older (see BOX WARNING).
Page 1 of 3
Patients, family members and caregivers should be instructed to keep patches (new and used) out of the reach
of children and others for whom fentanyl transdermal system was not prescribed. A considerable amount of active
fentanyl remains in fentanyl transdermal system even after use as directed. Accidental or deliberate application or
ingestion by a child or adolescent will cause respiratory depression that could result in death.
Cardiac Disease: Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients with
bradyarrhythmias.
Hepatic or Renal Disease: Insufficient information exists to make recommendations regarding the use of fentanyl
transdermal system in patients with impaired renal or hepatic function. If the drug is used in these patients, it should
be used with caution because of the hepatic metabolism and renal excretion of fentanyl.
Use in Pancreatic/Biliary Tract Disease: Fentanyl transdermal system may cause spasm of the sphincter of Oddi and
should be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like fentanyl
transdermal system may cause increases in the serum amylase concentration.
Tolerance: Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drugs effects over time. Tolerance may occur to both the desired and undesired effects of
drugs, and may develop at different rates for different effects.
Physical Dependence: Physical dependence is a state of adaptation that is manifested by an opioid specific
withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the
drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some
or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia,
mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia,
vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not be
abruptly discontinued (see DOSAGE AND ADMINISTRATION: Discontinuation of Fentanyl Transdermal System in full
prescribing information).
Ambulatory Patients: Strong opioid analgesics impair the mental or physical abilities required for the performance of
potentially dangerous tasks, such as driving a car or operating machinery. Patients who have been given fentanyl
transdermal system should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug.
Information for Patients: Patients and their caregivers should be provided with a Medication Guide each time
fentanyl transdermal system is dispensed because new information may be available.
Patients receiving fentanyl transdermal system should be given the following instructions by the physician:
1. Patients should be advised that fentanyl transdermal systems contain fentanyl, an opioid pain medicine
similar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone.
2. Patients should be advised that each fentanyl transdermal system may be worn continuously for 72 hours, and
that each patch should be applied to a different skin site after removal of the previous transdermal patch.
3. Patients should be advised that fentanyl transdermal system should be applied to intact, nonirritated, and
nonirradiated skin on a flat surface such as the chest, back, flank, or upper arm. Additionally, patients should
be advised of the following:
In young children or persons with cognitive impairment, the patch should be put on the upper back to lower
the chances that the patch will be removed and placed in the mouth.
Hair at the application site should be clipped (not shaved) prior to patch application.
If the site of fentanyl transdermal system application must be cleansed prior to application of the patch,
do so with clear water.
Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter its
characteristics.
Allow the skin to dry completely prior to patch application.
4. Patients should be advised that fentanyl transdermal system should be applied immediately upon removal from the
sealed package and after removal of the protective liner. Additionally the patient should be advised of the following:
The fentanyl transdermal system should not be used if the seal is broken or the patch is cut, damaged, or
changed in any way.
The transdermal patch should be pressed firmly in place with the palm of the hand for 30 seconds,
making sure the contact is complete, especially around the edges.
The patch should not be folded so that only part of the patch is exposed.
5. Patients should be advised that the dose of fentanyl transdermal system or the number of patches applied to
the skin should NEVER be adjusted without the prescribing healthcare professionals instruction.
6. Patients should be advised that while wearing the patch, they should avoid exposing the fentanyl transdermal
system application site and surrounding area to direct external heat sources, such as:
heating pads,
electric blankets,
sunbathing,
heat or tanning lamps,
saunas,
hot tubs or hot baths, and
heated water beds, etc.
7. Patients should also be advised of a potential for temperature-dependent increases in fentanyl release from the
patch that could result in an overdose of fentanyl; therefore, patients who develop a high fever or increased body
temperature due to strenuous exertion while wearing the patch should contact their physician.
8. Patients should be advised that if they experience problems with adhesion of the fentanyl transdermal system,
they may tape the edges of the patch with first aid tape. If problems with adhesion persist, patients may
overlay the patch with a transparent adhesive film dressing (e.g., Bioclusive or AskinaDerm).
9. Patients should be advised that if the patch falls off before 72 hours a new patch may be applied to a
different skin site.
10. Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush down
the toilet used fentanyl transdermal systems after removal from the skin.
11. Patients should be advised that fentanyl transdermal system may impair mental and/or physical ability
required for the performance of potentially hazardous tasks (e.g., driving, operating machinery).
12. Patients should be advised to refrain from any potentially dangerous activity when starting on fentanyl
transdermal system or when their dose is being adjusted, until it is established that they have not been
adversely affected.
13. Patients should be advised that fentanyl transdermal system should not be combined with alcohol or other CNS
depressants (e.g., sleep medications, tranquilizers) because dangerous additive effects may occur, resulting
in serious injury or death.
14. Patients should be advised to consult their physician or pharmacist if other medications are being or will be
used with fentanyl transdermal system.
15. Patients should be advised of the potential for severe constipation.
16. Patients should be advised that if they have been receiving treatment with fentanyl transdermal system and
cessation of therapy is indicated, it may be appropriate to taper the fentanyl transdermal system dose, rather
than abruptly discontinue it, due to the risk of precipitating withdrawal symptoms.
17. Patients should be advised that fentanyl transdermal system contains fentanyl, a drug with high potential
for abuse.
18. Patients, family members and caregivers should be advised to protect fentanyl transdermal system from theft
or misuse in the work or home environment.
19. Patients should be instructed to keep fentanyl transdermal system in a secure place out of the reach of
children due to the high risk of fatal respiratory depression.
20. Patients should be advised that fentanyl transdermal system should never be given to anyone other than the
individual for whom it was prescribed because of the risk of death or other serious medical problems to that
person for whom it was not intended.
21. Patients should be informed that, if the patch dislodges and accidentally sticks to the skin of another person,
they should immediately take the patch off, wash the exposed area with water and seek medical attention for
the accidentally exposed individual.
22. When fentanyl transdermal system is no longer needed, the unused patches should be removed from their
pouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.
23. Women of childbearing potential who become, or are planning to become pregnant, should be advised to
consult a physician prior to initiating or continuing therapy with fentanyl transdermal system.
24. Patients should be informed that accidental exposure or misuse may lead to death or other serious medical
problems.
Drug Interactions: Agents Affecting Cytochrome P450 3A4 Isoenzyme System: Fentanyl is metabolized mainly
via the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur when
fentanyl transdermal system is given concurrently with agents that affect CYP3A4 activity. Coadministration with
agents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system. The concomitant use
of transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin,
clarithromycin, nelfanivir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole,
fasamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, which
could increase or prolong adverse drug effects and may cause fatal respiratory depression. Patients receiving
fentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time,
and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY: Drug
Interactions in full prescribing information, WARNINGS, and DOSAGE AND ADMINISTRATION in full prescribing
information for further information).
Central Nervous System Depressants: The concomitant use of fentanyl transdermal system with other central
nervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g.,
benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratory
depression, hypotension, and profound sedation, or potentially result in coma or death. When such combined therapy
is contemplated, the dose of one or both agents should be significantly reduced.
MAO Inhibitors: Fentanyl transdermal system is not recommended for use in patients who have received MAOI within
14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Studies in animals to evaluate the carcinogenic
potential of fentanyl HCl have not been conducted. There was no evidence of mutagenicity in the Ames Salmonella
mutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformation
test, and the human lymphocyte and CHO chromosomal aberration in vitro assays.
The potential effects of fentanyl on male and female fertility were examined in the rat model via two separate
experiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via
continuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study,
female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for
14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in both
studies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female alone
produced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hr
patch on a mg/m2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility in
rats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.
Pregnancy: Teratogenic Effects: Pregnancy Category C: No epidemiological studies of congenital anomalies in
infants born to women treated with fentanyl during pregnancy have been reported.
The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models.
Published literature reports that administration of fentanyl (0, 10, 100, or 500 mcg/kg/day) to pregnant female
Sprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence of
teratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch on
a mg/m2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female rats
from gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the
0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.
Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenous
infusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetuses
at the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was no
evidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately
3 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis).
There are no adequate and well controlled studies in pregnant women. Fentanyl transdermal system should be
used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: Chronic maternal treatment with fentanyl during pregnancy has been associated with
transient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome in
newborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expected
in most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transient
neonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.
The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. Female
Wistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 of
pregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in male
and female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animals
demonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) and
transient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-dose
and the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m2 basis.
Labor and Delivery: Fentanyl readily passes across the placenta to the fetus; therefore, fentanyl transdermal system
is not recommended for analgesia during labor and delivery.
Nursing Mothers: Fentanyl is excreted in human milk; therefore, fentanyl transdermal system is not recommended for
use in nursing women because of the possibility of effects in their infants.
Pediatric Use: The safety of fentanyl transdermal system was evaluated in three open-label trials in 291 pediatric
patients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/hr and higher were used
by 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesic
dose of another opioid. Initiation of fentanyl transdermal system therapy in pediatric patients taking less than
60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinical
trials. Approximately 90% of the total daily opioid requirement (fentanyl transdermal system plus rescue medication)
was provided by fentanyl transdermal system.
Fentanyl transdermal system was not studied in children under 2 years of age.
Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of age
or older (see DOSAGE AND ADMINISTRATION in full prescribing information and BOX WARNING).
To guard against accidental ingestion by children, use caution when choosing the application site for fentanyl
transdermal system (see DOSAGE AND ADMINISTRATION in full prescribing information) and monitor adhesion of the
system closely.
Geriatric Use: Information from a pilot study of the pharmacokinetics of IV fentanyl in geriatric patients (N = 4)
indicates that the clearance of fentanyl may be greatly decreased in the population above the age of 60. The relevance
of these findings to fentanyl transdermal system is unknown at this time.
Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses in
nontolerant patients, or when opioids are given in conjunction with other agents that depress respiration.
Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as they
may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (see DOSAGE AND
ADMINISTRATION in full prescribing information).
ADVERSE REACTIONS: In post-marketing experience, deaths from hypoventilation due to inappropriate use of
fentanyl transdermal system have been reported (see BOX WARNING and CONTRAINDICATIONS).
Premarketing Clinical Trial Experience: Although fentanyl transdermal system use in postoperative or acute pain
and in patients who are not opioid-tolerant is CONTRAINDICATED, the safety of fentanyl transdermal system was
originally evaluated in 357 postoperative adult patients for 1 to 3 days and 153 cancer patients for a total of 510
patients. The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyl
transdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyl
transdermal system for more than 1 year.
Hypoventilation was the most serious adverse reaction observed in 13 (4%) postoperative patients and in 3 (2%) of
the cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients.
Various adverse events were reported; a causal relationship to fentanyl transdermal system was not always
determined. The frequencies presented here reflect the actual frequency of each adverse effect in patients who
received fentanyl transdermal system. There has been no attempt to correct for a placebo effect, concomitant use of
Page 2 of 3
other opioids, or to subtract the frequencies reported by placebo-treated patients in controlled trials.
Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in Table 1;
similar reactions were seen in the 357 postoperative patients.
In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 291 patients with
chronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patients
were treated for ) 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-five
patients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months.
There was no apparent pediatric-specific risk associated with fentanyl transdermal system use in children as young
as 2 years old when used as directed. The most common adverse events were fever (35%), vomiting (33%), and
nausea (24%).
Adverse events reported in pediatric patients at a rate of * 1% are presented in Table 1.
TABLE 1: ADVERSE EVENTS (at rate of 1%)
Adults (N = 380) and Pediatric (N = 291) Clinical Trial Experience
Body System
Body as a Whole
Cardiovascular
Digestive
Nervous
Respiratory
Skin and Appendages
Urogenital
Adults
Abdominal pain*, headache*, fatigue*,
back pain, fever, influenza-like symptoms*,
accidental injury, rigors
Arrhythmia, chest pain
Nausea**, vomiting**, constipation**,
dry mouth**, anorexia*, diarrhea*,
dyspepsia*, flatulence
Somnolence**, insomnia, confusion**,
asthenia**, dizziness*, nervousness*,
hallucinations*, anxiety*, depression*, euphoria*,
tremor, abnormal coordination, speech disorder,
abnormal thinking, abnormal gait,
abnormal dreams, agitation, paresthesia,
amnesia, syncope, paranoid reaction
Dyspnea*, hypoventilation*, apnea*,
hemoptysis, pharyngitis*, hiccups,
bronchitis, rhinitis, sinusitis,
upper respiratory tract infection*
Sweating**, pruritus*, rash, application site
reaction erythema, papules,
itching, edema
Urinary retention*, micturition disorder
Pediatrics
Pain*, headache*, fever,
syncope, abdominal pain,
allergic reaction, flushing
Hypertension, tachycardia
Nausea**, vomiting**,
constipation*, dry mouth,
diarrhea
Somnolence*, nervousness*,
insomnia*, asthenia*,
hallucinations, anxiety,
depression, convulsions,
dizziness, tremor, speech
disorder, agitation, stupor,
confusion, paranoid reaction
Dyspnea, respiratory
depression, rhinitis, coughing
Pruritus*, application site

reaction*, sweating increased,
rash, rash erythematous, skin
reaction localized
Urinary retention
*Reactions occurring in 3% to 10% of fentanyl transdermal system patients

**Reactions occurring in 10% or more of fentanyl transdermal system patients
The following adverse effects have been reported in less than 1% of the 510 adult postoperative and cancer
patients studied:
Cardiovascular: bradycardia
Digestive: abdominal distention
Nervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostility
Respiratory: stertorous breathing, asthma, respiratory disorder
Skin and Appendages, General: exfoliative dermatitis, pustules
Special Senses: amblyopia
Urogenital: bladder pain, oliguria, urinary frequency
Post-Marketing Experience: Adults: The following adverse reactions have been reported in association with the
use of fentanyl transdermal system and not reported in the premarketing adverse reactions section above:
Body as a Whole: edema
Cardiovascular: tachycardia
Metabolic and Nutritional: weight loss
Special Senses: blurred vision
Urogenital: decreased libido, anorgasmia, ejaculatory difficulty
DRUG ABUSE AND ADDICTION: Fentanyl transdermal system contains a high concentration of fentanyl, a potent
Schedule II opioid agonist. Schedule II opioid substances, which include hydromorphone, methadone, morphine,
oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression. Fentanyl, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.
The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuse
and diversion.
Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors
influencing its development and manifestations. It is characterized by behaviors that include one or more of the
following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction
is a treatable disease, utilizing a multidisciplinary approach, but relapse is common.
Drug seeking behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergency
calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated
loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact
information for other treating physician(s). Doctor shopping to obtain additional prescriptions is common among
drug abusers and people suffering from untreated addiction.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be
aware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence. In addition,
abuse of opioids can occur in the absence of true addiction and is characterized by misuse for nonmedical
purposes, often in combination with other psychoactive substances. Since fentanyl transdermal system may be
diverted for nonmedical use, careful record keeping of prescribing information, including quantity, frequency, and
renewal requests is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper
dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Fentanyl transdermal systems are intended for transdermal use (to be applied on the skin) only. Do not use a
fentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.
OVERDOSAGE: Clinical Presentation: The manifestations of fentanyl overdosage are an extension of its
pharmacologic actions with the most serious significant effect being hypoventilation.
Treatment: For the management of hypoventilation, immediate countermeasures include removing the fentanyl
transdermal system and physically or verbally stimulating the patient. These actions can be followed by
administration of a specific narcotic antagonist such as naloxone. The duration of hypoventilation following an
overdose may be longer than the effects of the narcotic antagonists action (the half-life of naloxone ranges from
30 to 81 minutes). The interval between IV antagonist doses should be carefully chosen because of the possibility
of renarcotization after system removal; repeated administration of naloxone may be necessary. Reversal of the
narcotic effect may result in acute onset of pain and the release of catecholamines.
Always ensure a patent airway is established and maintained, administer oxygen and assist or control
respiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary. Adequate body
temperature and fluid intake should be maintained.
If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managed
with appropriate parenteral fluid therapy.
ritis. Application of phenylephrine 10% will help distinguish
scleritis from episcleritis: Engorged vessels in episcleritis will
blanch, while those in scleritis will not.19 In RA, episcleritis
is more common than scleritis; however, scleritis tends to
be a more destructive process, with necrotizing scleritis with
inflammation being one presentation. It is important to
differentiate scleritis from episcleritis, as studies have documented a higher mortality rate and wider spread of systemic
disease in RA patients with scleritis.19
Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, multisystem disease that affects the eyes in up to a
third of patients. Ocular manifestations can be potentially
sight-threatening and may be the presenting symptom of
the disease. Ocular manifestations of SLE include external/
anterior segment complications (usually associated with pain
and redness) and posterior segment complications.
Common external eye complications in SLE include
keratoconjunctivitis and discoid lupus erythematosus. Keratoconjunctivitis is the most common symptom associated
with SLE, occurring in up to 30% of patients.19,20 Symptoms,
clinical assessment, and treatment of dry eye are similar to
those described in patients with RA (TABLE 3).19 Cyclosporine
0.05% is a commonly prescribed and effective treatment for
dry eye syndrome. Eyelid disease presents with a discoid
lupus-type rash over the eyelids that consists of raised, scaly
lesions that respond well to systemic steroids and antimalarials such as hydroxychloroquine and chloroquine.
Posterior segment complications consist mainly of retinal
disease. Retinopathy is present in 10% of patients with SLE,
with signs correlating to the severity of systemic inflammation;
it may indicate inadequate control of SLE.20 Some forms of
retinopathy in SLE are similar to hypertensive retinopathy
and DR, making management and monitoring difficult when
these diseases occur simultaneously. Aggressive, severe retinopathy, in extreme cases, may lead to exudative retinal
detachment, and treatment with systemic immunosuppression
is necessary to control the disease.
Clinicians should be aware that agents used to treat SLE
and RA may cause ophthalmic complications. The aminoquinolones chloroquine and hydroxychloroquine are antimalarials used to treatment SLE and RA. Chloroquine, and to
a lesser extent hydroxychloroquine, can cause irreversible
sight-threatening maculopathy at higher doses. Patients should
undergo routine screening for retinal toxicity when receiving
either of these drugs, as should patients who have been receiving therapy for more than 10 years or who have renal disease.
Doses of chloroquine >3.5 mg/kg/day or doses of hydroxychloroquine >6.5 mg/kg/day significantly increase the risk of
renal toxicity and should be monitored closely.21,22
References available online at www.uspharmacist.com.
Page 3 of 3
MYLAN
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
REVISED JUNE 2008 BS:FTS:R16
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BSIP / PHOTO RESEARCHERS, INC
Cataract Surgery
orldwide, the leading cause of blindness is

cataract. Globally, in 2002, there were more
than 161 million people with visual impairment, of whom about 37 million were blind.1 Vision
2020 estimates that 18 million people are bilaterally blind
from cataract.2 In North America, the amount of blindness due to cataract, as compared with all eye diseases,
is about 5%. Poorer regions account for about 50% of
cases of blindness as a result of cataract.1 In the United
States, the Framingham Eye Study found a decrease in
vision as a result of cataract in 15.5% of the population
overall and in 45.9% of people over 75 years of age.3
Vision loss was defined as vision of 20/30 or worse. The
Beaver Dam Eye Study, using a similar definition of
vision loss due to cataract, found a frequency of 38.8%
in men and 45.9% in women aged 75 years and older.4
cataract. Modifiable risk factors may include elevated

ocular exposure to ultraviolet B light, diabetes, and
smoking.11,12
Vitamin supplementation has not been shown definitively to prevent or cause cataract. Likewise, a link
between estrogen and cataract formation has not been
substantiated. Interestingly, specific types of cataract
have been associated with specific risk factors.9-11 Based
on longitudinal studies, racial and ethnic groups also
have shown specificity for certain cataract types.5-7
Economic Impact of Cataract

Delaying cataract by 10 years can have a significant impact
on quality of life while decreasing the economic burden.13
Changing modifiable risk factors may delay cataract, but
surgery is required to restore vision. In 1991, Medicare
spent $3.4 billion on cataract surgery, at an average cost
of $2,500 per procedure. This equates to about 1.5 million
people who underwent cataract surgery in 1991.14 It would
be expected that, owing to an aging population, the number of people undergoing cataract surgery and the cost in
the U.S. would be much higher in 2009. Regardless, the
cost of cataract surgery is relatively low when the cost of
not treating cataract is taken into consideration. Vision
loss related to cataract may affect employment opportunities and the ability to function independently.15 Patients
who wait more than 6 months for cataract surgery could
experience more negative outcomes during the waiting
period than those whose waiting period was less than 6
months. Negative outcomes during the waiting period
could include vision loss, an increased rate of falls, and
reduced quality of life.16
Background
A cataract is an opacification of the lens of the eye. There
are three specific types of cataract: nuclear, cortical, and
posterior subcapsular. Cataract formation is mainly a
result of aging; it is generally seen in both lenses and is
caused by changes in the lens protein. Adult cataract is
typically seen in patients 50 years and older.1 Patients
aged over 50 years have a lower prevalence of cataract
development than patients aged 60 years and older.5-7
A cataract may be symptomatic or asymptomatic.
Symptoms include glare, decreased visual function or
blurred vision, and blindness. The incidence of blindness
from cataract is expected to increase owing to the increase
in life expectancy.8 Age is considered a nonmodifiable
risk factor. Other risk factors include genetics, suggesting
a hereditary nature to cataract; oral and inhaled corticosteroid use; the use of oral and topical beta-blockers; When Surgery Should Be Performed
dose- and drug-dependent use of phenothiazines such as Nonsurgical options prior to surgery have a limited role,
but include changing the patients
chlorpromazine and thioridazine; and
Brenda Wood, BSPharm, PharmD
9,10
Some
refractive correction.17 Other nonsurbusulfan alkylating agents.
Freelance Medical Writer
San Diego, California
data suggest that myopia may cause
gical options include magnifiers for
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CATARACT SURGERY
commonly performed.15 PHACOs advantages over ECCE

include a smaller incision, lower intraoperative rates of
vitreous loss and iris prolapse, shorter surgery time, and
faster time to visual recovery. The ECCE procedure may
be chosen for a dense cataract that is more advanced. A
rapid recovery and significant improvement in visual
acuity occur in about 90% of patients.11
Sedation with topical anesthetic eyedrops is the most
frequently used anesthesia for cataract surgery. Lidocaine
is the topical anesthetic of choice.19 Rarely, general
anesthesia may be considered if a patient with advanced
age cannot cooperate, has poor mental status, or is
severely claustrophobic. Topical anesthesia with eyedrops
results in fewer complications than retrobulbar (space
behind the eyeball) and peribulbar (space outside the
muscle cone) injections.15 Less sedation is required in
patients receiving topical anesthesia; as a result, there
is less nausea and vomiting postoperatively. In addition,
topical anesthesia does not cause temporary paralysis
of the eye or affect vision; therefore, many patients have
improved vision immediately after surgery.
There is a small risk of intraocular infection or
endophthalmitis (occurring at a rate of 0.08% to 0.1%).
Prophylactic pre- or postoperative antibiotics administered to the eye are generally not given unless an intraoperative complication occurs or the surgeon has a
greater number of endophthalmitis cases than is typical.17 If a patient develops pain and decreased vision 2
Types of Surgery and
to 5 days after cataract surgery, immediate evaluation
Intraoperative Medications
by an ophthalmologist should be performed. An intraIn the U.S., there are two main types of extraction sur- ocular infection can cause severe permanent vision loss.
geries for cataract: extracapsular cataract extraction (ECCE)
Finally, approximately 25% of ECCE surgeries result
and phacoemulsification (PHACO); PHACO is more in posterior capsular opacification, generally occurring
within 5 years of surgery. This is due
to a proliferation of epithelial cells in
the lens. The risk is higher in younger
RECOMMENDED TOPICAL
PATIENTS AT RISK FOR CME
patients and in patients with certain
NSAID DOSING
Diabetic retinopathy
types of intraocular lenses.15
reading, the use of tinted lenses, and papillary dilation

for small central cataracts.
Typically, patients with cataract experience a decrease
in vision over months to years. Assessing whether a
decrease in vision has affected daily activities is vital for
determining when surgery should be performed. The
benefits of surgery may be much greater for a person
who drives, works, or is active in sports versus a patient
with dementia who lives in a nursing home. Generally,
surgery is performed only when a significant decline in
visual function is seen.15 If a patient presents with a
sudden decrease or change in vision, he or she should
immediately be referred to an ophthalmologist. Cataract
surgery may be performed prior to a decline in visual
function in a diabetic patient if the lens is too opaque
for the ophthalmologist to clearly evaluate the retina.
During surgery, the clouded lens is removed and
replaced with a synthetic monofocal or multifocal lens.
The monofocal lens has a single focus length; the multifocal lens has multiple focus lengths, which makes it
easier for the patient to see at a distance and close up
without the aid of glasses.15 Although the multifocal lens
may provide freedom from wearing glasses, more patients
with multifocal lenses have reported halos around lights
and reduced contrast sensitivity than patients who have
monofocal lenses.18 Contrast sensitivity is the ability to
distinguish an object from its background.
Ocular vascular disease

Cardiovascular disease
Preexisting ocular inflammation
Epiretinal or vitreoretinal
membrane
History of retinitis pigmentosa
Preoperative: 1 wk
Postoperative: 4 wkseveral
mo, one drop 4 times/day
(ketorolac or diclofenac
ophthalmic drops)
PATIENTS NOT AT RISK

Preoperative: 12 days
Postoperative: 34 wk, one drop
4 times/day (ketorolac or
diclofenac ophthalmic drops)
CME: cystoid macular edema; NSAID:

nonsteroidal anti-inflammatory drug.
Figure 1. Recommended topical NSAID dosing.
Preoperative and
Postoperative Medication
Generally, it is the standard of care to
use topical nonsteroidal anti-inflammatory drugs (NSAIDs) pre- and postoperatively; however, there is no consensus
for the therapeutic use of topical
NSAIDs.17 According to an article by
OBrien, surgeons dose NSAIDs 1 to
2 days prior to surgery and for only 1
week to 10 days after surgery.20 Since
a major postoperative complication of
cataract surgery is cystoid macular edema
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CATARACT SURGERY
REFERENCES
1. Resnikoff S, Pascolini D, Etyaale D, et al. Global data on visual impairment in
the year 2002. Bull World Health Organ. 2004;82:844-851.
2. Vision 2020. What is avoidable blindness? Cataract. www.vision2020.org/
main.cfm?type=WIBCATARACT.
3. Kahn HA, Leibowitz HM, Ganley JP. The Framingham Eye Study. I. Outline
and major prevalence findings. Am J Epidemiol. 1977;106:17-32.
4. Klein BE, Klein R, Linton KL. Prevalence of age-related lens opacities in a
population. The Beaver Dam Eye Study. Ophthalmology. 1992;99:546-552.
5. Varma R, Torres M. Prevalence of lens opacities in Latinos: The Los Angeles
Latino Eye Study. Ophthalmology. 2004;111:1449-1456.
6. Xu L, Cui T, Zhang S, et al. Prevalence and risk factors of lens opacities in
urban and rural Chinese in Beijing. Ophthalmology. 2006;113:747-755.
7. Murthy GVS, Gupta SK, Maraini G, et al. Prevalence of lens opacities in
north India: the INDEYE feasibility study. Invest Ophthalmol Vis Sci. 2007;
48:88-95.
8. Riaz Y, Mehta JS, Wormald R, et al. Surgical interventions for age-related cataract. Cochrane Database Syst Rev. 2006;(4):CD001323.
9. Kanthan GL, Wang JJ, Rochtchina E, Mitchell P. Use of antihypertensive medications and topical beta-blockers and the long-term incidence of cataract and cataract surgery. Br J Ophthalmol. 2009;93:1210-1214.
10. Li J, Tripathi RC, Tripathi BJ. Drug-induced ocular disorders. Drug Saf.
2008;31:127-141.
11. Abraham AG, Condon NG, West Gower E. The new epidemiology of cata-
been off the medication for 5 weeks to 9 months.21

Currently, there is no recommendation concerning
discontinuing the use of tamsulosin prior to cataract
surgery. In order for the ophthalmologist to be prepared
for a modification in surgical technique, the patient
must tell the surgeon whether he or she is currently
taking, or previously took, tamsulosin.
Conclusion
Cataract is a prevalent condition in developed and developing countries. Adult cataract is typically seen in people
aged 50 years and older, and prevalence increases with
advancing age.1,5-7 In the U.S., approximately 40% to
46% of people over the age of 75 years will have vision
loss of 20/30 or worse as a result of cataract.4 Delaying
cataract by 10 years can have a significant impact on
quality of life while decreasing the economic burden.13
Negative outcomes of unresolved cataract include vision
loss, an increased rate of falls, fewer work opportunities,
and the inability to live independently.15,16 Surgery, which
is necessary to restore vision, results in rapid recovery
and a significant improvement in visual acuity, generally
seen in about 90% of patients.11 Identifying patients
with risk factors may lead to referral to an ophthalmologist and ultimately to receiving the cataract surgery
covered by Medicare.
There is no consensus on the use of topical NSAIDs
and topical corticosteroids pre- and postoperatively.17
Generally, NSAIDs are used pre-, intra-, and postoperatively. The Canadian Ophthalmological Society recommends that topical NSAIDs be started 2 to 3 days before
surgery and continued 3 to 4 times per day for 3 to 4
weeks.17 However, OBrien recommends a longer treatment duration of 4 weeks to several months for patients
at risk for CME.20
(CME), typically occurring 4 to 6 weeks postoperatively,

OBrien recommends a more robust pre- and postoperative topical NSAID regimen that also considers patient
risk factors (FIGURE 1).20 Following cataract surgery,
topical NSAIDs are used for the management of postoperative inflammation, to prevent and treat CME, and
for pain.20 Topical NSAIDs are also used intraoperatively
to prevent miosis.
Topical corticosteroids have been used concomitantly
with topical NSAIDs to treat CME in some patients.
Data suggest that combination therapy is superior for
treating CME versus either agent alone.20 Although
the Canadian Ophthalmological Society recommends
topical steroids, topical NSAIDs, or both in the perioperative period and for the treatment of CME, consensus on therapeutic use has not been established.
Studies have shown that better visual outcomes and
decreased angiographic CME were seen when topical
NSAIDs were started 2 to 3 days before surgery and
continued 3 to 4 times per day for 3 to 4 weeks.17
These recommendations, not based on consensus,
differ somewhat from the recommendations made by
OBrien (FIGURE 1).20 The most common side effects
of topical NSAIDs are stinging and irritation. Rarely,
superficial punctate keratitis and epithelial defects
have been seen. Delayed corneal wound healing and
re-epithelialization may result.20
Aspirin or other anticoagulants may be taken without regard to cataract surgery; however, the international
normalized ratio should be in the therapeutic range.15
Intraoperative floppy iris syndrome has been reported
during cataract surgery in some patients who were
receiving or had received tamsulosin. In most cases,
tamsulosin had been stopped 2 to 14 days before surgery;
however, a few cases were reported after the patient had
ract. Ophthalmol Clin North Am. 2006;19:415-425.

12. Centers for Disease Control and Prevention. 2004 Surgeon Generals Report
The Health Consequences of Smoking. Chapter 6. Other effects. www.cdc.gov/
tobacco/data_statistics/sgr/2004/pdfs/chapter6.pdf. Accessed November 15, 2009.
13. McCarty CA, Taylor HR. The genetics of cataract. Invest Ophthalmol Vis Sci.
2001;42:1677-1678.
14. Steinberg EP, Javitt JC, Sharkey PD, et al. The content and cost of cataract
surgery. Arch Ophthalmol. 1993;111:1041-1049.
15. Bollinger KE, Langston RHS. What can patients expect from cataract surgery? Cleve Clin J Med. 2008;75:193-196,199-200.
16. Hodge W, Horsley T, Albiani D, et al. The consequences of waiting for cataract surgery: a systematic review. CMAJ. 2007;176:1285-1290.
17. Canadian Ophthalmological Society Cataract Surgery Clinical Practice Guideline Expert Committee. Canadian Ophthalmological Society evidence-based clinical practice guidelines for cataract surgery in the adult eye. Can J Ophthalmol.
2008;43:S7-S57.
18. Leyland M, Pringle E. Multifocal versus monofocal intraocular lenses after
cataract extraction. Cochrane Database Syst Rev. 2006;(4):CD003169.
19. Navaleza JS, Pendse SJ, Blecher MH. Choosing anesthesia for cataract surgery. Ophthalmol Clin N Am. 2006;19:233-237.
20. OBrien TP. Emerging guidelines for use of NSAID therapy to optimize cataract surgery patient care. Curr Med Res Opin. 2005;21:1131-1137.
21. Flomax (tamsulosin hydrochloride) package insert. Ridgefield, CT: Boehringer
Ingelheim Pharmaceuticals, Inc; December 2009.
HS-11
3/31/10 1:44 PM
Same Name. New Size.
Introducing 3 mL of Humalog and Humulin R U-100 in a Smaller Vial*

The New Smaller Vial, Another Insulin Delivery Option
Intended To: Give hospitals more exibility when evaluating
insulin storage and distribution (oor stock vs individual patient
supply), in addition to the 10 mL vial and Humalog KwikPen.
Indication
Humalog is for use in patients with diabetes mellitus for
the control of hyperglycemia. Humalog should be used with
longer-acting insulin, except when used in combination
with sulfonylureas in patients with type 2 diabetes.
Same Bar-Coding Technique, New Size

Same Color-Differentiating System, New Size
National Drug Code (NDC)
Humalog - NDC Number - 0002-7510-17
Humulin R U-100 - NDC Number - 0002-8215-17
Select Safety Information

Hypoglycemia is the most common adverse effect associated
with insulins, including Humalog.
When used as a mealtime insulin, Humalog should be given
within 15 minutes before or immediately after a meal.
*3 mL of Humalog and Humulin R U-100 are in a 5 mL vial.

Pens are for single-patient use only and should not be shared among patients.
Please see Important Safety Information on adjacent page and
accompanying Brief Summary of full Prescribing Information.
Indication
Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control of
hyperglycemia. Humalog should be used with longer-acting insulin, except when used in combination with
sulfonylureas in patients with type 2 diabetes.
Important Safety Information

Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients.
Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of action.
Therefore, when used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately
after a meal.
Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to
maintain glucose control (except when using an insulin pump). Glucose monitoring is recommended for all patients
with diabetes.
The safety and effectiveness of Humalog in patients less than 3 years of age have not been established. There are
no adequate and well-controlled clinical studies of the use of Humalog in pregnant or nursing women.
Starting or changing insulin therapy should be done cautiously and only under medical supervision.
Hypoglycemia
Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia
can happen suddenly, and symptoms may be different for each person and may change from time to time.
Severe hypoglycemia can cause seizures and may be life-threatening.
Other Side Effects
Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and
hypersensitivity. Systemic allergy is less common, but may be life-threatening. Because of the difference in action of
Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those
who are fasting, have autonomic neuropathy or renal impairment, are using potassium-lowering drugs, or taking drugs
sensitive to serum potassium level).
For additional safety prole and other important prescribing considerations, see accompanying Brief
Summary of full Prescribing Information.
Please see full user manual that accompanies the pen.
Humalog is a registered trademark of Eli Lilly and Company and is available by prescription only.
Humalog KwikPen is a trademark of Eli Lilly and Company and is available by prescription only.
Humulin is a registered trademark of Eli Lilly and Company.
HI59950-4
1109 PRINTED IN USA
2009, LILLY USA, LLC. ALL RIGHTS RESERVED.
HUMALOG
INSULIN LISPRO INJECTION (rDNA ORIGIN)
BRIEF SUMMARY: Consult package insert for complete prescribing information.
INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with
diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of
action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in
regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used
without a longer-acting insulin when used in combination therapy with sulfonylurea agents.
Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other
insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients
with type 2 diabetes.
CONTRAINDICATIONS: Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to
Humalog or any of its excipients.
WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well
as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given
within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog,
patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when
using an external insulin pump).
External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed
with any other insulin. Patients should carefully read and follow the external insulin pump manufacturers
instructions and the PATIENT INFORMATION leaet before using Humalog.
Physicians should carefully evaluate information on external insulin pump use in the Humalog physician
package insert and in the external insulin pump manufacturers instructions. If unexplained hyperglycemia or
ketosis occurs during external insulin pump use, prompt identication and correction of the cause is necessary.
The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients
Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION).
Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog.
As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose
monitoring is recommended for all patients with diabetes and is particularly important for patients using an
external insulin pump.
Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin
strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the
need for a change in dosage.
PRECAUTIONS: GeneralHypoglycemia and hypokalemia are among the potential clinical adverse effects
associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care
should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are
fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to
serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects
associated with the use of all insulins.
As with all insulin preparations, the time course of Humalog action may vary in different individuals or at
different times in the same individual and is dependent on site of injection, blood supply, temperature, and
physical activity.
Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual
meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress.
HypoglycemiaAs with all insulin preparations, hypoglycemic reactions may be associated with the
administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of
hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes,
diabetic nerve disease, use of medications such as beta-blockers, or intensied diabetes control.
Renal ImpairmentThe requirements for insulin may be reduced in patients with renal impairment.
Hepatic ImpairmentAlthough impaired hepatic function does not affect the absorption or disposition of
Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary.
AllergyLocal AllergyAs with any insulin therapy, patients may experience redness, swelling, or itching
at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances,
these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor
injection technique.
Systemic AllergyLess common, but potentially more serious, is generalized allergy to insulin, which may
cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure,
rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be lifethreatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an
injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients
receiving Humulin R (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053).
Antibody ProductionIn large clinical trials, antibodies that cross-react with human insulin and insulin lispro
were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the
antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy.
Usage of Humalog in External Insulin PumpsThe infusion set (reservoir syringe, tubing, and catheter),
Disetronic D-TRON2,3 or D-TRONplus2,3 cartridge adapter, and Humalog in the external insulin pump
reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external
insulin pump should not be exposed to temperatures above 37C (98.6F).
In the D-TRON 2,3 or D-TRONplus 2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However,
as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be
selected every 48 hours or less.
When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see
INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of
Insulins, DOSAGE AND ADMINISTRATION, and Storage).
Information for PatientsPatients should be informed of the potential risks and advantages of Humalog and
alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection
technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose
monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia,
and periodic assessment for diabetes complications.
Patients should be advised to inform their physician if they are pregnant or intend to become pregnant.
Refer patients to the PATIENT INFORMATION leaet for timing of Humalog dosing (<
_15 minutes before or
immediately after a meal), storing insulin, and common adverse effects.
For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the PATIENT
INFORMATION leaet that accompanies the drug product and the User Manual that accompanies the delivery
device. They should also reread these materials each time the prescription is renewed. Patients should be
instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose
of needles. Patients should be advised not to share their Pens with others.
For Patients Using External Insulin Pumps: Patients using an external infusion pump should be trained in
intensive insulin therapy and in the function of their external insulin pump and pump accessories. Humalog was
tested in the MiniMed1 Models 506, 507, and 508 insulin pumps using MiniMed1 Polyn1 infusion sets.
Humalog was also tested in the Disetronic 2 H-TRONplus V100 insulin pump (with plastic 3.15 mL insulin
reservoir), and the Disetronic D-TRON 2,3 and D-TRONplus 2,3 insulin pumps (with Humalog 3 mL cartridges)
using Disetronic Rapid2 infusion sets.
The infusion set (reservoir syringe, tubing, catheter), D-TRON2,3 or D-TRONplus 2,3 cartridge adapter,
and Humalog in the external insulin pump reservoir should be replaced, and a new infusion site selected
every 48 hours or less. Humalog in the external pump should not be exposed to temperatures above
37C (98.6F).
A Humalog 3 mL cartridge used in the D-TRON 2,3 or D-TRONplus 2,3 pump should be discarded after 7 days,
even if it still contains Humalog. Infusion sites that are erythematous, pruritic, or thickened should be reported to
medical personnel, and a new site selected.
Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump.
Laboratory TestsAs with all insulins, the therapeutic response to Humalog should be monitored by periodic
blood glucose tests. Periodic measurement of hemoglobin A1C is recommended for the monitoring of long-term
glycemic control.
Drug InteractionsInsulin requirements may be increased by medications with hyperglycemic activity, such
as corticosteroids, isoniazid, certain lipid-lowering drugs (eg, niacin), estrogens, oral contraceptives,
phenothiazines, and thyroid replacement therapy (see CLINICAL PHARMACOLOGY).
Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have
hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants
(monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blocking
agents, beta-adrenergic blockers, inhibitors of pancreatic function (eg, octreotide), and alcohol. Beta-adrenergic
blockers may mask the symptoms of hypoglycemia in some patients.
Mixing of InsulinsCare should be taken when mixing all insulins as a change in peak action may occur.
The American Diabetes Association warns in its Position Statement on Insulin Administration, On mixing,
physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological
response to the insulin mixture may differ from that of the injection of the insulins separately. Mixing Humalog
with Humulin N or Humulin U does not decrease the absorption rate or the total bioavailability of Humalog.
Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect
compared with regular human insulin.
PregnancyTeratogenic EffectsPregnancy Category BReproduction studies with insulin lispro have
been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average
human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired
fertility or harm to the fetus due to Humalog. There are, however, no adequate and well-controlled studies with
Humalog in pregnant women. Because animal reproduction studies are not always predictive of human response,
this drug should be used during pregnancy only if clearly needed.
Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human
insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and
during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been
well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually
fall during the rst trimester and increase during the second and third trimesters. Careful monitoring of the
patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to
mothers with diabetes is warranted.
Nursing MothersIt is unknown whether Humalog is excreted in signicant amounts in human milk. Many
drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when
Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments
in Humalog dose, meal plan, or both.
Pediatric UseIn a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years,
comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human
insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately
after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable
glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to
45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia
was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in
dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf
life may be reduced (see DOSAGE AND ADMINISTRATION).
Geriatric UseOf the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were
65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia
rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset
of Humalog action have not been performed.
ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a
difference in frequency of adverse events between the 2 treatments.
Adverse events commonly associated with human insulin therapy include the following:
Body as a Wholeallergic reactions (see PRECAUTIONS).
Skin and Appendagesinjection site reaction, lipodystrophy, pruritus, rash.
Otherhypoglycemia (see WARNINGS and PRECAUTIONS).
OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy
expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in
drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic
impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose.
Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery.
DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select
external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of
Humalog will vary among patients and should be determined by the healthcare provider familiar with the
patients metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic
studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same
glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucoselowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment
of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog,
particularly to prevent premeal hyperglycemia.
When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a
meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control,
the amount of longer-acting insulin being given may need to be adjusted when using Humalog.
The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of
injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human
insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or
femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other
insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection
sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog
concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog
is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin
preparations, the time course of action of Humalog may vary considerably in different individuals or within the
same individual. Patients must be educated to use proper injection techniques.
Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30,
and Humulin R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted
Humalog may remain in patient use for 28 days when stored at 5C (41F) and for 14 days when stored at 30C
(86F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump.
Parenteral drug products should be inspected visually before use whenever the solution and the container
permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not
be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not
designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be relled with insulin.
External Insulin PumpsHumalog was tested in MiniMed1 Models 506, 507, and 508 insulin pumps using
MiniMed1 Polyn1 infusion sets. Humalog was also tested in the Disetronic 2 H-TRONplus V100 insulin
pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON 2,3 and D-TRONplus 2,3 pumps (with
Humalog 3 mL cartridges) using Disetronic Rapid2 infusion sets. Humalog should not be diluted or mixed with
any other insulin when used in an external insulin pump.
HOW SUPPLIED:
Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each
presentation containing 100 units insulin lispro per mL [U-100]):
10 mL vials
NDC 0002-7510-01 (VL-7510)
3 mL vials
NDC 0002-7510-17 (VL-7533)
NDC 0002-7516-59 (VL-7516)
5 x 3 mL cartridges3
5 x 3 mL prelled insulin delivery devices (Pen)
NDC 0002-8725-59 (HP-8725)
5 x 3 mL prelled insulin delivery devices (Humalog KwikPen ) NDC 0002-8799-59 (HP-8799)

1
2
3
MiniMed and Polyn are registered trademarks of MiniMed, Inc.

Disetronic, H-TRONplus, D-TRON, and Rapid are registered trademarks of Roche Diagnostics GMBH.
3 mL cartridge is for use in Eli Lilly and Companys HumaPen MEMOIR and HumaPen LUXURA HD insulin
delivery devices, Owen Mumford, Ltd.s Autopen 3 mL insulin delivery device, and Disetronic D-TRON and
D-TRONplus pumps. Autopen is a registered trademark of Owen Mumford, Ltd. HumaPen,
HumaPen MEMOIR and HumaPen LUXURA HD are trademarks of Eli Lilly and Company.
Other product and company names may be the trademarks of their respective owners.
Storage Unopened Humalog should be stored in a refrigerator (2 to 8C [36 to 46F]), but not in the
freezer. Do not use Humalog if it has been frozen. Unrefrigerated (below 30C [86F]) 12 vials, cartridges, Pens,
and KwikPens must be used within 28 days or be discarded, even if they still contain Humalog. Protect from
direct heat and light.
Use in an External Insulin PumpA Humalog 3mL cartridge used in the D-TRON2,3 or D-TRONplus2,3
should be discarded after 7 days, even if it still contains Humalog. Infusion sets, D-TRON 2,3 and D-TRONplus 2,3
cartridge adapters, and Humalog in the external insulin pump reservoir should be discarded every 48 hours
or less.
Literature revised December 7, 2009
KwikPens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA.
Pens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France,
F-67640 Fegersheim, France.
Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Hospira, Inc.,
Lake Forest, IL 60045, USA or Lilly France, F-67640 Fegersheim, France.
Cartridges manufactured by Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company,
Indianapolis, IN 46285, USA.
www.humalog.com
Copyright 1996, 2008, Eli Lilly and Company. All rights reserved.
THINKSTOCK
Reporting
Adverse Drug
Events
decision by the FDA to approve a drug for market by federal law or regulation to submit reports of ADEs on
is based on a thorough review of that drugs safety any medical product, due to the challenges of enforcing
and efficacy to determine whether the benefits such a mandate.5 Many ADEs are likely never reported
outweigh the risks associated with its use. While clinical because they are not recognized as safety concerns, perhaps
trials help to establish the efficacy of a drug and to reveal because the HCP is unfamiliar with the reporting process
common adverse events, there are limitations in identifying and its importance. Moreover, incomplete fields or inacsafety concerns in this setting. For example, study participants curacies in the submitted data may limit the utility of the
may not necessarily represent real world patients receiving data.
Patients, HCPs, and the pharmaceutical industry all have
the drug once it is on the market. Pharmacovigilance involves
the continued monitoring of the safety profiles of products an interest in enhancing drug safety by reporting suspected
throughout their life cycles, and particularly once in the ADEs to the FDA. To encourage this, the FDA recently
marketplace, through scientific data-gathering activities released a final rule entitled, Toll-Free Number for Reportrelating to the detection, assessment, and understanding of ing Adverse Events on Labeling for Human Drug Products,
requiring the following statement to be distributed with
adverse events.
Adverse events are undesirable experiences associated dispensed new and refill prescription drugs: Call your
with the use of a medical product. In the regulatory setting, doctor for medical advice about side effects. You may report
adverse events are categorized as adverse drug events (ADEs) side effects to FDA at 1-800-FDA-1088.6 Moreover, the
and, as a subset of ADEs, adverse drug reactions (ADRs) recent focus on safety concerns surrounding several widely
used products has intensified the focus on the drug safety
(TABLE 1).1
It is challenging to estimate the true incidence of ADEs system, and timely and complete ADE reporting continues
in the general population, with uncertainty about the to be an integral component of this.
number of patients exposed to a given drug, poor docuThe aim of this article is to familiarize the reader with
mentation, and underreporting, as well as the effect of the process for ADE/ADR reporting for drugs currently in
publicity around a particular drug on the reported frequency the U.S. marketplace. This will include discussion of how
of an event. In 2008, the FDA received more than 530,000 the ADE reports are handled by the FDA and the pharmareports of suspected ADEs, of which some 33,000 were ceutical industry, and the measures currently being used
submitted directly to the FDA; most
and those under development to monitor
Mark
H.
Mayer,
PharmD,
MBA
2
were submitted by manufacturers.
patient safety. While there are global ADE
Principal Consultant in Global Scientific Policy
That same year, there were 320,000
reporting requirements, this article will
Eli Lilly and Company, Indianapolis, Indiana
serious adverse events and nearly
center on ADE reporting to the FDA. Also,
Sherie A. Dowsett, PhD
50,000 deaths.3 While reporting of Consultant in Global Medical Communications for simplicity of reading, the term ADE is
Eli Lilly and Company
ADEs is a vital component in ensurused throughout to encompass both ADEs
Brahmavar, PharmD
ing drug safety postapproval, the FDAs PharmacyKalpana
and ADRs.
Coordinator, St. Vincent Medical Center
Adverse Event Reporting System is Northeast, Indianapolis, Indiana. At the time of this
believed to capture only a small por- writing, Dr. Brahmavar was with Global Medical REPORTING OF ADVERSE EVENTS
Information, Eli Lilly and Company
THROUGH MEDWATCH
tion of ADEs that occur.4
Kenneth Hornbuckle, DVM, PhD
While adverse event reporting
MedWatch, established by the FDA in 1993,
Senior Epidemiology Advisor
Global Patient Safety, Eli Lilly and Company
guidelines are frequently in place at
was designed to expedite and broaden volWilliam P. Brookfield, MS, RPh
both institutional and professionaluntary reports of serious ADEs by HCPs
Consultant in Global Patient Safety
society levels, health care professionand manufacturers.7 The FDA requests that
Eli Lilly and Company
a serious ADE (i.e., the ADE is fatal, lifeals (HCPs) are currently not required
HS-15
HS15 REVAdverse Drugs 3_33rdsc.indd HS-15
4/1/10 1:12 PM
REPORTING ADVERSE DRUG EVENTS

Adverse Drug Event

Unfavorable and unintended response to a drug, whether
or not considered related to the product (i.e., no causality
implied)
Includes medical errors (miscalculations,
misadministrations, difficulty in interpreting handwritten
orders, misunderstanding of verbal orders, name
confusion of drugs, and packaging or labeling of drugs
are thus not included in this definition) and adverse drug
reactions
time frame (data on file, Eli Lilly and Company).10 Ensuring

that each manufacturer appropriately manages ADE reports
specific to their own drug is only likely to become more challenging as the number of available generics in the marketplace
increases.
While reports should be filed even when all the details
are not available, an HCP reporting an ADE should gather
as much information as possible when preparing to submit
the report so that the FDA and the drug manufacturer have
the information required to assess safety and to draw appropriate conclusions.
Adverse Drug Reaction

Noxious and unintended response to a medicinal product
if a medicine properly prescribed (normal dose, route,
etc.) and administered
Causal relationship between medicinal product and
adverse event cannot be ruled out
Medical errors are not included in this definition
Channels for Reporting ADEs

ADEs can be reported directly by the HCP or consumer
to the FDA using MedWatch, or they can be reported to
the manufacturer who in turn reports them to the FDA
(FIGURE 1).
ADEs: adverse drug events; ADRs: adverse drug reactions.

Reporting Directly to the FDA: There are three options for
Table 1. Definition of ADEs and ADRs
threatening, permanently/persistently/significantly disabling,

requires initial or prolonged hospitalization, causes congenital anomaly, requires intervention to prevent permanent
impairment or damage) be reported if there is suspicion
that it is related to the use of one or more medications.7,8
Reporting of a nonserious but unexpected ADE (i.e., not
listed in the product information) could also be useful in
uncovering previously unidentified adverse effects of drugs.
Reports should be submitted even where the HCP completing the report is not certain the product caused the event.
TABLE 2 lists the key information needed when reporting
an ADE.9 The importance of completing some of the fields
(e.g., description of the event) is obvious. However, the value
of information on other fields is often not so apparent. Reporting the lot number, for example, can provide relevant information if there is suspicion of involvement of a counterfeit product, and help with patient follow-up. Including the name of
the manufacturer will help identify whether the brand manufacturers or the generic companys product has been administered, to assist with finding the source of ADEs that may be
manufacturer specific. All manufacturers, whether a brand or
generic company, have the responsibility to appropriately
conduct follow-up on ADEs. Currently, however, brand manufacturers are receiving and subsequently reporting to the FDA
some ADE reports for products actually dispensed as generic
and thus originating from another manufacturer. From January 2004 to December 2007, for example, prescriptions of
fluoxetine HCl from Eli Lilly and Company made up only
4.5% of the prescriptions in the U.S., yet Eli Lilly submitted
almost 50% of the fluoxetine HCl ADE reports in the publicly
available safety database published by the FDA during that
submitting a voluntary report: 1) Complete Form 3500

online at www.accessdata.fda.gov/scripts/medwatch; 2) call
1-800-FDA-1088 to report by telephone; and 3) download
a copy of Form 3500 at www.fda.gov/downloads/Safety/
MedWatch/DownloadForms/UCM082725.pdf and either
fax it to 1-800-FDA-0178 or mail it back (MedWatch,
5600 Fishers Lane, Rockville, MD 20852-9787) back using
the postage-paid addressed form. This may be most appropriate where there are attachments to submit with the report.
Table 2. Characteristics of
a Good Case Report
Description of the adverse events or disease experience,
including time to onset of signs or symptoms
Suspected and concomitant product therapy details (i.e.,
dose, lot number, schedule, dates, duration), including
OTC medications, dietary supplements, and recently
discontinued medications
Patient characteristics, including demographic information
(e.g., age, race, sex), baseline medical condition prior to
product therapy, comorbid conditions, use of concomitant
medications, relevant family history of disease, and
presence of other risk factors
Documentation of the diagnosis of the events, including
methods used to make the diagnosis
Clinical course of the event and patient outcomes (e.g.,
hospitalization or death)
Relevant therapeutic measures and laboratory data at
baseline, during therapy, and subsequent to therapy,
including blood levels, as appropriate
Information about response to dechallenge and rechallenge
Any other relevant information (e.g., other details relating
to the event or information on benefits received by the
patient, if important to the assessment of the event)
HS-16
HS15 Adverse Drugs 3_33rdsc.indd HS-16
3/31/10 1:44 PM
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This helps determine whether the ADE may be related

to the use of the drug and whether there may be a safety
signal. A safety signal can be defined as a concern about
an excess of adverse events compared to what would be
predicted to be associated with a products use.12 Safety
signals may include new adverse events (particularly if
serious) that were not seen in clinical trials and thus
were not captured on the product label; an apparent
increase in the severity of an event seen in clinical trials;
occurrence of serious events thought to be extremely
rare in the general population; new product-product,
product-device, product-food, or product-dietary supplement interactions; identification of a previously unrecognized at-risk population (e.g., populations with specific
racial or genetic predispositions or comorbidities); or
WHAT HAPPENS TO ADE REPORTS AT FDA?
concerns arising from the way a product is used (e.g.,
At the FDA, ADE reports, including manufacturers expe- adverse events seen at higher than labeled doses or in
dited reports of serious adverse events as well as the manu- populations not recommended for treatment).
facturers other reports provided within periodic safety
It is often not possible to tell from an individual ADE
updates, are captured in a postmarketing surveillance data- report if there is a causal relationship between the drug and
base, the Adverse Event Reporting System (AERS) (FIGURE the medical event, and the importance of including as
1). The AERS is a computerized database of adverse event detailed case information as possible when submitting an
reports, containing more than 4 million ADE records.11 ADE cannot be overemphasized. In addition to reviewing
Not all ADE reports are entered into the database.11 The individual cases, the FDA will use further information
FDA screens and assesses all ADE reports received, and provided by the drug manufacturer.
prioritizes those entered based upon the associated safety
Case reports are assessed at the aggregate level to create
and public health concern.
a case series to characterize the potential safety risk and to
At the FDA, each ADE case report is evaluated for identify risk factors. Creating a case series commonly involves
the adequacy of the information, the temporal associa- an analysis of the clinical and laboratory manifestations and
tion of the product and the event, potentially confound- course of the event; demographic characteristics of patients
ing factors such as patient comorbidities or concomitant with events, exposure duration, time from initiation of
drug therapy, and dechallenge-rechallenge information. product exposure to the adverse event; doses used (including labeled doses, greater than labeled doses,
and overdoses); use of concomitant mediADE REPORTED BY HCP, PATIENT, OTHERS
cations; the presence of comorbid conditions;
and the lot numbers for products used in
patients with events. Data miningutilizReported to manufacturer
Reported to FDA through MedWatch
ing statistical methods to identify potential
safety signals from data in the AERS dataAt manufacturer:
At FDA:
base, as well the large manufacturers safety
Reported to FDA following
ADE entered into
databaseswill also help in identifying
reporting requirements
AERS database
ADE reporting trends and in directing
Also included in periodic
Safety signal
safety questions to the manufacturer. Other
safety reports sent to FDA
identified?
activities to help with risk identification
and assessment include the conduct of
YES
NO
Alerts from FDA
further trials and observational studies by
and manufacturers
No action
Safety
NO
the manufacturer to assess the risk attributed
YES
required or
signal
Regulatory actions,
continue to
to drug exposure; creation of registries to
confirmed?
e.g., label changes
monitor
collect information from multiple sources
(e.g., physician records, hospital summaries,
Figure 1. Flow diagram to show how reported adverse events are handled by both the
pathology reports); and the conduct of
drug manufacturer and the FDA. ADE: adverse drug event; AERS: Adverse Event
patient and HCP surveys.
Reporting System; HCP: health care professional.
Reporting to the FDA Via the Manufacturer: The major-
ity of ADEs are reported to the drug manufacturer, whose

contact information can be found at the relevant manufacturer Web sites. The manufacturer collects all pertinent
information from the reporter and is required to send this
information to the FDA. Serious and unexpected ADEs are
expedited by the manufacturer to the FDA within 15 days
of the manufacturers receipt of the ADE. All ADEs are also
periodically reported by the manufacturer to regulatory
agencies through periodic safety reports. These reports
contain summaries of all ADE reports in a designated time
period and include patient exposure (both postmarketing
and clinical trial), presentation of case summaries, study
findings, and overall safety evaluation.
HS-18
3/31/10 2:29 PM
THE FUTURE OF DRUG SURVEILLANCE

In this article, we have discussed the critical role of ADE
reporting in the drug postmarketing safety system. While
the resulting AERS data may provide the initial signal of a
safety concern that can then be further investigated, there
are certain limitations to data in the current system. For
example, there is no information on the number of users
of a specific drug that can be used to calculate the proportion of patients experiencing an event; there is often inadequate case documentation in the reports; and there is
substantial underreporting of ADEs.13
Due to these limitations, the FDA, drug manufacturers,
and others (academics, HCPs, professional associations,
patient advocacy groups, computer/software companies,
managed care organizations, and think tanks) are working
together to advance and improve the current system, develop
methods for integration of ADE reports with other postmarket safety approaches, and to improve information
sharing. In this regard, e-prescriptions, e-health care records,
integrated electronic claims, patient information databases,
and broad electronic communication targeted to the appropriate health care professionals and patients hold much
promise.
While some of these advances may be years away, in a
recent draft Prescription Drug User Fee Act (PDUFA) IV
Drug Safety Five-Year Plan, the FDA proposes to use the
new user fees (fees collected from drug manufacturers to
fund the drug review process) to add resources to monitor
OUTCOMES OF ADE REPORTING

If, on completion of review of all available clinical data, the
safety signal or signals are confirmed, further steps and
actions may be necessary in the interest of patient safety
(TABLE 3). Even before these definitive steps are taken, the
FDA may at times communicate risk information about
the drug safety issues that are under review to the HCP as
well as to the general public. This occurs as a result of an
early safety signal that suggests an association between the
drug and the ADE being evaluated. These actions are
designed to assist with decision making around use of these
drugs, to prompt discussions between HCP and patient,
and to stimulate additional adverse event reporting. Early
risk information is communicated through various outlets
(i.e., public health advisories, HCP sheets, indexes to drugspecific information, drug safety podcasts, drug safety
newsletters, consumer information Web sites), available at
the MedWatch and Center for Drug Evaluation and Research
(CDER) Web sites of the FDA. An HCP can also sign up
to receive safety alerts and information on safety-related
label changes by e-mail. If, on clinical data review, a safety
signal is not confirmed, the manufacturer and the FDA will
continue to monitor relevant safety information.
Table 3. Examples of Outcomes

of Postmarket ADE Reporting
Product recall or withdrawal

Boxed warning included
Contraindications modified
New warnings, precautions, or adverse reactions
Monitoring recommendations for patients
Dosage adjustments (prescribing or dispensing limitations)
Medication guides useda patient friendly instruction
sheet that is provided to the patient by the pharmacist
each time a prescription is dispensed
Letters to health care professionals (Dear Doctor letters)
drug safety of marketed drugs.14 Steps proposed include the

adoption of new tools and the improvement of existing
tools. Further, under the recently passed FDA Amendments
Act of 2007, the FDA will be establishing a postmarket risk
identification and analysis system utilizing federal and
private sector health-related electronic data.15 Progress to
implement the postmarket risk identification system has
already occurred. On May 22, 2008, the FDA launched
the Sentinel Initiative with the goal of creating and implementing the Sentinel System, an integrated, electronic
system for monitoring medical product safety, which will
enable the agency to examine existing data sources from the
private and public sector, such as electronic health record
systems and medical claims databases, for information about
medical products. Such a system could improve the FDAs
ability to monitor the performance of a product throughout
its life cycle and facilitate data mining and other safety
research-related activities.
In the future, HCPs will likely be able to access a patients
electronic health care record on a wireless computer chart,
submit an adverse event report, receive comprehensive
information based on the patients medical history to communicate immediately to the patient, and order an alternative product all within a matter of seconds. Until then, it
is important that the health care community optimize the
current tools within the drug safety system, which include
timely, complete, and accurate reporting of ADEs. The most
updated information on the MedWatch program and ADE
reporting can be found by visiting the FDAs Web site.
CONCLUSION
As a result of recent safety concerns surrounding widely
used drugs, there is an increasing focus on drug safety.
Timely, complete, and accurate ADE reporting is an essential component of monitoring, and subsequently improving,
patient safety.
The authors gratefully acknowledge Patrick DeLisle for his assistance.
HS-19
3/31/10 2:29 PM
LASIK
Refractive Eye
Surgery in the
21st Century
OLIVIER VOISIN / PHOTO RESEARCHERS, INC
During the LASIK procedure, the stroma of the cornea is treated

with an excimer laser in order to correct vision.
he goal of eliminating refractive errors and allowing individuals to obtain uncorrected optimal
visual performance without glasses or contact
lenses can be successfully achieved by several surgical
procedures. This article will focus primarily on the use
of the excimer laser to reshape the cornea with a quick,
painless, and popular operation known as LASIK (laserassisted in situ keratomileusis).
appears to have several advantages, especially in its speed

of recovery and minimal postoperative discomfort.4,5
Other Refractive Surgeries: Besides LASIK, other forms
of refractive eye surgery include radial keratotomy (RK),
which is used to treat myopia; lamellar surgery, upon
which LASIK is based; and PRK, which was the earliest
application of the excimer laser to treat myopia.
History of Eye Surgery

Presurgical Considerations for LASIK
LASIK: LASIK is a surgical procedure that combines A wide range of refractive errors including low-to-high
the application of the excimer laser (ultraviolet [UV] myopia, low-to-moderate hyperopia, and large amounts
193 nm light energy) under a hinged corneal flap (in of astigmatism can be easily corrected by LASIK. In
situ keratomileusis) to alter the refractive properties of addition, many common systemic disorders such as
the cornea. The technique was developed in the late diabetes are no longer a contraindication to surgery.
1980s by Ioannis Pallikaris, MD, PhD, and was used TABLE 1 lists specific criteria for patient selection for
in other countries before the first FDA trial in 1989.1-3 the LASIK procedure.6,7
LASIK, compared to other refractive surgical procedures,
The FDA has approved LASIK in people 18 years
allows for specific sculpting and subtraction of corneal and older with stable refractions. Some contraindicatissue under a protective corneal flap, making possible tions include pregnancy and having had eye diseases in
the correction of a broad range of
the past such as ocular herpes, catMea A. Weinberg, DMD, MSD, RPh
optical errors including myopia
aract, glaucoma, and keratoconus.
Clinical Associate Professor
(nearsightedness), hyperopia (far- Department of Periodontology and Implant Dentistry In addition to a thorough preopNew York University College of Dentistry
sightedness), and astigmatism (blurerative examination and counseling
New York, New York
ring of vision due to irregular shape
of any patient interested in refractive
Michael S. Insler, MD
of the cornea). In contrast to other
surgery, some additional testing is
Ophthalmologist, Formerly Professor of Ophthalmology
refractive surgeries and photorefracwarranted to help screen for posLouisiana State University Medical School
New Orleans, Louisiana
tive keratectomy (PRK), LASIK
sible postoperative side effects.
HS-20
HS20 LASIK 3_30sc.indd HS-20
3/31/10 1:45 PM
LASIK REFRACTIVE EYE SURGERY

Pupil Examination: The pupil should be measured in from 110 to 180 microns. The minimum residual
both scotopic (dim) and normal (photopic) light. Mea- stromal thickness is recommended as no less than 250
surements may be obtained with infrared pupillometers microns.11
or with a simple pupil card.8 There is a possibility that
young patients with large scotopic pupils may be at Types of LASIK Surgery
higher risk for developing symptoms of glare, halos, and The patient is conscious during surgery but can be
nighttime visual disturbances following refractive surgery. given mild sedation with an oral benzodiazepine such
as diazepam. Anesthetic ophToday, with large ablation zones
thalmic drops (e.g., proparaand the use of aberrometers for
Table 1. Patient Selection
caine) are given immediately
custom ablations, this is less
Criteria
for
LASIK
before the drapes are applied
likely.
and the speculum inserted. The
Adults 18 years of age and older
Dry Eye Testing: Dryness after
patient is asked to look directly
Stable refractions
LASIK is one of the most comat a fixation target under the
Low-to-moderate
myopia
(between
-0.50
and
mon symptoms reported by
laser (patient cooperation is very
-12.00 diopters)
patients.9 It is believed to result
helpful).
Myopia with astigmatism (-5.00 diopters or less)
from the cutting of the anterior
LASIK involves photoablation
flap and the loss of cornea sen(pulses
of UV light energy) of
Low-to-moderate hyperopia without astigmatism
(<6.00
diopters)
sation that eliminates reflex
the corneal stroma after a cornea
tearing. Proper preoperative testflap has been created. The laser
Cannot have certain medical conditions, including
ing evaluating the precorneal
energy can be programmed to
autoimmune disease (e.g., lupus erythematosus,
pemphigus, rheumatoid arthritis, Sjgrens
tear film, the use of artificial
flatten the central cornea to corsyndrome,
uveitis),
uncontrolled
vascular
disease,
tears before surgery, and discusrect myopic errors (nearsightedimmunosuppression (e.g., HIV/AIDS)
sions about this common conness) or steepen the peripheral
Source: References 6, 7.
dition with the patient should
cornea to correct hyperopic
be documented. The prescription
errors (farsightedness). Traditioneye drops Restasis (cyclosporine ophthalmic emulsion ally, flaps have been produced with mechanical micro0.05%) can also be used.
keratomes, but more recently femtosecond laser technology has emerged as an alternative for flap creation.12
Topography: It is critical for all potential refractive This procedure uses ultrafast lasers (all-laser LASIK) that
surgery candidates to undergo preoperative cornea map- precisely photodisrupt tissue by using very short duraping (topography) and cornea thickness (pachymetry) tion energy pulses. The precision of this technique has
measurements to exclude patients at risk who may resulted in wide acceptance of the technology.
respond poorly to the surgery.7 Many computerized
machines are available to analyze the anterior and pos- Conventional LASIK: Conventional LASIK does not
terior curvature of the cornea to aid in selecting and use aberrometry (measurement of the imperfections in
screening good candidates for surgery. These instruments the optical system of the eye) when correcting the
map the surface of the cornea and generate data, which refractive error.13 Treatment is based upon using the
help eliminate patients with abnormal corneas such as refraction from responses obtained with a phoropter
seen in keratoconus (a thinning disorder of the cornea and recent eyeglass prescription. This corrects only
low-order aberrations known as sphere and cylinder. The
that changes it from a round shape to a cone.)
data are manually entered into the laser.
Pachymetry: Pachymetry is a measurement of the thickness of the cornea. The average cornea thickness is Wavefront-Guided LASIK: Wavefront aberrometry has
approximately 540 microns. Preoperative cornea thick- redefined the diagnosis and treatment of refractive errors
ness is an important measure used to determine the in the 21st century. This technology allows the capturstromal thickness that will result from subtracting the ing and measurement of the total optical system of the
flap thickness and the amount of tissue removed by the eye. Aberrometers using advanced polynomials are
treatment.10 It is crucial to leave behind enough corneal capable of measuring higher-order imperfections smaller
thickness to maintain cornea integrity so that the cor- than the wavelength of light and using this information
nea does not become ectatic (see Cornea Ectasia and to reduce imperfections produced by the application of
Collagen Cross-Linking). Cornea flap thickness can range the excimer laser.14
HS-22
3/31/10 1:45 PM

Studies have shown that precise wavefront-guided demonstrated its potential for correction of refractive
ablation minimizes postoperative higher-order aberra- errors. Many FDA clinical trials have resulted in the
tion, resulting in better contrast sensitivity compared approval of the excimer laser to reduce or eliminate a
to conventional treatment.15 Patients theoretically have wide spectrum of refractive errors.13
Surface applications (PRK) have gained a small resurbetter nighttime vision and less chance of needing an
enhancement. This has been promoted as high-defini- gence in patients with thin corneas and in poor candidates
for LASIK who may be at risk
tion LASIK utilizing optical
for ectasia (a bulging of the corfingerprints made possible by
Table 2. Select Medications
nea). Management of postopwavefront aberrometry.
for Dry Eyes
erative pain and the application
Mechanical Keratome: In this
of the chemotherapeutic drug
OTC Medications (Products)
procedure, an automated, precimitomycin C (MMC) to prevent
Carboxyl methylcellulose artificial tears
sion gear-driven machine with
haze and scarring have added to
(Refresh Tears, TheraTears)
an oscillating blade is used to
PRKs safety and popularity.18-20
Glycerin artificial tears (Advanced Eye Relief Dry
make a thin (110-160 micron)
Eye Environmental)
Postoperative Period
superior hinged flap on the ante Hydroxypropyl methylcellulose artificial tears
(Bion Tears, GenTeal Mild)
During the early postoperative
rior surface of the cornea. This
Polyethylene glycol artificial tears (Systane,
period, patients may experience
is done once the eye is immoBlink
Tears)
significant tearing, photophobia,
bilized with a low-pressure suc Polyvinyl alcohol artificial tears (Akwa Tears,
blurred vision, and discomfort
tion ring. Complications during
Murine Tears)
because of the central corneal
translation of the keratome are
Oil-based drops (Soothe XP)
abrasion. With the use of the
uncommon but can be a major
Ophthalmologic ointments/gels (Refresh PM
bandage contact lens and nonconcern. Incomplete flaps are
Ointment, Tears Again Night & Day Gel)
steroidal anti-inflammatory drug
easily handled but prevent the
Prescription Medications
(NSAID) eye drops (e.g., dicloapplication of the laser until a
fenac sodium 0.1%, ketorolac
later time.
FreshKote Ophthalmic Solution (polyvinyl
pyrrolidone 2.0%, polyvinyl alcohol
0.4%), postoperative pain is
[87% hydrolyzed] 0.9%, polyvinyl alcohol
Femtosecond Laser (All-Laser
usually mild to moderate; how[99% hydrolyzed] 1.8%, Amisol Clear)
LASIK): More recently, femtoever, patients occasionally require
Restasis (cyclosporine ophthalmic emulsion
second laser technology (all-laser
systemic analgesia for more
0.05%)
LASIK) has emerged as an altersevere pain. The contact lens
Source: References 38-40.
native to mechanical flap creremains on the eye until the
ation.16 This method precisely
epithelial defect is healed (an
photodisrupts tissue with short-duration energy pulses average of 3-4 days). Antibiotic eye drop therapy (e.g.,
that cleave cornea tissue at a predetermined depth, tobramycin or gatifloxacin 0.3%) is usually continued
forming bubbles of water and carbon dioxide at a plane for 2 to 3 days after the defect has healed, and topical
that allows for a smooth interface once the flap is lifted.17 steroid eye drops (e.g., 1% prednisolone) may be conThere appears to be no difference between femtosecond tinued for up to 3 months postoperatively.
and microkeratome flap creation as far as visual outcomes.
However, femtosecond flaps can be made thinner and Complications
their parameters more precise than conventional meth- Intraoperative complications related to the use of the
ods. There is also an expectation of greater safety to the microkeratome occur at a rate of less than 1% in experienced hands and usually result in an incomplete or
patient than with mechanical devices.
partial primary cut.21-23 When the flap appears less than
Photorefractive Keratectomy (PRK): Laser refractive ideal, it should be replaced, and the procedure can be
surgery procedures can either be performed by intra- successfully repeated in 2 to 3 months.
stromal ablation (LASIK) or by surface ablation, generDry Eyes: There is a high incidence of the development
ally known as PRK. Both use the excimer laser.
Experimental studies evaluating the excimer laser of dry eyes after refractive surgery (up to 36.36%).24,25
with its UV light energy began in the early 1980s. In This symptom may last up to 6 months after surgery
the mid 1980s, animal and human applications per- or be permanent. A proper preoperative evaluation for
formed at Louisiana State University in New Orleans dry eyes is necessary to help prevent this postoperatively.
HS-23
3/31/10 1:45 PM

Pharmacologic management of dry eyes includes prescription and nonprescription medications (TABLE 2).
Another therapy is punctal occlusion, where a collagen
plug is placed in the natural drain of the eye.
hours. These folds are easily fixed by relifting and

repositioning of the flap, and respond to treatment days
and even weeks after their occurrence.
Epithelial Ingrowth: Epithelial ingrowth manifests itself
Cornea Ectasia and Collagen Cross-Linking: Ectasia
(protrusion) can follow LASIK when the cornea takes

on an appearance similar to keratoconus. Visual acuity
is reduced, and glasses or soft contact lenses can no
longer improve vision. Ectasia is a serious complication
with certain preoperative risk factors, including abnormal cornea topography and thin corneas.26
By combining a solution of riboflavin and UV light
exposure, corneas that have suffered ectasia are being
treated to strengthen their weakened status. The procedure
is a strengthening of the cross-links of the collagen fibers
to allow stability.27,28 Under topical anesthesia, the central area epithelium is removed. The riboflavin is topically
applied for a period of minutes followed by irradiation
with intense 365-nm UVA light for approximately 30
minutes. The process has been compared to snow blindness that occurs after UV exposures.
Presently, there is a multicenter FDA clinical trial
analyzing the safety and efficacy of cross-linking for
postoperative ectasia.29 Other clinical studies have shown
that it may be just as effective to inject the riboflavin
directly into the stroma without removing the epithelium.30 Cornea cross-linking may be helpful in treating
keratoconus and in strengthening borderline corneas
in patients who are interested in refractive cornea surgery but have suspect or slightly distorted corneas.
Over- and Undercorrections: Residual refractive errors
present immediately following LASIK usually result
from undercorrections.31-34 Regression can occur months
later. Once the prescription stabilizes, retreatment can
be performed.34
Glare, Halos, and Starbursts: Some patients complain
of halos, starbursts, and a general reduction of qualitative vision under conditions of reduced illumination.
These are usually temporary but can persist in a small
number of cases. The use of larger optical zones and
wavefront technology has reduced the incidence of these
symptoms. Some surgeons believe there may be a relationship between the scotopic pupil diameter (size that
pupils dilate to a dark room) and nighttime visual
disturbances. Some clinicians use topical brimonidine
for night vision disturbances.
by small islands of epithelial cells that are seen beneath

the flap.35 They usually are found in the midperiphery
but may extend centrally and reduce visual acuity. If
epithelial ingrowth is extensive and threatens vision,
the flap should be lifted and the cells removed. This
may need to be repeated with sutures placed in the flap
to prevent recurrences. The incidence of ingrowth is
reported to be increased following enhancement or
follow-up surgery.23
Diffuse Lamellar Keratitis (DLK): This nonspecific
intralamellar inflammation appears in the early postoperative period as a granular or sandlike appearance
in the flap interface.23 The condition can occur in
clusters, affecting several patients on a given surgery
day. It is of unclear etiology, and most cases follow
uncomplicated LASIK. In rare instances, DLK can result
in stromal melting, haze, and loss of best-corrected
vision. Management with topical and systemic steroids
and irrigation of the stromal bed (material under the
surface of the cornea) are usually effective in treating
severe cases.
Enhancements
Enhancements are follow-up surgeries that are used to
correct residual refractive errors (i.e., over- or undercorrections) or to suit the visual needs of a patients
changing lifestyle (e.g., monovision correction, a technique that reduces the need for reading glasses or
bifocals). The timing of retreatment should be based
on a stable refraction.36
Options include recutting a flap, lifting the prior
flap, or performing PRK on top of the previous LASIK.
With increasing use of MMC for the prevention of
haze and the avoidance of epithelial ingrowth, more
surgeons are turning to PRK for enhancements.
Dislocated, Wrinkled Flaps: Flap displacement with
Summary
LASIK surgery for the correction of all kinds of refractive errors offers patients a fast, safe, reproducible,
and cost-effective alternative to glasses and contact
lenses. Refinements in the delivery systems of the
excimer laser and wavefront technology have greatly
increased visual outcomes with this commonly performed procedure and have improved the quality of
life for many people.37
folds or wrinkles usually occurs within the first 24
HS-24
3/31/10 1:45 PM
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References: 1. Delsym product labeling. 2. Food and

Drug Administration Web site. Electronic Orange Book.
http://www.fda.gov/cder/ob. Accessed March 18, 2009.
dextromethorphan polistirex
Bc`\=TTbVS1]cUV
Senior Care
Kaposis Sarcoma
Prognosis Varies With Form
aposis sarcoma (KS) is a

multicentric, vascular proliferation considered to be
neoplastic and malignant.1 It was
first described by the Hungarian
dermatologist Moritz Kaposi in
1872.2 Characteristically, KS
presents with bluish red or purple
discolored skin lesions that are rich
in blood vessels and can be associated with widespread visceral
involvement.1,3 Among the different
forms of KS, the clinical manifestations and course of the disease differ
dramatically (TABLE 1).
The classic form of this disease
occurs most often in men over 60
years of age of Italian, Jewish, or
Eastern European ancestry and is
usually not fatal.4 In patients with
AIDS, KS develops very quickly and
may involve not only the skin, but
lungs, gastrointestinal tract, and
Mary Ann E. Zagaria, PharmD, MS, CGP
Senior Care Consultant Pharmacist and
President of MZ Associates, Inc.
Norwich, New York
www.mzassociatesinc.com
Recipient of the Excellence in Geriatric Pharmacy Practice Award from the Commission for
Certification in Geriatric Pharmacy
Clinical Features and Diagnosis

TABLE 1 provides an overview of the
clinical manifestations and prognosis
for the different types of KS.
Cutaneous Lesions: Most patients
have multiple cutaneous lesions that
are often bilaterally symmetrical and
tend to initially involve the lower
extremities; cases have been
reported, however, in which only
one or no skin lesions have been
present.6 These asymptomatic skin
lesions are described as purple, pink,
or red macules; if fusion occurs,
they become plaques with a blueviolet to black hue and eventually
form nodules.4 Nodules have the
potential to grow rapidly, penetrate
soft tissue, and invade bone.1,4
Patients with cutaneous lesions may
also present with edema.4
intestinal lesions are usually asymptomatic, they have the potential to

bleed; on occasion, the bleeding
may be extensive.4
Other Symptoms and Complications: Lesions in the lung may cause
cough, shortness of breath, and

bloody sputum.3 Pleuropulmonary
KS is considered an ominous sign; it
usually occurs late in the course of
AIDS-associated KS, particularly in
patients whose death is directly
attributed to KS.2 If lymph nodes
are affected, leg swelling may cause
pain or infection.3 An aggressive
form of endemic KS can quickly
spread to the bones.3
Diagnosis: Diagnosis is confirmed
by biopsy.3 A CT of the abdomen
and chest is performed to evaluate
for visceral spread in patients with
AIDS or immunosuppression.4 If
NATIONAL CANCER INSTITUTE / PHOTO RESEARCHERS, INC
The classic form of this

disease, which is
usually not fatal, occurs
most often in men over
60 years old of Italian,
Jewish, or Eastern
European lineage.
other organs.3 Several cancers

deemed uncommon in the general
population are often seen with higher
prevalence in transplant recipients
KS being one of them.5 Patients who
are immunocompromised experience
a particularly virulent, disseminated
form of the disease.1 In the elderly,
KS may be discovered as an incidental finding.6 Human herpesvirus type
8 has been identified in KS tissue
biopsies from practically all patients
with the following forms of the disease: classic, endemic, AIDS-associated, and iatrogenic.2,7
Mucosal Lesions: The appearance
of mucosal lesions is bluish to violaceous (i.e., violet in color) macules,

plaques, and tumors.4 While gastro-
Kaposis sarcoma is a neoplastic and malignant vascular proliferation.
20
20 Senior Care 3_30sc.indd 20
3/31/10 1:40 PM
Brimonidine Tartrate Ophthalmic Solution, 0.15%

JVTWHYLZ[V(SWOHNHU76WO[OHSTPJ:VS\[PVU
First-Time Generic
NEW STRENGTH
Available for immediate shipment.

Introducing Brimonidine Tartrate Ophthalmic Solution, 0.15%. A lower price alternative that
is AT Rated and therapeutically equivalent to Alphagan P* Ophthalmic Solution, 0.15%.
Available in 5 mL, 10 mL, and 15 mL DROP-TAINER** dispensers.
2010 Falcon Pharmaceuticals, Ltd.
PLEASE SEE BRIEF PRESCRIBING INFORMATION ON ADJACENT PAGE
*Alphagan P is a registered trademark of Allergan, Inc.

** DROP-TAINER is a registered trademark of Alcon Research, Ltd.
Brimonidine Tartrate
Ophthalmic Solution, 0.15%
Sterile
INDICATIONS AND USAGE

Brimonidine Tartrate Ophthalmic Solution, 0.15% is indicated for
the lowering of intraocular pressure in patients with open-angle
glaucoma or ocular hypertension.
CONTRAINDICATIONS
Brimonidine Tartrate Ophthalmic Solution, 0.15% is contraindicated
in patients with hypersensitivity to brimonidine tartrate or any
component of this medication. It is also contraindicated in patients
receiving monoamine oxidase (MAO) inhibitor therapy.
PRECAUTIONS
General:
Although Brimonidine Tartrate Ophthalmic Solution, 0.15% had
minimal effect on the blood pressure of patients in clinical studies,
caution should be exercised in treating patients with severe
cardiovascular disease.
Brimonidine Tartrate Ophthalmic Solution, 0.15% has not been
studied in patients with hepatic or renal impairment; caution should
be used in treating such patients.
Brimonidine Tartrate Ophthalmic Solution, 0.15% should be used
with caution in patients with depression, cerebral or coronary
insufficiency, Raynauds phenomenon, orthostatic hypotension,
or thromboangiitis obliterans. Patients prescribed IOP-lowering
medication should be routinely monitored for IOP.
Information for Patients:
As with other drugs in this class, Brimonidine Tartrate Ophthalmic
Solution, 0.15% may cause fatigue and/or drowsiness in some
patients. Patients who engage in hazardous activities should be
cautioned of the potential for a decrease in mental alertness.
Drug Interactions:
Although specific drug interaction studies have not been
conducted with Brimonidine Tartrate Ophthalmic Solution,
0.15%, the possibility of an additive or potentiating effect with
CNS depressants (alcohol, barbiturates, opiates, sedatives,
or anesthetics) should be considered. Alpha-2 agonists, as a
class, may reduce pulse and blood pressure. Caution in using
concomitant drugs such as beta-blockers (ophthalmic and
systemic), anti-hypertensives and/or cardiac glycosides is advised.
Tricyclic antidepressants have been reported to blunt the
hypotensive effect of systemic clonidine. It is not known
whether the concurrent use of these agents with Brimonidine
The safety and effectiveness of brimonidine tartrate ophthalmic

solution have not been studied in pediatric patients below the
age of 2 years. Brimonidine tartrate ophthalmic solution is not
recommended for use in pediatric patients under the age of 2
years. (Also refer to ADVERSE REACTIONS section.)
Geriatric Use:
No overall differences in safety or effectiveness have been
observed between elderly and other adult patients.
ADVERSE REACTIONS
Adverse events occurring in approximately 10-20% of the subjects
included: allergic conjunctivitis, conjunctival hyperemia, and eye pruritis.
Adverse events occurring in approximately 5-9% of the subjects
included: burning sensation, conjunctival folliculosis, hypertension,
ocular allergic reaction, oral dryness, and visual disturbance.
Events occurring in approximately 1-4% of subjects included:
allergic reaction, arthralgia, arthritis, asthenia, blepharitis,
blepharoconjunctivitis, blurred vision, bronchitis, cataract, chest
pain, conjunctival edema, conjunctival hemorrhage, conjunctivitis,
cough, dizziness, diabetes mellitus, dyspepsia, dyspnea,
epiphora, eye discharge, eye dryness, eye irritation, eye pain,
eyelid edema, eyelid erythema, fatigue, flu syndrome, follicular
conjunctivitis, foreign body sensation, gastrointestinal disorder,
headache, hypercholesterolemia, hypotension, infection, insomnia,
joint disorder, keratitis, lid disorder, osteoporosis, pharyngitis,
photophobia, rash, rhinitis, sinus infection, sinusitis, somnolence,
stinging, superficial punctate keratopathy, tearing, visual field
defect, vitreous detachment, vitreous disorder, vitreous floaters,
and worsened visual acuity.
The following events were reported in less than 1% of subjects:
corneal erosion, nasal dryness, and taste perversion.
The following events have been identified during post-marketing
use of brimonidine tartrate ophthalmic solutions in clinical practice.
Because they are reported voluntarily from a population of unknown
size, estimates of frequency cannot be made. The events, which have
been chosen for inclusion due to either their seriousness, frequency
of reporting, possible causal connection to brimonidine tartrate
ophthalmic solutions, or a combination of these factors, include:
bradycardia; iritis; miosis; skin reactions (including erythema, eyelid
pruritis, rash, and vasodilation); and tachycardia. Apnea, bradycardia,
hypotension, hypothermia, hypotonia, and somnolence have been
reported in infants receiving brimonidine tartrate ophthalmic solutions.
OVERDOSAGE
No information is available on overdosage in humans. Treatment of
an oral overdose includes supportive and symptomatic therapy; a
patent airway should be maintained.
Tartrate Ophthalmic Solution, 0.15% in humans can interfere

with its IOP-lowering effect. No data on the level of circulating
catecholamines after Brimonidine Tartrate Ophthalmic Solution,
0.15% administration are available. Caution, however, is advised
in patients taking tricyclic antidepressants, which can affect the
metabolism and uptake of circulating amines.
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
No compound-related carcinogenic effects were observed in
either mice or rats following a 21-month and a 24-month study,
respectively. In these studies, dietary administration of brimonidine
tartrate at doses up to 2.5 mg/kg/day in mice and 1.0 mg/kg/
day in rats achieved 60 and 50 times, respectively, the plasma
drug concentration estimated in humans treated with one drop of
Brimonidine Tartrate Ophthalmic Solution, 0.15% into both eyes.
Brimonidine tartrate was not mutagenic or cytogenic in a series of
in vitro and in vivo studies including the Ames test, chromosomal
aberration assay in Chinese hamster ovary (CHO) cells, a host-mediated
assay and cytogenic studies in mice, and dominant lethal assay.
Pregnancy: Teratogenic Effects: Pregnancy Category: B
Reproductive studies performed in rats and rabbits with oral doses
of 0.66 mg base/kg revealed no evidence of harm to the fetus due
to Brimonidine Tartrate Ophthalmic Solution, 0.15%. Dosing at this
level produced an exposure in rats and rabbits that is 80 and 40
times higher than the exposure seen in humans, respectively.
There are no adequate and well-controlled studies in pregnant
women. In animal studies, brimonidine crossed the placenta and
entered into the fetal circulation to a limited extent. Brimonidine
Tartrate Ophthalmic Solution, 0.15% should be used during
pregnancy only if the potential benefit to the mother justifies the
potential risk to the fetus.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. In
animal studies, brimonidine tartrate was excreted in breast milk.
A decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the
drug to the mother.
Pediatric Use:
In a well-controlled clinical study conducted in pediatric glaucoma
patients (ages 2 to 7 years) the most commonly observed adverse
events with brimonidine tartrate ophthalmic solution 0.2% dosed
three-times-daily were somnolence (50%-83% in patients ages 2
to 6 years) and decreased alertness. In pediatric patients 7 years of
age or older (>20 kg), somnolence appears to occur less frequently
(25%). Approximately 16% of patients on brimonidine tartrate
ophthalmic solution discontinued from the study due to somnolence.
KAPOSIS SARCOMA: PROGNOSIS VARIES WITH FORM

CT is negative in patients with
gastrointestinal or pulmonary
symptoms, a gastrointestinal
endoscopy or bronchoscopy
should be considered.3,4
ment.3 Treatment for KS does not

improve survival from AIDS itself;
prognosis depends on the patients
immune status and viral load.3
Indolent Lesions: Often, no treat-
Characteristics of KS in Seniors
The onset of KS in the elderly is
often subtle and, as previously
mentioned, with a predisposition
to American men of Italian, Jewish, and Eastern European ancestry.4,6 Cutaneous patches and papules are violaceous and present on
the lower extremities; lesions of
the gastrointestinal tract often
require endoscopy for visualization. KS in the elderly is often
associated with diabetes mellitus
and an increased incidence of
lymphoma.6
Treatment
Lesions may return after treat-
ment is necessary for indolent

(slow growing and causing little
pain) lesions; excision, cryotherapy, or electrocoagulation may be
used for treatment of one or a few
superficial lesions.4 Also useful is
intralesional vinblastine (intravenous use only; dose adjusted based
on clinical response) or interferonalfa (e.g., for AIDS-associated KS,
interferon-alfa- 2b 30 million
units/m2 SC/IM 3 times per week;
dosage is decreased by 50% or discontinued if not tolerated).4,8,9
Radiation therapy is utilized for
more extensive disease, such as the
treatment of multiple lesions and
lymph node disease.4
AIDS-Related KS: Antiretrovirals

provide the best treatment for
AIDS-associated KS, as this condition responds markedly to highly
active antiretroviral therapy
(HAART).4 In AIDS-associated KS,
patients with indolent disease and
CD4 counts greater than 150/L
and HIV RNA less than 500 copies/mL can be treated with intravenous interferon-alfa (see above).4
Liposomal doxorubicin (e.g., 20
mg/m2 intravenously every 3 weeks)
can be administered to patients with
more extensive or visceral disease;
paclitaxel (e.g., 100 mg/m2 intravenously every 2 weeks) may be used
if doxorubicin fails.4,9 Investigations
continue regarding adjunct agents.
Iatrogenic KS: While not always
possible, the best treatment
response for iatrogenic KS is the
discontinuation of immunosup-
22
20 Senior Care 3_30sc.indd 22
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KAPOSIS SARCOMA: PROGNOSIS VARIES WITH FORM

Table 1. Types of Kaposis Sarcoma
Type
General Features
Prognosis
Comments
Indolent ; usually not fatal
Disease of the middle-aged and

elderly; most often in men >60
years old of Italian, Jewish, or
Eastern European ancestry.
AIDS-associated Multiple skin lesions often of

(epidemic)
the face and trunk; mucosal,
GI, and lymph node involvement;
most patients develop disseminated
disease; pleuropulmonary KS,
usually late in the course, is an
ominous sign
Fulminantb; HAART has led to increased

survival; treatment of KS does not
improve survival from AIDS itself;
prognosis depends on the patients
immune status and viral loadmost
patients succumb to opportunistic
infectious complications of AIDS rather
than consequences of KS
KS can be the first manifestation of

AIDS and is the most common
AIDS-associated malignancy; about
95% of all cases in the U.S.
diagnosed in homosexual or
bisexual men
Endemic
Occurs in Africa independent of HIV

infection; peaks in prepubescence
(see lymphadenopathic type below)
and adulthood (resembling classic
KS; see above)
Prepubertal form is more aggressive

and usually fatal; adult form
resembles classic KS (see above).
See lymphadenopathic type, below
Iatrogenic
(immunosuppressive
treatment
related)
Develops several years after organ

transplantation (e.g., especially
kidney); often remains localized to
skin; widespread dissemination with
mucocutaneous or visceral organ
involvement common
Dependent on degree of immunosuppression: more or less fulminantb

(complicated clinical management
requires a balance between risk of
death from generalized KS, risk of
graft rejection, and complications of
renal failure upon discontinuation
of immunosuppressant)
Incidence of KS in immunosuppressed renal transplant recipients

is 150-200 times the expected
incidence of KS in the general population; average time to develop KS
posttransplantation is 16 months
Lymphadenopathic
Predominantly affects children with

primary tumors involving lymph
nodes and visceral organs; with or
without skin lesions
Fulminantb and fatal
Most common in endemic KS
Classic
Small number of skin lesions on

lower extremities; lesions frequently
remain asymptomatic; visceral
involvement occurs in <10%
Causing little pain and slow growing.

Occurs suddenly with great intensity, spreads rapidly, and is invasive.
HAART: highly active antiretroviral therapy; KS: Kaposis sarcoma.
Source: References 2-4 ,6, 10, 11.
b
pressants.4 A reduction of KS
lesions has been seen in organ
transplant patients when the
immunosuppressant dosage is
reduced; for patients who are
unable to tolerate such a reduction,
experts recommend local and systemic therapies used in the other
types of KS.4
Conclusion
Kaposis sarcoma is associated with
infection by human herpesvirus
type 8, which has been identified
in KS tissue biopsies in patients
with all forms of the disease. Pharmacists should be aware of the
clinical manifestations and course
of KS and how they differ dramat-
REFERENCES
1. Dorlands Pocket Medical Dictionary. 28th ed. Philadelphia, PA: Elsevier Saunders; 2009:743.
2. General Information About Kaposi Sarcoma. National
Cancer Institute. U.S. National Institutes of Health
[updated September 1, 2009.] www.cancer.gov/cancertopics/
pdq/treatment/kaposis/HealthProfessional/page2. Accessed
March 15, 2010.
3. Kaposis Sarcoma. MedlinePlus. National Library of Medicine. National Institutes of Health. Updated September 28,
2008. www.nlm.nih.gov/medlineplus/ency/article/000661.
htm. Accessed March 15, 2010.
4. Beers MH, Porter RS, Jones TV, et al. The Merck Manual
of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ:

Merck Research Laboratories; 2006:1024-1025.
5. Johnson HJ, Schonder KS. Solid organ transplantations.
In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York, NY:
McGraw-Hill Inc; 2005:1613-1643.
6. Schwartz RA, Cohen PJ. Kaposis sarcoma. In: Newcomer
VD, Young EM Jr, eds. Geriatric Dermatology: Clinical
Diagnosis and Practical Therapy. New York, NY: IgakuShoin; 1989:645-652.
7. Samuelson J. Infectious diseases. In: Cotran RS, Kumar
V, Collins T, eds. Robbins Pathologic Basis of Disease, 6th ed.
Philadelphia, PA: WB Saunders Company; 1999:361.
ically depending on the particular

form of the disease. KS may also
be discovered in senior men as an
incidental finding.
Note: Refer to individual drug
product labeling for FDA-approved
status and individualized dosing
guidelines.
8. Howland RD, Mycek MJ. Pharmacology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:436,471472,483.
9. Epocrates Rx. Version 9.0. San Mateo, CA: Epocrates, Inc.
www.epocrates.com. Accessed March 28, 2010.
10. Schoen FJ, Cotran RS. Blood vessels. In: Cotran RS,
Kumar V, Collins T, eds. Robbins Pathologic Basis of Disease,
6th ed. Philadelphia, PA: WB Saunders Company;
1999:535-537.
11. Volberding PA. Hematology and oncology in patients
with human immunodeficiency virus infection. In: Goldman L, Ausiello D, eds. Cecil Medicine. 23rd ed. Philadelphia, PA: Saunders Elsevier; 2007:chap416.
23
20 REVSenior Care 3_30sc.indd 23
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TrendWatch
Visual Impairment in Adults
Types of Vision Problems: Refractive errors, the most common eye

problem in a persons 40s, can be
corrected with eyeglasses, contact
lenses, or surgery. Myopia is the
most prevalent condition (33.1%)
in this age group, whereas hyperopia is the most prevalent among
people older than 60 years. The
National Eye Institute found that
the prevalence of myopia
increased 66% between 1971
1972 and 19992004. Refractive
correction could improve vision
in 11 million Americans aged 12
years and older.
By age 80, more than half of
Americans have a cataract or have
Professor of Pharmacy
Administration, College of
Pharmacy & Allied Health
Professions, St. Johns University,
Jamaica, New York
Comorbid Conditions Among Visually Impaired People Aged 65 years

Skeletal
system 18%
Severe
condition 2%
Cardiovascular
system 17%
Mental
health 29%
Auditory
system 15%
Circulatory
system 11%
Mild
condition
16%
Nonrisky
condition
11%
Cerebrovascular
system 4%
THINKSTOCK
isual impairment is among

the top 10 disabilities in
people older than 70 years.
Blindness or low vision affected
more than 3.3 million people aged
40 years and older, and the Centers for Disease Control and Prevention (CDC) predicts this number to double by 2030. The
leading causes of low vision are
age-related macular degeneration
(AMD), cataract, diabetic retinopathy (DR), and glaucoma. AMD,
which affects 1.8 million people,
will affect an estimated 2.95 million by 2020, and another 7.3
million are at substantial risk for
developing it. Although 61 million
adults are at high risk for serious
vision loss, only half have visited
an eye doctor.
Endocrine
system 6%
had a cataract removed. Roughly

1.35 million cataract operations
are performed annually, at a cost
of $3.5 billion. Healthy People
2010 (HP2010) has set a goal of
reducing cataract prevalence from
118.8 per 1,000 persons (in
2002) to 91.4.
People with diabetes are at risk
for developing DR. While the
prevalence of DR is lowest among
those with type 1 diabetes, the
rate increases with age for diabetic patients older than 40 years.
HP2010 aims to reduce the number of adults with DR from 45.9
per 1,000 (in 2002) to 40.9. An
estimated 4.1 million and
899,000 Americans, respectively,
are affected by retinopathy and
vision-threatening retinopathy.
Comorbid Conditions: A 2006
CDC study (Crews et al) revealed

that 5.7 million people aged 65
years and older reported vision
loss and were more likely than
people without vision loss to

experience comorbid chronic conditions. The number of older
people with vision loss and
comorbid conditions is sizable:
1.2 million experience vision loss
and diabetes; 3 million have compromised hearing and vision; 3
million have vision loss and mildto-moderate depression; 350,000
experience vision loss and severe
depression; and nearly 900,000
have stroke and vision loss.
Consequences: Vision loss
exacts a heavy toll from millions
of people, including significant
suffering, disability, loss of productivity, and diminished quality
of life. More than 70% of CDC
survey respondents indicated
that loss of eyesight would have
the greatest impact on their dayto-day life; however, fewer than
11% of respondents knew that
there are no early warning signs
for glaucoma or DR.
24
24 Trendwatch 3_30sc.indd 24
3/31/10 1:41 PM
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ge-related macular degeneration (AMD) is the

most common cause of blindness in the developed world.1-3 In this disease, the photoreceptors
of the macula (the central retina) become damaged and
die.3 AMD results in central vision loss and is responsible for one-third of all forms of untreatable loss of
vision.4 An estimated 9 million older Americans have
some form of AMD, and about 1.75 million have
advanced AMD.5,6 AMD is a disease of the elderly, and
evidence suggests that 10% of individuals aged 65 to
74 years and 30% of those aged 75 to 85 years have
evidence of AMD.5 AMD is a gradual, painless, irreversible process in which the patient loses bilateral vision.1,7
AMD starts with deposits of lipid material that
accumulate under the retinal pigment epithelium
(RPE). These deposits, which appear as pale yellow
spots on the retina, are called drusen.8 With increasing
age, the RPE cells, which form the bloodretinal barrier, become less efficient and the retina is no longer
able to receive the proper nutrition. This decline in
the efficiency of the RPE cells also results in the
accumulation of waste products (drusen).3 However,
most people with evidence of drusen deposits maintain
good vision.5
BSIP / PHOTO RESEARCHERS, INC
Age-Related
Macular
Degeneration
involve atrophy of the macula (which occurs in dry

AMD) or growth of new blood vessels under the retina
and pigment epithelium (which occurs in wet AMD).4
Dry AMD
Dry AMD is also called geographical atrophy.1 In the
dry form, there is no abnormal vascularization in the
subretinal space, and therefore there is no exudate.2,7
Drusen deposits are clustered on the macula, and these
become larger and more numerous over time. Eventually, the RPE becomes detached and atrophies. This
results in a loss of vision due to the interference of
photoreceptor function.7 There is no treatment for
dry AMD.4
The most common symptom of dry AMD is blurred
vision, which may go away in bright light. Patients may
experience difficulty with reading or recognizing faces.
There may also be a blind spot in the middle of their
field of vision. The blind spot may be small initially,
but it can grow over time.10
Wet AMD
Wet AMD, also known as choroidal neovascularization
(CNV), is less prevalent.1,7 Only about 10% of cases
of AMD are the neovascular form; however, 80% to
TYPES OF AMD
90% of patients with severe vision loss secondary to
There are two forms of advanced AMD: dry (atrophic) AMD have neovascular AMD.9,11 The neovascular form
and wet (exudative).2 The dry form is more common, involves angiogenesis and inflammation.11 Blood vessels
but the vision loss is more severe with the wet form.9 grow from the choroid through defects in Bruchs
It is thought that inflammation may
membrane underneath the retina and
Suzanne Albrecht, PharmD, MSLIS
play an important role in both forms
pigment epithelium.2,7 These new,
Freelance Medical Writer
4,7
Woodstock, Illinois
of AMD. The late stages of AMD
immature blood vessels leak lipids
26
26 MacularDegen 3_26mb.indd 26
3/31/10 1:41 PM
AGE-RELATED MACULAR DEGENERATION

and blood, causing elevation of the retina and pigment exposure, and obesity.1,5 Patients with a high body mass
epithelium.7 Irreversible damage occurs, resulting in index (BMI) are twice as likely to develop AMD as
the blurring and distortion of vision.7,11 With repeated patients with a healthy body weight.1
There is some evidence that exposure to Chlamydia
bleeding under the retina, there is permanent loss of
central vision.7 Mast cells, macrophages, and lympho- pneumoniae is associated with the development and
cytes have been found in the areas of disruption in progression of AMD.4 C pneumoniae DNA has been
Bruchs membrane, the CNV tissue, and the atrophied found in the neovascular tissue of AMD-affected eyes.4
pigment epithelium. This observation strengthens the The Cardiovascular Health and Age-Related Macupostulation that inflammation is a factor in the devel- lopathy study examined the association between AMD
and C pneumoniae exposure.4 The
opment of AMD.12
Neovascular AMD may be charinvestigators collected serum from
Table 1.
acterized as either occult or classic,
254 study participants with features
Risk Factors for AMD
based on the appearance of the CNV
of early AMD (intermediate drusen,
Older age
on fluorescein angiography. Occult
soft drusen, and pigment epithelium
Smoking
CNV is usually limited to the space
abnormalities) and quantified the
Family history
beneath the RPE, and the degree
titers of antibodies against C pneuGender (female)
of vision loss is usually mild commoniae using enzyme-linked immuObesity
pared with classic CNV. Classic
nosorbent assay. They found that
Excessive sunlight exposure
CNV often penetrates the pigment
the progression rate of AMD over
Cardiovascular disease
epithelium and grows into the suba 7-year period was greater in
Atherosclerosis
retinal space.13
patients with higher C pneumoniae
Hypertension
The symptoms of neovascular
antibody titers. This observation
Dyslipidemia
Oxidative
stress
AMD are usually gradual, but acute
held true even after differences in
Infectious agents
vision loss may result from bleedage, smoking status, family history,
ing of the subretinal CNV.7 Sympand history of heart attack, stroke,
toms of neovascular AMD include
and/or hypertension were controlled
4
a blind spot and a distortion of vision that makes for. However, in a later cohort study, the investigators
straight lines appear crooked.9,10 One or both eyes failed to find an association between C pneumoniae and
may be affected, at the same time or sequentially.9 early AMD. The study was not powerful enough to
Symptoms may develop gradually and not be noticed determine whether there was an association between C
at first, or the patient may experience difficulty with pneumoniae and late AMD.12
A different study exploring the relationship between
normal activities such as reading, watching television,
C pneumoniae and AMD was conducted. Genomic
recognizing faces, or driving.9
DNA was extracted from the peripheral blood of 148
RISK FACTORS
subjects with advanced AMD and 162 controls. The
The cause of AMD is unknown, but there are factors researchers found that prior infection with C pneumoniae
that increase the likelihood of developing the disease was associated with an increased risk of AMD.14
(TABLE 1).2 Smoking is the only proven modifiable risk
factor.1-4 Smokers are twice as likely as nonsmokers to TREATMENT
develop AMD.1 High blood levels of homocysteine have There is no treatment for the dry form of AMD or the
been associated with a higher risk of developing AMD.6 early stages of neovascular AMD.1,4,6 All FDA-approved
Elevated homocysteine levels may be another modifiable treatment modalities for the neovascular form of AMD
risk factor, but this has not been clinically proven. Older target CNV.
age and family history are known risk factors.1,3,4,14
Individuals with a family history of AMD are four times Photodynamic Therapy (PDT)
more likely to develop the disease than those with a PDT is used to treat predominantly classic subfoveal
CNV, but only about a third of patients with neovasnegative family history.5
Women seem to be more likely to develop AMD cular AMD have the classic form.9 PDT involves injectthan men.3 AMD has been associated with cardiovas- ing a photosensitizing drug intravenously. This drug,
cular disease and atherosclerosis and their risk factors called verteporfin (Visudyne, QLT), was approved by
(hypertension and dyslipidemia).1,4,5 Other risk factors the FDA in 2006.15 Verteporfin has a high affinity for
for AMD include oxidative stress, excessive sunlight CNV.9 A low-energy laser is focused on the CNV, which
29
26 REVMacularDegen 3_26mb.indd 29
4/1/10 1:07 PM

activates the dye.16 The laser is then used to occlude
the CNV vessels. This procedure causes little to no
persistent short-term damage to the adjacent CNV or
to the retina.9 More than 90% of patients who undergo
PDT require retreatment after 3 months, and most
patients need multiple treatments during the first year.9
of VEGF-A, and it is used off-label to treat wet AMD

and macular edema. The agent is administered intravitreously, and in several uncontrolled studies it has
been shown to be safe and effective against wet AMD.
It is less expensive than ranibizumab and is often used
as an alternative when cost is an issue.11
Antiangiogenic Therapy
Unlike PDT, which destroys existing CNV, antiangiogenic therapy prevents further neovascularization. 9
Angiogenesis is the formation of new blood vessels. It is
a complex process and requires interactions between
various factors, some of which are inhibitory and some
of which are stimulatory. Antiangiogenic therapy works
by either promoting inhibitory factors or blocking
stimulatory factors.9 Vascular endothelial growth factor
(VEGF) stimulates the formation of endothelial blood
vessels; it also increases the permeability of CNV and
acts as a vasodilator.11,16 There are many isoforms of
VEGF, but VEGF-A121 and VEGF-A165 are the most
prevalent in the retina.11 Moieties that inhibit VEGF
prevent the growth of these vessels.9 The three FDAapproved anti-VEGF agents used in the United States
are pegaptanib (Macugen, Eyetech), bevacizumab (Avastin, Genentech), and ranibizumab (Lucentis, Genentech).
Ranibizumab: This agent, another monoclonal antibody,
Pegaptanib: This agent, which has been proven to

reduce vision loss, was approved by the FDA in 2004.9
An RNA aptamer, pegaptanib binds to the VEGF-A165
isoform, which is the most predominant isoform found
in the CNV.11 It is injected into the vitreous every 6
weeks.17 The most common adverse events reported
with the use of pegaptanib 0.3 mg for up to 2 years
are anterior chamber inflammation, blurred vision,
cataract, conjunctival hemorrhage, corneal edema, eye
discharge, eye irritation, eye pain, increased intraocular pressure, punctate keratitis (corneal inflammation),
reduced visual acuity (VA), visual disturbances, vitreous floaters, and vitreous opacities. These events occurred
in approximately 10% to 40% of patients.17 The most
serious adverse events are endophthalmitis (inflammation of the ocular cavities), traumatic injury to the
lens, and retinal detachment.11
Bevacizumab: Bevacizumab is a monoclonal antibody
that is three times as large as ranibizumab. Approved
in 2004 for the treatment of metastatic colon cancer,
it has since been approved, as monotherapy or in combination with other agents, for the treatment of nonsquamous nonsmall cell lung cancer, metastatic breast
cancer, glioblastoma, and metastatic renal cell carcinoma.11,18 Bevacizumab inhibits all of the known isoforms
was approved in 2006 for the treatment of wet AMD

and is active against all forms of VEGF-A.11 The recommended dose is 0.5 mg injected intravitreously once a
month; however, the dosing interval may be increased
to once every 3 months after the first four injections.
The longer dosing interval is not as effective as the
monthly interval, but it may be necessary if cost is
prohibitive or if monthly injections are not tolerated.19
More than one-third of patients using ranibizumab have
experienced improvement of vision, and vision loss has
been prevented in 95% of patients using ranibizumab
over a 2-year period.20 No other treatment for AMD
has come close to this success, with the possible exception of bevacizumab.16
The ANCHOR study was a multicenter (83 sites),
double-blind, active-treatment, controlled, phase III
trial comparing the efficacy and adverse-event profile
of ranibizumab versus PDT in treating patients with
predominantly classic subfoveal CNV.13 At least 50%
of a patients lesions had to be the classic type, and only
one eye per patient was treated. Patients received either
verteporfin PDT and a sham injection or sham verteporfin PDT and a monthly intravitreous injection of
ranibizumab (either 0.3 mg or 0.5 mg). In the activePDT arm, 110 patients completed the study; active
ranibizumab treatment was completed by 117 patients
and 116 patients, respectively, receiving 0.3 mg or 0.5
mg. CNV lesions were examined by fluorescein angiography every 3 months. VA was measured at baseline,
12 months, and 24 months with Early Treatment Diabetic Study charts at a starting distance of 2 m and
using standardized refraction.
Ranibizumabs superiority over PDT was evident at
1 month.13 At 24 months, 90.0% of patients in the
0.3-mg ranibizumab group and 89.9% of patients in
the 0.5-mg ranibizumab group had lost <15 letters from
baseline VA, whereas only 65.7% of PTD patients lost
<15 letters. Furthermore, a gain of 15 letters was
observed in 34.3% of the 0.3-mg ranibizumab group
and 41.0% of the 0.5-mg ranibizumab group. Only
6.3% of PDT patients gained 15 letters. At 24 months,
60.8% of PDT patients versus 22.9% of the 0.3-mg
ranibizumab group and 20% of the 0.5-mg ranibizumab
group demonstrated a VA Snellen equivalent of 20/200
30
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Based on these results, the AREDS research group
suggests that everyone over 55 years of age should
have dilated eye examinations. Patients with extensive
intermediate-size drusen, 1 large druse, noncentral
geographical atrophy in one or both eyes, or advanced
AMD or vision loss secondary to AMD should consider
taking the antioxidants-plus-zinc formulation used in
this study. This recommendation excludes individuals
with contraindications such as smoking.21 Bausch &
Lomb, which collaborated in AREDS, currently marANTIOXIDANTS
kets PreserVision, a supplement based on the formula
Because oxidative stress is thought be involved in the used in the AREDS.22
Other natural supplements, including lutein and
development of AMD, many studies have been conducted to assess the role antioxidants may play in the zeaxanthin, have shown some evidence of reducing
prevention or treatment of AMD.2 The Age-Related the risk of AMD development.3 One study suggested
Eye Disease Study (AREDS), a
a 35% to 40% decrease in the
landmark study sponsored by the
risk of developing AMD in women
National Eye Institute, was a mulaged 40 years and older who
The most common
ticenter (11 sites), longitudinal,
supplemented their diet with folic
symptom of dry
double-blind, placebo-controlled,
acid (2.5 mg/day), pyridoxine
clinical trial examining the effect
(50 mg/day), and cyanocobalamin
AMD is blurred
of high doses of vitamins C and
(1 mg/day).6
vision. Patients may
E, beta carotene, and zinc on the
21
progression of AMD. Patients
have trouble reading CONCLUSION
AMD, which affects primarily older
had to have extensive small, intermediate, or large drusen, noncenor recognizing faces, people, is a debilitating disease that
can lead to blindness. The only
tral geographical atrophy, or pigand there may be
proven modifiable risk factor for
ment abnormalities in one or both
developing AMD is smoking, but
eyes or advanced AMD or vision
a blind spot in the
other factors, such as genetics,
loss secondary to AMD in one
middle
of
their
elevated BMI, presence of cardioeye. Patients, aged 55 to 80 years,
vascular disease, hypertension,
were randomized to receive a daily
visual field.
female gender, and exposure to
oral dose of (1) the antioxidants
certain infectious agents, also may
vitamin C (500 mg), vitamin E
(400 IU), and beta carotene (15 mg); (2) zinc (80 mg increase the risk. Currently, only wet AMD is treatable.
zinc oxide) and copper (2 mg cupric oxide); (3) anti- PDT and antiangiogenic pharmaceuticals are the only
oxidants plus zinc; or (4) placebo. Primary outcomes options available at present, but there are other comwere progression to advanced AMD and VA loss of pounds in the drug-development pipeline that may aid
15 letters. Patients were assigned to one of four AMD in the battle against AMD.10 PreserVision, a Bausch &
categories based on the size and extent of drusen and Lomb product, is based on the supplement formulation
RPE abnormalities in each eye, the presence of advanced used in the AREDS.
Since endophthalmitis may develop following
AMD, and VA, with category 1 being least severe and
antiangiogenic therapy, the pharmacist should instruct
category 4 being most severe.
The risk of progression to advanced AMD in AMD these patients to contact their ophthalmologist immecategories 3 and 4 was reduced by 17% in patients diately if they notice eye redness or pain, sensitivity
taking only antioxidants, 21% in patients taking only to light, or vision changes.17,19 The pharmacist should
zinc, and 25% in patients taking both antioxidants and advise patients who have just undergone PDT that
zinc.21 There were too few cases of advanced AMD in they will experience temporary sensitivity to light.
category 2 to assess whether treatment affected progres- For 5 days, patients should avoid exposing unprotected
sion of AMD in that category. Only category 3 and 4 skin to direct sunlight and bright indoor light, includpatients in the antioxidants-plus-zinc arm had a reducing tanning salons, bright halogen lighting, and
tion in VA loss of 15 letters (27%; P = .008).
high-power lighting such as that used in operating
(P <.0001). At 24 months, severe vision loss (loss of
30 letters) was apparent in only 1.4% of the 0.3-mg
ranibizumab group and in none of the 0.5-mg ranibizumab group versus 16.1% of PDT patients.
No other treatment to date has been able to improve
VA as well as preserve it. Serious adverse events have
occurred in less than 0.1% of patients and include
retinal detachment, endophthalmitis, and iatrogenic
traumatic cataracts.19
32
3/31/10 1:41 PM

rooms or dental offices. During the first 5 days,
patients should wear dark glasses and protective
clothing. Ultraviolet sunscreens are not effective
protection because photoactivation of verteporfin in
the skin can be caused by visible light. Patients should
be instructed not to stay in the dark, but rather to
expose their skin to indoor light; this will help inacREFERENCES
1. Baird PN, Hageman GS, Guymer Franzco RH. New era for personalized medicine: the diagnosis and management of age-related macular degeneration. Clin Experiment Ophthalmol.
2009;37:814-821.
2. Katzung BG. Special aspects of geriatric pharmacology. In: Katzung BG, Masters SB, Trevor AJ,
eds. Basic and Clinical Pharmacology. 11th ed. New York, NY: McGraw-Hill Medical; 2009:
1037-1045.
3. Carpentier S, Knaus M, Suh M. Associations between lutein, zeaxanthin, and age-related macular degeneration: an overview. Crit Rev Food Sci Nutr. 2009;49:313-326.
4. Robman L, Mahdi O, McCarty C, Dimitrov P, et al. Exposure to Chlamydia pneumoniae
infection and progression of age-related macular degeneration. Am J Epidemiol. 2005;161:
1013-1019.
5. Phillips CO, Higginbotham EJ. Multivitamin supplements, ageing, and loss of vision: seeing
through the shadows. Arch Intern Med. 2009;169:1180-1182.
6. Christen WG, Glynn RJ, Chew EY, et al. Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Womens Antioxidant and
Folic Acid Cardiovascular Study. Arch Intern Med. 2009;169:335-341.
7. Horton JC. Disorders of the eye. In: Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrisons
Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Medical; 2008.
8. Evans JR, Henshaw KS. Antioxidant vitamin and mineral supplements for preventing agerelated macular degeneration. Cochrane Database Syst Rev. 2008;(1):CD000253.
9. Vedula SS, Krzystolik MG. Antiangiogenic therapy with anti-vascular endothelial growth factor
modalities for neovascular age-related macular degeneration. Cochrane Database Syst Rev.
2008;(2):CD005139.
10. National Eye Institute. Facts about age-related macular degeneration. www.nei.nih.gov/health/
maculardegen/armd_facts.asp#1c. Accessed February 18, 2010.
11. Ni Z, Hui P. Emerging pharmacologic therapies for wet age-related macular degeneration.
Ophthalmologica. 2009;223:401-410.
tivate the drug through photobleaching.23

The pharmacist is in a key position to counsel
patients about risk factors for AMD. In addition,
the pharmacist can be a valuable resource for informing patients about the symptoms of AMD and the
utility of antioxidants plus zinc for reducing their
risk of developing advanced AMD.
12. Robman L, Mahdi OS, Wang JJ, et al. Exposure to Chlamydia pneumoniae infection and agerelated macular degeneration: the Blue Mountains Eye Study. Invest Ophthalmol Vis Sci.
2007;48:4007-4011.
13. Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two year results of the ANCHOR study.
Ophthalmology. 2009;116:57-65.
14. Shen D, Tuo J, Patel M, et al. Chlamydia pneumoniae infection, complement factor H variants, and age-related macular degeneration. Br J Ophthalmol. 2009;93:405-408.
15. Visudyne.com. Welcome to the Visudyne AMD resource center. www.visudyne.com.
Accessed January 30, 2010.
16. Bressler NM. Antiangiogenic approaches to age-related macular degeneration today. Ophthalmology. 2009;116(suppl 10):S15-S23.
17. Macugen (pegaptanib sodium injection) package insert. Cedar Knolls, NJ: Eyetech Inc; August
2008.
18. Avastin (bevacizumab) package insert. South San Francisco, CA: Genentech Inc; July 2009.
19. Lucentis (ranibizumab injection) package insert. South San Francisco, CA: Genentech Inc;
April 2008.
20. Do DV. Antiangiogenic approaches to age-related macular degeneration in the future. Ophthalmology. 2009;116(suppl 10):S24-S26.
21. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical
trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related
macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119:
1417-1436.
22. Bausch & Lomb. PreserVision Eye Vitamin AREDS Soft Gel formula.
www.bausch.com/en_US/consumer/visioncare/product/vitamins/preservision_softgel.aspx. Accessed
February 17, 2010.
23. Visudyne (verteporfin for injection) package insert. Vancouver, Canada: QLT Inc; January
2010.
Want
Fast
Cold Sore Healing?

Recommend
The Abreva Dierence.

Its one thing for an OTC cold sore remedy to say it
heals fast. Being able to back it up is quite another.
Only Abreva is FDA-approved to shorten healing time.
infected cells
Only Abreva has a unique Viral Entry Blocking mode-of-action. 2

Only Abreva inhibits the virus from entering healthy cells.
The virus needs to enter a cell to reproduce. 2*
pro
p
rotec
tected
ted
ed cells
cceells
lls
protected
#1 pharmacist recommended.
3,4
Early treatment with Abreva ensures best results. If a cold sore lasts for more than 10 days, you should
encourage your patient to see their physician.
Speed healing. Recommend Abreva.
* Based on laboratory studies (1) Sacks SL et al. Clinical efcacy of topical docosanol 10% cream for
herpes simplex labialis: a multicenter, randomized, placebo-controlled trial. J Am Acad Dermatol. 2001;
45:222-230. (2) Pope LE et al. Anti-herpes simplex virus activity of n-docosanol correlates with intracellular
metabolic conversion of the drug. Jnl Lipid Research V27, Issue 10, 1996: 2167-2178. (3) Pharmacy
Times OTC Recommendation Survey 2009 (4) Pharmacy Today Annual OTC Product Survey 2010
For more information visit www.abrevapharmacist.com
2010 GlaxoSmithKline
Consumer Healthcare
3/31/10 1:41 PM
Treatment
Options for
Dry Eye
Disease
THINKSTOCK
ry eye disease (DED), also known as keratoconjunctivitis sicca, is a common ophthalmologic

disorder experienced by many people and can
be a reason for pharmacist consultation.1 It is a condition that can adversely affect a patients quality of life,
impacting daily activities such as reading, using a computer, driving, and watching television.2 The prevalence
of DED varies, but it has been estimated to affect up
to 33% of the population, although this number may
be underreported.1,3
In 2007, the International Dry Eye Workshop (DEWS)
acknowledged the multifactorial nature of the disease
and defined DED as a multifactorial disease of the tears
and ocular surface that results in symptoms of discomfort,
visual disturbance, and tear film instability with potential
damage to the ocular surface. It is accompanied by
increased osmolarity of the tear fill and inflammation of
the ocular surface.4
lid/globe incongruity, and decreased blink rate. Extrinsic

causes include ocular surface disorders due to vitamin A
deficiency, use of topical anesthetics and preservatives,
contact lens wear, and allergic conjunctivitis.4 TABLE 1
lists risk factors associated with DED.1,5,6
Symptoms
Patients with DED typically experience ocular discomfort,
photosensitivity, and blurry vision. Ocular discomfort is
described as a dry, scratchy, gritty, or sandy feeling, as
well as foreign body sensations, irritation, soreness or
pain, burning, itching, and ocular fatigue. Patients may
also complain about mucous discharge, contact lens
intolerance, and red eyes. Initially, patients may present
with excessive tearing due to corneal irritation, causing
reflex tearing.6,7 The onset of symptoms is usually gradual, bilateral, and chronic; symptoms typically become
more bothersome later in the day and are intensified by
various environmental factors (TABLE 1).6
Etiology
The DEWS recommendations classified the etiology of Diagnosis
DED into two categories: aqueous tear-deficient and DED may be diagnosed by an eye care professional,
although the diagnosis may be challenging due to the
evaporative.4
Aqueous tear-deficient dry eye is due to decreased lack of uniform criteria.6,8,9
A combination of tests, both subjective and objective,
volume and production of tears. This may be caused by
Sjgrens syndrome or stem from non-Sjgrens causes. are used in the evaluation of DED. Objective clinical
Sjgrens syndrome, an autoimmune disease, attacks the measures include assessing tear film instability, ocular
lacrimal and salivary glands, leading to dry mouth and surface damage, and aqueous tear flow.6,8,10 Tear osmolardry eyes. Non-Sjgrens dry eye is caused by lacrimal ity measurement has been suggested to be highly diagnostic for dry eye, as it is testing for
dysfunctions, including lacrimal defiEmily M. Ambizas, PharmD, CGP
a factor that is directly related to the
ciencies, obstruction of the lacrimal
Associate Clinical Professor
gland ducts, and reflex hyposecretion.4 St. Johns University, College of Pharmacy & cause.8,10 Questionnaires are used to
Allied Health Professions
determine the severity of symptoms,
Evaporative dry eye is due to
Queens, New York
effect on daily activities, and impact
increased tear evaporation in the presClinical Specialist, Rite Aid Pharmacy
Whitestone, New York
on quality of life. However, questionence of normal lacrimal secretion. The
naires should never be used alone when
cause of this may be described as intrinPriti N. Patel, PharmD, BCPS
Assistant Clinical Professor
diagnosing DED and should always
sic or extrinsic. Intrinsic causes include
Director, Drug Information Center
be used in combination with objective
meibomian gland dysfunction (the
St. Johns University, College of Pharmacy &
data collected through the use of diagmost common cause of evaporative
Allied Health Professions
Queens, New York
nostic tests.
dry eye), eyelid aperture disorders or
34
34 Dry Eye 3_30sc.indd 34
3/31/10 1:41 PM
TREATMENT OPTIONS FOR DRY EYE DISEASE
Table 1. Risk Factors Associated With

Development of Dry Eye Disease
Patient Factors
Female gender (especially postmenopausal women),
increasing age
Environmental Aspects
Low humidity, high temperatures, high air velocity,
air pollution (including tobacco smoke)
Nutritional Factors
Diet low in omega-3 fatty acids, diet with a higher ratio of
omega-6 to omega-3 fatty acids
Daily Activities
Computer use, television watching, prolonged reading
Other Factors
Refractive surgery (e.g., LASIK), HIV, Parkinsons disease,
diabetes mellitus
Systemic and Topical Medications
Significant anticholinergic effects (e.g., antihistamines,
tricyclic antidepressants, antispasmodics), beta-blockers,
diuretics, amiodarone, systemic isotretinoin, chemotherapy,
interferon, topical ocular agents containing certain preservatives
LASIK: laser-assisted in situ keratomileusis.
Source: References 1, 5, 6.
Treatment Options
The goals of treatment for DED are to reduce ocular
discomfort, improve quality of life, and return the ocular surface and tear film to their normal states, preventing further damage to the ocular tissue and cornea.
Treatment approaches vary; there are many nonpharmacologic and pharmacologic therapies to choose from.11
Ultimately, the underlying cause should be identified
and corrected. The mainstay of treatment is to lubricate
the eye with artificial tear supplements.1,12
Nonpharmacologic Treatment: Educating patients about
the avoidance of environmental factors can help improve

the symptoms of DED. This can be accomplished by
advising the patient to avoid wind, smoke, and dust,
and to use a humidifier. Taking breaks from reading and
computer use and increasing blink frequency can also
help. The patient may also try washing the eyelid with
a mild soap or baby shampoo to decrease bacterial
colonization, and applying warm compresses to reduce
evaporative loss. Exacerbating medications may be discontinued if appropriate and feasible. These interventions
will alleviate symptoms but will not completely control
them; the patient will need to utilize topical or systemic
medications to adequately manage DED.12,13
OTC Products: The numerous OTC products available

may cause confusion (TABLE 2). The aspects of the differing formulations that pharmacists should be aware of
include the ingredients and the presence of preservatives.
Artificial tears may contain any number of ingredients
to increase viscosity, including carboxymethylcellulose,
polyethylene glycol, hydroxypropyl methylcellulose,
glycerin, and polyvinyl alcohol. Increased viscosity of the
product will increase tear retention time.13 Viscosityenhancing agents may protect the epithelium of the eye
by coating the surface.11 Oil-containing eye drops also
lubricate the eye. These may decrease tear evaporation
by restoring the lipid layer of tear film.11 Ophthalmic
ointments are not considered artificial tears and are
typically reserved for overnight use due to their high
viscosity and increased chance of blurring the vision.13
Ointments are formulated with white petrolatum and
mineral oil, and some also contain the potentially irritating agent lanolin. Electrolyte ingredients can help treat
the surface of the eye. Most notably, potassium helps
maintain corneal thickness, while bicarbonate helps
maintain normal epithelial structure.11
Preservatives are included in many ophthalmic formulations to decrease the chance of bacterial contamination
during product application and to increase shelf life of the
product. The FDA requires multidose ophthalmic agents
to contain preservatives.11 Single-use containers of ophthalmic agents typically do not contain preservatives.
Preservatives can exacerbate ocular inflammation of
dry eye. The DEWS recommendations state that for
patients with moderate-to-severe dry eye who require
frequent application of ocular lubricant, the absence of
preservative is a more important consideration than the
active lubricating agent.11
Benzalkonium chloride, a common preservative found
in ophthalmic agents, has toxic effects on the eye when
used topically and is not recommended for patients with
severe DED. The DEWS recommendations state that
benzalkonium chloride is generally well tolerated when
used less than 4 to 6 times per day.11
Ethylenediaminetetraacetic acid (EDTA) is another
preservative frequently found in ophthalmic products,
and it may also cause irritation in patients who use the
drops several times per day.11 Newer preservatives include
polyquaternium-1, sodium chlorite, and sodium perborate. These were developed as alternatives to benzalkonium
chloride and EDTA and are less irritating because they
dissociate upon contact with the ocular surface and
therefore do not spend time on the surface as the older
preservatives do.11
Since osmolarity of tear film in dry eye patients is
increased, hypo-osmotic products have been created (e.g.,
36
3/31/10 1:42 PM

Hypotears, TheraTears). These products may help counteract the proinflammatory nature of the high osmolarity tear film. Products with higher colloidal osmolarity
may help restore appropriate water transport across
ocular membranes. Compatible solutes, including glycerin
and levocarnitine, have been incorporated into products.
These are taken up by ocular epithelial cells without
disrupting their normal functions and help to increase
intracellular osmolarity.11
A list of representative artificial tear products and
ocular lubricants is given in TABLE 2.
Prescription Products: Patients who do not respond to

OTC treatments or require multiple doses of OTC treatments daily may benefit from prescription products.
FreshKote is a prescription product that is FDA approved
as an ocular lubricant for moderate-to-severe dry eye.
This product is a formulation of polyvinyl pyrrolidone
2.0%, polyvinyl alcohol (87% hydrolyzed) 0.9%, polyvinyl alcohol (99% hydrolyzed) 1.8%, and Amisol Clear.
Amisol Clear is a proprietary ingredient that is claimed
to stabilize the lipid layer of tear film.14 This product is
preserved with EDTA and polixetonium.
Table 2. Select OTC Artificial Tear Solutions, Gels, and Ointments

Product
Lubricating Agents
Preservatives
Akwa Tears Ointment
Lanolin 2%, mineral oil 15%,

white petrolatum 83%
No preservative
Bausch & Lomb Advanced Eye Relief

Dry Eye Environmental Lubricant Eye Drops
Glycerin 1%
Benzalkonium chloride 0.01%,

EDTA
Bausch & Lomb Advanced Eye Relief

Night Time Lubricant Eye Ointment
Mineral oil 20%, white petrolatum 80%
No preservative
Bion Tears, Single-Use Vials
Dextran 70 0.1%, HPMC 0.3%
No preservative
GenTeal Gel Drops
CMC 0.25%, HPMC 0.3%
GenAquaa
GenTeal Mild
HPMC 0.2%
GenAquaa
GenTeal PM
No preservative
Hypotears
PVA 1%, polyethylene glycol 400 1%
Benzalkonium chloride
Murine Tears Dry Eyes
PVA 0.5%, povidone 0.6%
Benzalkonium chloride, EDTA
Refresh Celluvisc
CMC 1%
No preservative
Refresh Classic
PVA 1.4%, povidone 0.6%
No preservative
Refresh Dry Eye Therapy Sensitive
Glycerin 1%, polysorbate 80 1%
No preservative
Refresh Liquigel
CMC 1%
Puriteb
Refresh Optive
CMC 0.5%, glycerin 0.9%
Puriteb,c
Refresh PM
Mineral oil 42.5%, white petrolatum 57.3% No preservative
Soothe XP
Light mineral oil 1.0%, mineral oil 4.5%
EDTA, octoxynol-40, PHMB
Systane
Polyethylene glycol 400 0.4%,

propylene glycol 0.3%
Polyquadc,d
Systane Nighttime Ointment
Anhydrous liquid lanolin 3%
Tears Naturale Forte
HPMC 0.3%, glycerin 0.2%,

dextran 70 0.1%
Polyquadd 0.001%
Tears Naturale PM
No preservative
Tears Naturale II Polyquad
HPMC 0.3%, dextran 70 0.1%
Polyquadc,d 0.001%
Tears Renewed
HPMC 0.3%, dextran 70 0.1%
Benzalkonium chloride, EDTA
TheraTears (bottle)
CMC 0.25%
Sodium perboratec
Visine Tears Dry Eye Relief
Glycerin 0.2%, HPMC 0.2%,

polyethylene glycol 400 1%
Benzalkonium chloridec
Visine Tears Long Lasting Dry Eye Relief
Glycerin 0.2%, HPMC 0.36%,

polyethylene glycol 400 1%
Benzalkonium chloride
GenAqua: sodium perborate. b Purite: sodium chlorite. c Also available preservative free. d Polyquad: polyquaternium. CMC: carboxymethylcellulose;
EDTA: ethylenediaminetetraacetic acid; HPMC: hydroxypropyl methylcellulose; PHMB: polyhexamethylene biguanide; PVA: polyvinyl alcohol.
37
3/31/10 1:42 PM
Mealtime therapy can t into

cubicle #8.
Humalog KwikPen, part of the Humalog approach, is designed to help t mealtime therapy into
your patients life. Its small, doesnt need refrigeration after the rst use, and can be used almost
anywhere. To nd out more, go to www.Humalog.com or see your Lilly sales representative.
Humalog is for use in patients with diabetes mellitus for the control
of hyperglycemia. Hypoglycemia is the most common adverse effect
associated with insulins, including Humalog.
For complete safety prole, please see Important Safety Information
and Brief Summary of full Prescribing Information on adjacent pages.
Indication
Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control of
hyperglycemia. Humalog should be used with longer-acting insulin, except when used in combination with sulfonylureas
in patients with type 2 diabetes.
Important Safety Information

Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients.
Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of action. Therefore,
when used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal.
Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to
maintain glucose control (except when using an insulin pump). Glucose monitoring is recommended for all patients
with diabetes.
The safety and effectiveness of Humalog in patients less than 3 years of age have not been established. There are no
adequate and well-controlled clinical studies of the use of Humalog in pregnant or nursing women.
Starting or changing insulin therapy should be done cautiously and only under medical supervision.
Hypoglycemia
Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia
can happen suddenly, and symptoms may be different for each person and may change from time to time.
Severe hypoglycemia can cause seizures and may be life-threatening.
Other Side Effects

Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and
hypersensitivity. Systemic allergy is less common, but may be life-threatening. Because of the difference in action of
Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those
who are fasting, have autonomic neuropathy or renal impairment, are using potassium-lowering drugs, or taking drugs
sensitive to serum potassium level).
For additional safety prole and other important prescribing considerations, see accompanying Brief Summary
of full Prescribing Information.
Humalog is a registered trademark of Eli Lilly and Company and is available by prescription only.
Humalog KwikPen is a trademark of Eli Lilly and Company and is available by prescription only.
HI62001
0110 PRINTED IN USA
2010, LILLY USA, LLC. ALL RIGHTS RESERVED.
HUMALOG
INSULIN LISPRO INJECTION (rDNA ORIGIN)
BRIEF SUMMARY: Consult package insert for complete prescribing information.
INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with
diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of
action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in
regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used
without a longer-acting insulin when used in combination therapy with sulfonylurea agents.
Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other
insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients
with type 2 diabetes.
CONTRAINDICATIONS: Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to
Humalog or any of its excipients.
WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well
as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given
within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog,
patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when
using an external insulin pump).
External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed
with any other insulin. Patients should carefully read and follow the external insulin pump manufacturers
instructions and the PATIENT INFORMATION leaet before using Humalog.
Physicians should carefully evaluate information on external insulin pump use in the Humalog physician
package insert and in the external insulin pump manufacturers instructions. If unexplained hyperglycemia or
ketosis occurs during external insulin pump use, prompt identication and correction of the cause is necessary.
The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients
Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION).
Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog.
As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose
monitoring is recommended for all patients with diabetes and is particularly important for patients using an
external insulin pump.
Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin
strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the
need for a change in dosage.
PRECAUTIONS: GeneralHypoglycemia and hypokalemia are among the potential clinical adverse effects
associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care
should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are
fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to
serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects
associated with the use of all insulins.
As with all insulin preparations, the time course of Humalog action may vary in different individuals or at
different times in the same individual and is dependent on site of injection, blood supply, temperature, and
physical activity.
Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual
meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress.
HypoglycemiaAs with all insulin preparations, hypoglycemic reactions may be associated with the
administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of
hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of
hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes,
diabetic nerve disease, use of medications such as beta-blockers, or intensied diabetes control.
Renal ImpairmentThe requirements for insulin may be reduced in patients with renal impairment.
Hepatic ImpairmentAlthough impaired hepatic function does not affect the absorption or disposition of
Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary.
AllergyLocal AllergyAs with any insulin therapy, patients may experience redness, swelling, or itching
at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances,
these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor
injection technique.
Systemic AllergyLess common, but potentially more serious, is generalized allergy to insulin, which may
cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure,
rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be lifethreatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an
injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients
receiving Humulin R (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053).
Antibody ProductionIn large clinical trials, antibodies that cross-react with human insulin and insulin lispro
were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the
antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy.
Usage of Humalog in External Insulin PumpsThe infusion set (reservoir syringe, tubing, and catheter),
Disetronic D-TRON2,3 or D-TRONplus2,3 cartridge adapter, and Humalog in the external insulin pump
reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external
insulin pump should not be exposed to temperatures above 37C (98.6F).
In the D-TRON 2,3 or D-TRONplus 2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However,
as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be
selected every 48 hours or less.
When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see
INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of
Insulins, DOSAGE AND ADMINISTRATION, and Storage).
Information for PatientsPatients should be informed of the potential risks and advantages of Humalog and
alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection
technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose
monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia,
and periodic assessment for diabetes complications.
Patients should be advised to inform their physician if they are pregnant or intend to become pregnant.
Refer patients to the PATIENT INFORMATION leaet for timing of Humalog dosing (<
_15 minutes before or
immediately after a meal), storing insulin, and common adverse effects.
For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the PATIENT
INFORMATION leaet that accompanies the drug product and the User Manual that accompanies the delivery
device. They should also reread these materials each time the prescription is renewed. Patients should be
instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose
of needles. Patients should be advised not to share their Pens with others.
For Patients Using External Insulin Pumps: Patients using an external infusion pump should be trained in
intensive insulin therapy and in the function of their external insulin pump and pump accessories. Humalog was
tested in the MiniMed1 Models 506, 507, and 508 insulin pumps using MiniMed1 Polyn1 infusion sets.
Humalog was also tested in the Disetronic 2 H-TRONplus V100 insulin pump (with plastic 3.15 mL insulin
reservoir), and the Disetronic D-TRON 2,3 and D-TRONplus 2,3 insulin pumps (with Humalog 3 mL cartridges)
using Disetronic Rapid2 infusion sets.
The infusion set (reservoir syringe, tubing, catheter), D-TRON2,3 or D-TRONplus 2,3 cartridge adapter,
and Humalog in the external insulin pump reservoir should be replaced, and a new infusion site selected
every 48 hours or less. Humalog in the external pump should not be exposed to temperatures above
37C (98.6F).
A Humalog 3 mL cartridge used in the D-TRON 2,3 or D-TRONplus 2,3 pump should be discarded after 7 days,
even if it still contains Humalog. Infusion sites that are erythematous, pruritic, or thickened should be reported to
medical personnel, and a new site selected.
Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump.
Laboratory TestsAs with all insulins, the therapeutic response to Humalog should be monitored by periodic
blood glucose tests. Periodic measurement of hemoglobin A1C is recommended for the monitoring of long-term
glycemic control.
Drug InteractionsInsulin requirements may be increased by medications with hyperglycemic activity, such
as corticosteroids, isoniazid, certain lipid-lowering drugs (eg, niacin), estrogens, oral contraceptives,
phenothiazines, and thyroid replacement therapy (see CLINICAL PHARMACOLOGY).
Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have
hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants
(monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blocking
agents, beta-adrenergic blockers, inhibitors of pancreatic function (eg, octreotide), and alcohol. Beta-adrenergic
blockers may mask the symptoms of hypoglycemia in some patients.
Mixing of InsulinsCare should be taken when mixing all insulins as a change in peak action may occur.
The American Diabetes Association warns in its Position Statement on Insulin Administration, On mixing,
physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological
response to the insulin mixture may differ from that of the injection of the insulins separately. Mixing Humalog
with Humulin N or Humulin U does not decrease the absorption rate or the total bioavailability of Humalog.
Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect
compared with regular human insulin.
PregnancyTeratogenic EffectsPregnancy Category BReproduction studies with insulin lispro have
been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average
human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired
fertility or harm to the fetus due to Humalog. There are, however, no adequate and well-controlled studies with
Humalog in pregnant women. Because animal reproduction studies are not always predictive of human response,
this drug should be used during pregnancy only if clearly needed.
Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human
insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and
during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been
well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually
fall during the rst trimester and increase during the second and third trimesters. Careful monitoring of the
patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to
mothers with diabetes is warranted.
Nursing MothersIt is unknown whether Humalog is excreted in signicant amounts in human milk. Many
drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when
Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments
in Humalog dose, meal plan, or both.
Pediatric UseIn a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years,
comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human
insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately
after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable
glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to
45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia
was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in
dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf
life may be reduced (see DOSAGE AND ADMINISTRATION).
Geriatric UseOf the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were
65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia
rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset
of Humalog action have not been performed.
ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a
difference in frequency of adverse events between the 2 treatments.
Adverse events commonly associated with human insulin therapy include the following:
Body as a Wholeallergic reactions (see PRECAUTIONS).
Skin and Appendagesinjection site reaction, lipodystrophy, pruritus, rash.
Otherhypoglycemia (see WARNINGS and PRECAUTIONS).
OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy
expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in
drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic
impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose.
Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after
apparent clinical recovery.
DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select
external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of
Humalog will vary among patients and should be determined by the healthcare provider familiar with the
patients metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic
studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same
glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucoselowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment
of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog,
particularly to prevent premeal hyperglycemia.
When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a
meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control,
the amount of longer-acting insulin being given may need to be adjusted when using Humalog.
The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of
injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human
insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or
femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other
insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection
sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog
concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog
is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin
preparations, the time course of action of Humalog may vary considerably in different individuals or within the
same individual. Patients must be educated to use proper injection techniques.
Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30,
and Humulin R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted
Humalog may remain in patient use for 28 days when stored at 5C (41F) and for 14 days when stored at 30C
(86F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump.
Parenteral drug products should be inspected visually before use whenever the solution and the container
permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not
be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not
designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be relled with insulin.
External Insulin PumpsHumalog was tested in MiniMed1 Models 506, 507, and 508 insulin pumps using
MiniMed1 Polyn1 infusion sets. Humalog was also tested in the Disetronic 2 H-TRONplus V100 insulin
pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON 2,3 and D-TRONplus 2,3 pumps (with
Humalog 3 mL cartridges) using Disetronic Rapid2 infusion sets. Humalog should not be diluted or mixed with
any other insulin when used in an external insulin pump.
HOW SUPPLIED:
Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each
presentation containing 100 units insulin lispro per mL [U-100]):
10 mL vials
NDC 0002-7510-01 (VL-7510)
3 mL vials
NDC 0002-7510-17 (VL-7533)
NDC 0002-7516-59 (VL-7516)
5 x 3 mL cartridges3
5 x 3 mL prelled insulin delivery devices (Pen)
NDC 0002-8725-59 (HP-8725)
5 x 3 mL prelled insulin delivery devices (Humalog KwikPen ) NDC 0002-8799-59 (HP-8799)

1
2
3
MiniMed and Polyn are registered trademarks of MiniMed, Inc.

Disetronic, H-TRONplus, D-TRON, and Rapid are registered trademarks of Roche Diagnostics GMBH.
3 mL cartridge is for use in Eli Lilly and Companys HumaPen MEMOIR and HumaPen LUXURA HD insulin
delivery devices, Owen Mumford, Ltd.s Autopen 3 mL insulin delivery device, and Disetronic D-TRON and
D-TRONplus pumps. Autopen is a registered trademark of Owen Mumford, Ltd. HumaPen,
HumaPen MEMOIR and HumaPen LUXURA HD are trademarks of Eli Lilly and Company.
Other product and company names may be the trademarks of their respective owners.
Storage Unopened Humalog should be stored in a refrigerator (2 to 8C [36 to 46F]), but not in the
freezer. Do not use Humalog if it has been frozen. Unrefrigerated (below 30C [86F]) 12 vials, cartridges, Pens,
and KwikPens must be used within 28 days or be discarded, even if they still contain Humalog. Protect from
direct heat and light.
Use in an External Insulin PumpA Humalog 3mL cartridge used in the D-TRON2,3 or D-TRONplus2,3
should be discarded after 7 days, even if it still contains Humalog. Infusion sets, D-TRON 2,3 and D-TRONplus 2,3
cartridge adapters, and Humalog in the external insulin pump reservoir should be discarded every 48 hours
or less.
Literature revised December 7, 2009
KwikPens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA.
Pens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France,
F-67640 Fegersheim, France.
Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Hospira, Inc.,
Lake Forest, IL 60045, USA or Lilly France, F-67640 Fegersheim, France.
Cartridges manufactured by Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company,
Indianapolis, IN 46285, USA.
www.humalog.com
Copyright 1996, 2008, Eli Lilly and Company. All rights reserved.

Cyclosporine topical emulsion 0.05% (Restasis) was
approved in 2003 for the treatment of dry eye.15 Cyclosporine reduces T-cell activation, which can improve
ocular surface health and decrease lacrimal gland inflammation. Cyclosporine also decreases cytokine production.
This product is unique in that it is FDA approved to
increase tear production, not just to lubricate the eye.
Restasis is contraindicated in patients with active ocular
infections and in patients with hypersensitivity to any
ingredients. Restasis should be used as 1 drop in each
eye twice daily, 12 hours apart. It can be used along with
artificial tears, provided that the two are administered at
least 15 minutes apart. Common adverse events include
burning and stinging upon instillation, ocular discharge,
eye pain, pruritus, foreign body sensation, and blurring
of vision.15
Oral Supplements: Studies have shown that oral supple-
mentation with omega-3 fatty acids decreases the likelihood of a woman experiencing dry eye.16 Supplementation with omega-3 fatty acids has also been shown to be
useful in the treatment of dry eye. Omega-3 fatty acids
can help restore the lipid layer of tear film, decrease
inflammation, and increase tear production.13,17
Other Treatments: If the OTC and prescription products
fail to achieve adequate ocular comfort for the patient,

moisture chamber spectacles, contact lenses, tear stimulation via secretagogues, topical ocular corticosteroids,
and various surgical techniques may be available through
the care of an ophthalmologist or other eye care provider.11
Helping Patients
Depending on the severity of the patients case, a pharmacist may recommend a variety of products. Patients suffering from mild DED will have episodic occurrences usually
due to environmental stress. Severe DED is seen in those
patients who persistently experience symptoms, which can
be disabling, and may have possible damage to the ocular
surface.1,4 For mild cases of DED, using an artificial tear
product 1 to 2 times a day is recommended. For more
severe cases, pharmacists can recommend a product to be
used 3 to 4 times daily.18 When recommending a product,
pharmacists should remember that patients who use eye
drops for dry eye frequently throughout the day would
benefit from formulations that are either preservative free
or include the less irritating preservatives polyquaternium-1,
sodium chlorite, and sodium perborate.
Artificial tear preparations with higher viscosity tend
to have longer-lasting effects, as the products stay on the
eye for a longer period of time. These products, however,
also cause buildup around the eye, and for cosmetic
reasons may not be preferred by patients. Patients should

also be instructed on lifestyle modifications and nonpharmacologic treatments as previously discussed.
Pharmacists should also be aware that elderly patients
may have trouble instilling eye drops with smaller unitdose systems.19 For such patients, larger, easier-to-use
bottles may help. Visine Pure Tears No Mess SingleDrop Dispenser is a preservative-free product designed
to instill eye drops without contamination and may be
useful in patients who have difficulties with manual
dexterity.20
It is important for pharmacists to counsel patients on
proper administration of the various ophthalmic products.
A step-by-step guide should be provided to patients:
Wash hands and areas of the face around the eyes
before use
Tilt head back
While grasping the lower eyelid, pull it away from
the eye to form a pouch
While looking up, place a single drop into the eye
Close the eye and gently apply pressure to the tear duct
Blot excess solution.
If an ointment is needed, the patient should place 1/4
to 1/2 inch of ointment inside the lower eyelid and close
eyes gently for 2 minutes. If more than one medication
is needed, wait at least 5 minutes between products. If
a suspension ophthalmic product is needed, remind the
patient to shake it well prior to use and to use this particular product last. In addition, patients should use
ophthalmic drops at least 10 minutes prior to the use of
ointments.18
Pharmacists should inform patients that although
these products may relieve symptoms, they will not cure
DED. If one product does not produce a response, the
patient may try several others. If the patient does not
feel any relief after using different products, he or she
should be referred to an eye care specialist.
In addition, if patients present with any of the following conditions, they should not attempt self-treatment
and should be referred to a specialist: eye pain, blurred
vision, light sensitivity, chemical exposure, symptoms
persisting for more than 72 hours following the use of
OTC products, history of contact lens wear, red eye,
blunt trauma to the eye, and exposure to heat.18
Conclusion
Dry eye disease is a common disorder experienced by
many people, and it is a frequent cause of patient visits
to pharmacies for OTC treatments. Pharmacists should
be familiar with the various products available in order
to assist patients in choosing an appropriate product.
41
3/31/10 1:42 PM
THINKSTOCK
Managing Common Eye

Conditions in the Pharmacy
ith pharmacists increasingly becoming the

first port of call for many patients, it is useful to have basic knowledge of common eye
disorders. This article will discuss distinctive signs and
symptoms for common eye conditions and provide a
rationale for their management. TABLE 1 lists possible
questions pharmacists may ask during a consultation
with a patient presenting with an eye problem.1
disappear when the patient is no longer in proximity

to the inciting allergen. The condition is often associated with runny nose, itching of the soft palate of the
mouth, and sneezing. Approximately 70% of patients
with allergic conjunctivitis also have asthma and/or
atopic dermatitis.2
Cold compresses and tear substitutes are useful in
relieving burning and dry eyes in patients with a mild
allergy. However, many patients require more aggresRed Eye
sive therapy with selective histamine-1 (H1)-receptor
Red eye is commonly presented to pharmacists, and its antihistamines (e.g., levocabastine) that relieve itching
causes vary from a minor subconjunctival hemorrhage and watery eyes. Ketotifen (available OTC as Alaway,
to a more severe chemical burn; most often it is indic- Zaditor, Zyrtec Itchy-Eye Drops, and Claritin Eye) is
ative of conjunctivitis, commonly referred to as pink a multiple-action H1-receptor antihistamine that preeye.1 Other common causes include blepharitis, corneal vents the activation of inflammatory mediators.3 While
abrasion, foreign body, keratitis, iritis, glaucoma, and first- and second-generation oral antihistamines are
scleritis. In addition to the redness, patients may expe- effective in treating allergic conjunctivitis, topical
rience eye discharge, pain, photophobia, itching, and ophthalmic products are superior in treating this
visual changes. There are certain distinctive signs that condition.3
For rapid but short-lived relief of redness, patients
assist in identifying the cause of red eye, such as watermay choose a topical decongestant such as naphazoline,
ing and itching.
Apart from red eye, pharmacists may come across a tetrahydrozoline, or oxymetazoline. These are available
number of eye disorders in everyday practice. It is as single-ingredient OTC preparations, including All
important to distinguish when to recommend nonpre- Clear, Murine, and Visine, respectively.4 Preparations
scription therapies and when a referral may be necessary. such as Naphcon-A, Opcon-A, and Visine-A are combinations of a topical decongestant and an antihistamine.4
Allergic Conjunctivitis
When recommending topical decongestants, it is imporAllergic conjunctivitis is usually a bilateral condition tant to note that these products can cause further
caused by pollen or other allergens. In cases where only complications such as conjunctivitis medicamentosa
one eye comes into contact with the allergen, the response and irritation if used over long periods of time.
may be unilateral. Typical symptoms
If OTC medications do not proKiran Panesar, BPharmS (Hons), MRPharmS, RPh, CPh
are red, itchy eyes associated with Consultant Pharmacist and Freelance Medical Writer vide effective relief within 7 days
Orlando, Florida
tearing and burning that gradually
or the condition worsens, patients
42
42 Common Eye 3_30bosc.indd 42
3/31/10 1:42 PM
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1/20/10 8:09 PM
MANAGING COMMON EYE CONDITIONS

Herpes Simplex
Herpes simplex is a viral infection that first appears
between the age of 6 months and 5 years.7 The herpes
simplex virus-1 strain affects the eyelids, conjunctiva,
and cornea. Typically, the patient presents with an
uncomfortable eye, pain, redness, tearing, photophobia,
and blurred vision. It is not uncommon to see herpetic
Bacterial Conjunctivitis
vesicles on the eyelids or skin around the eye that rupAcute bacterial conjunctivitis is
ture, crust, and heal without
characterized by a copious, puruscarring after about 7 days.7 All
Table 1. Questions to Ask
patients presenting with a herpes
lent discharge, mild-to-moderate
pain with a tingling sensation, During an Eye Care Consultation simplex eye infection should be
referred to their physician or
and diminished vision. Other
How long have you had the problem?
Have you had this problem before?
ophthalmologist.6
symptoms include red eye with
What is the pattern of occurrence of this
Antiviral treatment using
a foreign body sensation. The
problem?
topical
or oral agents is the
best diagnostic indicator is glued
Has it gotten worse or better over time?
mainstay
of therapy. Topical
eye(s) upon waking.5 Bacterial
Is there any pain?
conjunctivitis can only be treated
trifluridine
1% solution (admin Is there any discharge?
Is
your
vision
affected?
using prescription medications;
istered 5-8 times per day) and
Do you know what the problem could be?
therefore, patients should be
200 to 400 mg of oral acyclovir
Is there an obvious cause?
referred to their physician.
administered 5 times daily are
Have you been using a computer for
available by prescription. Other
prolonged periods of time?
Blepharitis
options include acyclovir ophSource: Reference 1.
Chronic inflammation of the
thalmic ointment, oral valacyeyelids causes a condition known
clovir (500 mg 2-3 times daily),
as blepharitis. Patients commonly complain of an itchy, and oral famciclovir (250 mg twice daily). Since topgritty, uncomfortable red eye that is worse upon waking. ical antivirals can cause toxicity if used for more than
It is not uncommon to see dandrufflike scaling on 2 weeks, they are generally avoided. Similarly, topical
eyelashes, missing or misdirected eyelashes, and swollen steroids are not recommended since they can worsen
eyelids.5,6 Patients should be advised that they should the infection.8
wash the eyelids with diluted baby shampoo or eye
scrub solution. Gentle lid massages and warm compresses Marginal Keratitis
will also provide some relief. While patients should Marginal keratitis is an inflammation of the cornea
experience relief within one month, this treatment characterized by reduced vision, a painful red eye,
should be continued indefinitely. If this fails, however, sensitivity to light, foreign body sensation, and a mucoa prescription ophthalmic antibiotic may be required.5,6 purulent discharge. It is a common, transient, usually
Oral antibiotics and topical steroids may be required unilateral condition that may be associated with chronic
in severe cases.
staphylococcal blepharitis.7 Patients presenting with the
above listed symptoms should be referred to an ophEpiscleritis
thalmologist for a diagnosis. Marginal keratitis can be
The episclera is the layer found under the conjunctiva, successfully treated using topical steroids.1
covering the white of the eye. Inflammation of this
layer presents as redness as a result of dilation of the Subconjunctival Hemorrhage
blood vessels that are found in this layer. This maybe A subconjunctival hemorrhage is characterized by red,
sectoral whereby only one part is affected, or diffuse, flat discoloration due to bleeding from the small blood
in which case most of the episclera is inflamed. Episcle- vessels that run through the conjunctiva. The most
ritis is commonly self-limiting and resolves itself within common cause for spontaneous subconjunctival hemor3 weeks. In rare cases, episcleritis has been associated rhage is idiopathic in nature; the condition is painless,
with rheumatoid arthritis. Patients with recurring clearing itself within 7 to 14 days. In a few cases, the
episodes should be referred to an ophthalmologist. redness may be associated with bleeding disorders, the
Topical NSAIDs and topical steroids may be prescribed use of anticoagulants, conjunctivitis, scleritis, or trauma
to the eye. Warm compresses may be useful in sympfor severe cases.5,6
should be referred to their physician for further investigation. Prescription medications for allergic conjunctivitis include mast-cell stabilizing agents such as sodium
cromolyn and nedocromil, as well as anti-inflammatory
agents and topical nonsteroidal anti-inflammatory drugs
(NSAIDs), namely ketorolac.5
44
3/31/10 1:42 PM

tomatic relief. Treatment involves the identification and
appropriate management of the underlying cause.1,5,7
Uveitis
Uveitis or iritis is an inflammation of the iris, the ciliary body, or the choroid. Iritis may result in pain that
radiates to the brow and temple; it develops with time
along with redness in the eye. Other symptoms of
iritis include watering, red eye, blurred vision, and
photophobia. Iritis should be referred for further investigation. Patients are commonly treated with steroid
eye drops to alleviate the pain and inflammation.6
Arcus Senilis
Arcus senilis (corneal arcus) is a bilateral condition
manifesting as a white ring in the periphery of the
cornea.7 It is a lipid-rich corneal deposit that does not
affect the patients vision. It begins at the top and bottom of the cornea and spreads to form a complete ring.
It is most commonly seen in elderly patients. Therefore,
arcus senilis in patients below 50 years of age should
be referred for a lipid profile, since it may indicate
hyperlipidemia, hypercholesterolemia, or hyperlipoproteinemia.8 However, the relationship between arcus
senilis and cardiovascular disease is yet to be established.9
Dry Eye Syndrome
Dry eye syndrome, due to decreased production of tears
or excessive tear evaporation, causes discomfort and
soreness. Patients may also complain about a foreign
body sensation in the eye(s). Underlying causes of dry
eye include Sjgrens syndrome, aging, staring at a
computer screen for too long, blinking problems, and
environmental factors. Additionally, patients taking
such medications as oral contraceptives, antihistamines,
and beta-blockers may experience dry eyes. Pharmacists
are in an ideal position to discover this adverse reaction.
Dry eye syndrome can be managed using nonprescription artificial tear products (e.g., Murine Tears
Dry Eyes, Visine Tears Dry Eye Relief ).10 Many OTC
products are available, and preservative-free formulations are recommended if the patient experiences
itching and irritation with the drops (e.g., Bion Tears,
Refresh Celluvisc).10 Dryness can also be prevented by
the use of humidifiers. Cyclosporine eye drops that
increase tear production are available by prescription
(e.g., Restasis).5
Floaters
Patients describe floaters as dark specks or cobwebs that
are seen in the field of vision. They are shadows of the
fibers that clump together in the vitreous gel. While
floaters are a normal part of the aging process and occur

as some point or another in most patients, individuals
suddenly experiencing new floaters, with or without
flashing lights, should be referred to an ophthalmologist
immediately.6
Meibomian Cysts (Chalazia)

A chalazion, or meibomian cyst, is a benign lipogranulomatous inflammation of the meibomian glands lining
the tarsal plate of the eyelid.11 It is caused by lipid
blockage of the gland duct, causing a pea-like swelling.
Patients usually present when the lump becomes symptomatic, either because of cosmetic reasons or, if the
chalazion is of a considerable size, because it is causing
ptosis, astigmatism, and/or vision loss. If left untreated,
chalazia may resolve over many months. A warm compress can be applied over the cyst to allow the oils to
liquefy and flow properly. The cyst should be massaged
daily for about 1 minute following the warm compress.
If this does not work or the cyst is too large, surgery
on the everted eyelid may be required.6,11
Nevi
A pigmented or nonpigmented mole on the conjunctiva
of the eye is known as a nevus. The nevus may be flat
or slightly raised.1 Since nevi are normally harmless, no
treatment is necessary, unless they become malignant.
Patients should be referred for further investigation if
the nevus is growing. The presence of nevi on the iris
is an indication of neurofibromatosis type 1, an autoimmune disease.
Pingueculae and Pterygia
Pingueculae are yellow-white, flat or slightly raised,
usually bilateral lesions on the conjunctiva found adjacent to the nasal or temporal limbus.1,7 Pterygia are
similar asymmetrical lesions that encroach on the cornea.7 Pterygia can either grow as separate entities or
start out as pingueculae.12 Pingueculae do not normally
require treatment except mild steroid drops to reduce
any inflammation. However, pterygia can stretch the
cornea, resulting in astigmatism and blurred or low
vision. It is essential that these be surgically removed.12
Any patients presenting with such a growth should
therefore be referred for further investigation.
Styes
A bacterial infection of the eyelash follicle causes a
painful swelling at the margin of the eyelid known as
a stye. The causative organism is usually Staphylococcus
species. Warm compresses are typically recommended
to provide symptomatic relief and quicken recovery. In
45
3/31/10 1:42 PM

most cases the stye will heal itself within 1 to 2 weeks.
Referral and a prescription for oral antibiotics may be
necessary if no relief is seen in approximately 14 days.7
affected or there may be a complete loss of vision. In

less serious situations, whereby there is no corneal abrasion or loss of vision, a simple eye wash can be used to
remove the foreign body.
Trichiasis
Trichiasis is a condition whereby the eyelashes grow Preservatives in Eye Care Products
inwards, causing corneal abrasion and thus affecting Additives, such as preservatives, need to be taken into
the eyesight. The eyelash needs to be regularly pulled consideration when selecting an appropriate medication.
out with a tweezer by a qualified health care profes- Preservatives in eye drops can cause stinging and itching as well as keratitis.13 Fursional, and sometimes electrolythermore, preservatives decrease
sis or cryotherapy of the hair
the stability of the precorneal
follicles may be considered.
Table 2. Symptoms That
tear film and have a detergent
Require Immediate Referral
Watery Eyes
effect on the lipid layer, worsen Pain in the eyes
Watery eyes are caused by excesing a dry eye. 14 Preservatives,
Blurred or distorted vision
Worsening symptoms
sive tear production, a natural
such as benzalkonium chloride,
Any doubt about the diagnosis
process that keeps the eye lubriare taken up by contact lenses,
No improvement with any OTC medications
cated and clean. Allergies are a
particularly soft contact lenses.
previously used (after 7 days)
common cause of watery eyes,
The accumulation of such preSource: Reference 1.
in addition to blepharitis and
servatives eventually reaches toxic
infection. The choice of treatlevels, causing further irritation
ment will be based upon the cause. Nonprescription to the eye. Patients should be advised not to wear any
antihistamines may be useful in preventing watery eyes lenses for an hour after instilling eye drops containing
related to allergies.
preservatives.15
Xanthelasma
Xanthelasma is a frequently bilateral condition that is
usually found in elderly individuals and those with
hypercholesterolemia. It presents as a yellow subcutaneous plaque on the eyelids. Since it can be an indication
of hypercholesterolemia, patients should be referred for
a cholesterol test.7
Foreign Body in the Eye
The symptoms of a foreign body include sharp pain,
burning, irritation, tearing, and redness. The patient
may feel something in the eye when moving the eye
around while it is closed and a scratching sensation
upon blinking. Bleeding may be seen in the white part
of the eye, and in more severe cases the vision may be
REFERENCES
1. Elton M. Ocular conditions from A to Z (ii). Pharm J. 2007;278:255-258.
2. Berdy GJ, Berdy SS. Ocular allergic disorders: disease entities and differential
diagnoses. Curr Allergy Asthma Rep. 2009;9:297-303.
3. Bielory L, Lien KW, Bigelsen S. Efficacy and tolerability of newer antihistamines
in the treatment of allergic conjunctivitis. Drugs. 2005;65:215-228.
4. Terrie YC. A pharmacists guide to OTC therapy: ophthalmic products.
Pharmacy Times. May 1, 2005. www.pharmacytimes.com/issue/pharmacy/2005/
2005-05/2005-05-9515. Accessed February 2, 2010.
5. Cronau H, Kankanla RR, Mauger T. Diagnosis and management of red eye in
primary care. Am Fam Physician. 2010;81:137-144.
6. Elton M. Ocular conditions from A to Z (i). Pharm J. 2007;278:195-198.
7. Kanski JJ, Nischal KK. Ophthalmology: Clinical Signs and Differential Diagnosis.
London, UK: Mosby; 1999.
8. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred
Practice Pattern Guidelines. Conjunctivitis. San Francisco, CA: American Academy
of Ophthalmology; 2008. www.aao.org/ppp. Accessed March 4, 2010.
Role of the Pharmacist

Pharmacists should demonstrate the proper use of
ophthalmic drops to patients so that the medication is
applied correctly. Leaflets that instruct patients on how
to instill eye drops are readily available and should be
used to reinforce the explanation. TABLE 2 lists the
symptoms that require immediate referral. As a rule of
thumb, any patients presenting with pain in the eye
should be referred for further investigation immediately.
Many symptoms, particularly dryness, watery eyes, and
redness, are common to a number of ocular conditions.
While pharmacists are not experts in treating eye conditions, they are in a position to give patients advice
based upon the symptoms presented and explain the
correct use of the medications.
9. Fernandez AB, Keyes MJ, Pencina M, et al. Relation of corneal arcus to
cardiovascular disease (from the Framingham Heart Study data set). Am J Cardiol.
2009;103:64-66.
10. Dry eyes drug treatment. Artificial tears. The Eye Digest.
www.agingeye.net/dryeyes/dryeyesdrugtreatment.php. Accessed March 23, 2010.
11. Lee G. Management of chalazia in general practice. Aust Fam Physician.
2009;38:311-314.
12. Peiretti E, Dessi S, Putzolu M, Fossarello M. Hyperexpression of low-density lipoprotein receptors and hydroxy-methylglutaryl-coenzyme A-reductase in
human pinguecula and primary pterygium. Invest Ophthalmol Vis Sci.
2004;45:3982-3985.
13. Wills S. Reacting to additives in medicines. Clin Pharm. 2009;1:449-450.
14. Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs
with preserved and preservative free glaucoma medication. Br J Ophthalmol.
2002;86:418-423.
15. Chapman JM, Cheeks L, Green K. Interactions of benzalkonium chloride with
soft and hard contact lenses. Arch Ophthalmol. 1990;108:244-246.
46
3/31/10 1:42 PM
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PharmQD.com
Contemporary Compounding
Estradiol 0.1 mg/g Vaginal Solution

Menopausal symptoms and some female hormonal
disorders can benefit from treatment with this preparation.
FORMULA
Estradiol 0.1 mg/g Vaginal Solution
Rx (for 100 g):
Ingredient
Estradiol
Pluronic P105
Propylene glycol
Purified water
Method of Preparation: Calculate

the quantity of each ingredient
for the amount to be prepared.
Accurately weigh or measure each
ingredient. Add the estradiol
powder to the propylene glycol
and mix well. Add the Pluronic
P105 and the water to the mixture and mix well. Package and
label.
Use: Estradiol vaginal solution
has been used for the treatment
of atrophic vaginitis, atrophic
dystrophy of the vulva, menopausal symptoms, female hypogonadism, and mild-to-severe vasomotor symptoms associated with
menopause.
Packaging: Package in tight,
light-resistant containers.
Labeling: Keep out of the reach
of children. For vaginal use.
Loyd V. Allen, Jr, PhD
Professor Emeritus, College of Pharmacy,
University of Oklahoma, Oklahoma City
10 mg
45 g
48 g
7g
Use only as directed. Discard

after ____ [time period].
Stability: A beyond-use date of 30
days may be used for this preparation.1

Quality Control: Quality-control
assessment can include weight/volume, pH, specific gravity, active

drug assay, color, clarity, rheologic
properties/pourability, physical
observation, and physical stability
(discoloration, foreign materials,
gas formation, mold growth).2
Discussion: Estradiol is a naturally
occurring steroidal estrogen that
occurs as small, white or creamy
white crystals or as a crystalline
powder. Estradiol is odorless and
hygroscopic; it is practically
insoluble in water, but it has a
solubility of about 35.7 mg/mL
in alcohol at 25C. Estradiol
should be stored in tight, lightresistant containers. In the body,
estradiol is reversibly oxidized to
estrone, and both estradiol and

estrone can be converted to
estriol. Generally, estradiol is not
used orally owing to extensive
first-pass hepatic metabolism.
Estradiol is indicated for the
treatment of atrophic vaginitis,
atrophic dystrophy of the vulva,
menopausal symptoms, female
hypogonadism, ovariectomy
(oophorectomy), primary ovarian
failure, inoperable breast cancer,
inoperable prostatic cancer, and
mild-to-severe vasomotor symptoms associated with menopause.3
Pluronic P105 is a difunctional
block copolymer surfactant terminating in primary hydroxyl
groups. The poloxamers are a
series of closely related block
copolymers of ethylene oxide and
propylene oxide that are used as
emulsifying agents, solubilizing
agents, and wetting agents. The
poloxamers are available in different grades and as liquids, pastes,
or solids, with average molecular
weights ranging from 2,090 to
14,600. Pluronic P105 has an
average molecular weight of
6,500. Pluronic P105 is slightly
milky and cloudy in appearance.
Pluronic P105 has a specific gravity of 1.05, and it is soluble in
water to the extent of greater
than 10%. The pH of a 2.5%
w/v aqueous solution is in the
range of 6.0 to 7.4. The poloxamers are stable; aqueous solu-
48
48 Compounding 3_30sc.indd 48
3/31/10 1:42 PM
Contemporary Compounding
tions are stable in the presence of

acids, alkalis, and metal ions, but
the aqueous solutions do support
mold growth.4
Propylene glycol (C3H8O2)
occurs as a clear, colorless, viscous, practically odorless liquid
with a sweet taste, somewhat
resembling glycerin. Propylene
glycol has a specific gravity of
1.038 g/mL and is miscible with
acetone, 95% ethanol, glycerin,
and water. Propylene glycol is not
REFERENCES
1. USP Pharmacists Pharmacopeia. 2nd ed.
Rockville, MD: US Pharmacopeial Convention, Inc; 2008:775-779.
2. Allen LV Jr. Standard operating procedure
for performing physical quality assessment of
oral and topical liquids. IJPC. 1999;3:
146-147.
miscible with fixed oils or light

mineral oil; it will, however, dissolve some essential oils. Propylene glycol is actually a better solvent than glycerin and is similar
to ethanol as an antiseptic. Propylene glycol is stable and may be
mixed with numerous other solvents. Aqueous solutions of propylene glycol can be sterilized by
autoclaving. Since propylene glycol is hygroscopic, it should be
stored in an airtight container
3. McEvoy GK. AHFS 2010 Drug Information. Bethesda, MD: American Society of
Health-System Pharmacists; 2010:3131-3136.
4. Collett JH. Poloxamer. In: Rowe RC, Sheskey PJ, Quinn ME, eds. Handbook of Pharmaceutical Excipients. 6th ed. London, England:
Pharmaceutical Press; 2009:506-509.
5. Weller PJ. Propylene glycol. In: Rowe RC,
ormula for com

pou
en f
v
o
nd
pr
ing
e
im
TRADITIONAL FORMULA
and protected from light.5

Purified water is water that is
obtained by distillation, ion
exchange, reverse osmosis, or
some other suitable process.
Water has a specific gravity of
0.9971 at room temperature, a
melting point at 0C, and a boiling point at 100C. Water is miscible with most polar solvents,
and it is chemically stable in all
physical states (ice, liquid, and
steam).6
Sheskey PJ, Quinn ME, eds. Handbook of

Pharmaceutical Excipients. 6th ed. London,
England: Pharmaceutical Press; 2009:592-594.
6. Dubash D, Shah U. Water. In: Rowe
RC, Sheskey PJ, Quinn ME, eds. Handbook
of Pharmaceutical Excipients. 6th ed.
London, England: Pharmaceutical Press;
2009:766-770.
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48 Compounding 3_30sc.indd 49
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Generic Trends
Teva to Acquire Ratiopharm

Teva Pharmaceutical Industries
Ltd. announced its acquisition of
German generic drug maker Ratiopharm for $5 billion. The companies had combined sales of $16.2
billion in 2009, and Ratiopharm
was already the sixth largest generic
drug company in the world. This
is an important acquisition for
Teva, Teva President and CEO
Shlomo Yanai said. This transaction is perfectly aligned with our
long-term strategy in which Europe
is an important pillar and growth
driver.
Synthon First to File
Generic Tadalafil 20 mg
Synthon Pharmaceuticals, Inc., was
sued by Eli Lilly and Company
and Icos Corporation after filing an
Abbreviated New Drug Application
(ANDA) for tadalafil 20 mga
generic bioequivalent of Lillys and
United Therapeutics Adcirca tablets for the treatment of pulmonary
arterial hypertension to improve
exercise ability. Synthon indicated
that it is the Single First Filer of
an ANDA with a Paragraph IV
certification for Adcirca (tadalafil)
tablets, 20 mg. As a result, Synthon
is expected to be eligible for 180
days of Hatch-Waxman exclusivity.
Mylan Settles Actoplus
Met and Actos Suits
Mylan Inc. announced that it has
entered into agreements with
Takeda Pharmaceutical Industries
Ltd. related to two treatments for
type 2 diabetes: Actoplus Met 15
mg/500 mg and 15 mg/850 mg
(pioglitazone hydrochloride [HCl]
and metformin HCl tablets) and
Actos 15 mg, 30 mg, and 45 mg
(pioglitazone HCl tablets). As are-
GPhA Comments on Health Reform Bill

Generic Pharmaceutical Association (GPhA) President and CEO
Kathleen Jaeger weighed in on House passage of the Health Care
and Education Affordability Reconciliation Act of 2010 in a statement released on March 21st: [The] passage of health care reform
in the House provides both good and bad news for consumers. The
good news is that more Americans will have health care coverage
and more seniors will have access to generic medicines, thanks to a
fix to the so-called doughnut hole. GPhA is pleased that the House
has taken these steps to close the Medicare drug coverage gap and
has eliminated the patent settlement provision that would have had
the unintended consequence of delaying generic access.
The bad news, Jaeger said, is that the bill provides a biogeneric pathway in name only, giving false hope to patients who desperately need access to life-saving biogeneric medicines. Simply put,
the bill fails to infuse competition and choice into the health care
system due to the excessive and unprecedented market exclusivity
protections for the brand industry. Until the brand evergreen loophole is closed and the indefinite brand biologic monopolies are
addressed, our health care system will not see true savings from
biogenerics for decades, she added.
sult of the agreements, Mylan
can market pioglitazone HCl and
metformin HCl in the U.S. on
December 14, 2012, and pioglitazone HCl in the U.S. on
August 17, 2012.
Teva Announces Favorable Ruling

in Hyzaar and Cozaar Litigation
Teva Pharmaceutical Industries Ltd.
announced that the U.S. Court of
Appeals for the District of Columbia Circuit ruled in its favor by
overturning a July 2009 district
court decision, which held that Teva
forfeited 180-day marketing exclusivity for its generic versions of Mercks
antihypertensive agents Hyzaar
(hydrochlorothiazide; losartan potassium) and Cozaar (losartan potassium). Tevas ANDAs will be eligible
for final approval this month, when
the method of use patent expires.
Teva should be eligible to receive

180-day Hatch-Waxman statutory
exclusivity to market these products.
Hospira Completes
Acquisition of Orchid
Hospira finalized its $400 million
acquisition of the generic injectables business of Orchid Chemicals
& Pharmaceuticals. The deal
includes Orchids beta-lactam antibiotic formulations operations,
encompassing its penicillin, cephalosporin, and carbapenem facilities,
and an R&D site. We are excited
to acquire new capabilities that will
create opportunities for commercial
growth, position us strongly in a
key antibiotics area, expand out
global footprint, and enhance our
ability to provide lower cost, highquality products to patients, said
Hospira COO Terry Kearney.
50
50 REVGeneric Trends 4_1rd.indd 50
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Illustration: 2010 Elaine Kurie
2 CE Credits
An Overview
of
Glaucoma Management
for Pharmacists
www.ekurie.com
laucoma is a chronic disease of the eye character- ary. Primary glaucoma refers to a glaucomatous eye
ized by progressive neuropathy of the optic nerve with no pre-existing disease, while secondary glaucoma
(ON) that can lead to irreversible blindness if results from other ocular or systemic disease, trauma,
untreated or inadequately treated. Primary open-angle or the effects of some drugs.2,4 Underlying pathology
glaucoma (POAG), the most common form of this dis- must be addressed when treating secondary glaucomas.
Primary ACG represents a medical
order, affects approximately 2.2 million
emergency because permanent blindindividuals in the United States and
U.S. Pharmacist Continuing Education
GOAL: To provide pharmacists with an
ness may quickly develop if it is not
is strongly associated with increased
overview of glaucoma and its treatment strategies.
promptly treated.4 Further discussion
intraocular pressure (IOP) and aging.1-3
OBJECTIVES: After completing this
As the proportion of elders in the U.S.
will be limited to POAG.
activity, the participant should be able to:
continues to rise, estimates target greater
1. Compare and contrast the anatomy
and physiology of the normal eye with that
ANATOMY
than 3 million cases of POAG by
of a glaucomatous eye.*
3
AND PHYSIOLOGY
2020. Because the disease is largely
2. Discuss the pathophysiology, diagnosis,
The eye is broadly divided into the
asymptomatic, many persons may be
goals of therapy, and general treatment
strategies
for
glaucoma.*
anterior and posterior segments (FIGunaware they have POAG until loss
3. Describe the pharmacologic
of vision occurs. Thus, glaucoma repURE 1). The anterior segment begins
management of primary open-angle
at the limbus and consists of the corresents an important public health
glaucoma.*
4. Discuss management strategies
nea, anterior and posterior chambers
concern. The purpose of this article
pharmacists
can
employ
to
improve
care
for
(not to be confused with anterior and
is to provide an overview of the disease
glaucoma patients.
posterior segments), pupil, iris, lens,
process and treatment strategies, allow* Also applies to pharmacy technicians.
zonules, and ciliary body. The posteing pharmacists to help improve care
rior segment lies posterior to the antefor their patients with glaucoma.
Karen K. OBrien, BS Pharm, PharmD
rior segment and consists of the vitrePharmacy Sciences Department
CLASSIFICATION
ous chamber, retina, choroid, sclera,
Creighton University School of Pharmacy &
Glaucoma is not a single disease, but
optic disc, and ON. The trabecular
Health Professions, Omaha, Nebraska
a group of disorders resulting in optic
meshwork and Schlemms canal are
Alan W. Y. Chock, PharmD
neuropathy and vision loss. These
part of the limbus, a transitional strucPharmacy Practice Department
Creighton University School of Pharmacy &
may be broadly classified as openture between the sclera and cornea
Health Professions, Omaha, Nebraska
angle or angle-closure glaucoma
(FIGURE 2). The uvea is the vascular
Catherine A. Opere, PhD
middle layer of the eye, consisting of
(ACG) based on the anatomy of the
Pharmacy Sciences Department
the iris and ciliary body in the anterior
eyes anterior chamber, and are furCreighton University School of Pharmacy &
segment and the choroid in the posther classified as primary or secondHealth Professions, Omaha, Nebraska
52
52 REVCE-Glaucoma 3_31rdsc.indd 52
4/1/10 1:10 PM
ANTERIOR SEGMENT
GLAUCOMA MANAGEMENT FOR PHARMACISTS

Anterior cavity
(aqueous humor):
Anterior chamber
Posterior chamber
Cornea
Pupil
Iris
Lens
Ciliary body
Zonules
Sclera
POSTERIOR SEGMENT
Lateral rectus
muscle
Medial rectus
muscle
Vitreous chamber
(vitreous body)
Retina
Choroid
(mostly blood
vessels)
iris meet, and forms the apex of the

anterior chamber angle of the eye.
The trabecular meshwork is a sievelike structure that filters and controls
the flow of aqueous humor (AH)
from the anterior chamber into Schlemms canal, ultimately leading to
the bloodstream.
The posterior chamber is bordered
laterally by the ciliary processes. The
lens surface forms the floor and the
posterior surface of the iris forms the
roof of the chamber (FIGURE 2).
Retinal arteries
and veins
Aqueous Humor
Hydrodynamics
Central retinal artery
Sclera
AH functions to maintain the global
Central retinal vein
shape of the eye; supply nourishment
Optic disc
to the avascular lens, cornea, and
trabecular meshwork; and remove
Optic nerve
metabolic waste. AH also participates
Figure 1. Anatomy of the eye. Yellow arrows indicate increased intraocular pressure on the optic
in immunologic responses, contribnerve. Reprinted with permission from Creighton University SPAHP.
utes to the optical system by providterior segment.
ing a transparent refractive medium between lens and
The anterior segment is further divided into anterior cornea, and facilitates some ocular distribution of drugs.5
and posterior chambers by the lens-iris diaphragm. The AH is derived from plasma within the capillary network
anterior chamber is defined by the iris (forms the floor) of the ciliary processes (FIGURE 2) and is continually
and cornea (forms the roof) (FIGURE 2). The trabecular secreted into the posterior chamber at a rate of approximeshwork is positioned at the point where the cornea and mately 2.7 L per minute in healthy individuals.6 The
entire chamber content is replaced every
CONVENTIONAL
100 minutes to 2 hours.
PATHWAY
From the posterior chamber, AH flows
Cornea
Trabecular meshwork
through the pupil into the anterior chamCanal of Schlemm
ber to exit the eye via conventional and
Anterior
chamber
unconventional pathways. The conventional
UNCONVENTIONAL
Iris
PATHWAY
pathway accounts for the majority of outflow and refers to AH coursing through
Dilator
Sclera
the trabecular meshwork and the canal of
Sphincter
Schlemm, ultimately draining into the
systemic circulation (FIGURE 2).
In unconventional pathways, AH seeps
Posterior
through tissues rather than flowing through
chamber
the usual channels and vessels. The most
Lens
common unconventional pathway is the
uveoscleral pathway in which AH drains
Zonules
Ciliary process
from the base of the ciliary muscle, through
Ciliary
Ciliary epithelium
body
tissues in and around the uvea, and evenCiliary muscle
tually into the sclera.5
Figure 2. A schematic representation of conventional and unconventional aqueous humor

(AH) pathways. As indicated by the arrows, AH is produced in the ciliary processes, then flows
into the posterior chamber and through the pupil into the anterior chamber, exiting via the
conventional pathway (trabecular meshwork and Schlemms canal) or unconventional pathway (uveoscleral route). Reprinted with permission from Creighton University SPAHP.
Intraocular Pressure
IOP refers to the pressure generated by
flow of AH against resistance within
53
52 CE-Glaucoma 3_31rdsc.indd 53
3/31/10 1:43 PM

ocular structures. IOP, maintained at about 15 mmHg
in healthy individuals, is determined by a delicate balance
between the rates of AH entering (inflow) and leaving
(outflow) the eye. Whereas inflow is dependent upon
rate of production of AH, outflow is regulated by resistance to aqueous drainage.7 Any condition that alters the
equilibrium between inflow and outflow of AH may
result in abnormal IOP levels. Resistance to outflow is
usually responsible for elevated IOP, but other factors
may contribute.5
the retina, transmit visual information from retinal photoreceptor cells, via the ON, to the visual cortex in the brain.
Axonal fibers projecting from RGCs converge at the optic
disc and exit the eye through a meshwork of collagen fibers
known as the lamina cribosa (FIGURE 3). In addition to
RGC axons, the normal optic disc contains retinal vasculature (central artery and vein) and glial elements that
provide support and protection to the neurons. The center
of the optic disc does not contain RGC axons and is known
as the cup because it appears as a concave indentation on
ophthalmic examination (FIGURE 3).
PATHOPHYSIOLOGY AND ETIOLOGY

A basic understanding of the relationship between
elevated IOP and visual loss will help the pharmacist
appreciate clinical findings and the importance of
lowering IOP in glaucoma.
Irrespective of cause, degeneration of retinal ganglion
cells (RGCs) is a feature common to all forms of optic
neuropathy. RGCs, specialized nerve cells localized within
Muller
cell
Sclera
Retinal
ganglion
cell
Glial
cell
Central
retinal
vein
Central
retinal
artery
ELEVATION IN OCULAR PRESSURE
Optic disc
Optic cup
Elevated IOP and RGC Degeneration

As indicated in FIGURE 3, elevation in IOP exerts pressure posteriorly to cause both structural and functional
damage to the optic disc. The tough sclera that envelops
most of the posterior segment of the eye is relatively
immobile, but the gelatinous lamina cribosa is pushed
posteriorly with increased IOP. This displacement is
thought to cause structural changes in the
meshwork of the lamina cribosa. The
deformed meshwork is presumed to pinch
Ganglioncell axon
Retina
the nerve fibers and blood vessels present
in the ON bundle, resulting in damage to
RGC axons and ultimately death to RGCs.5
This pathologic process can be seen upon
ophthalmic examination as increased optic
disc cupping. The diameter of the cup can
be compared to that of the entire optic disc
(cup-to-disc ratio). The cup-to-disc ratio
Lamina cribosa
correlates with extent of ON fiber damage.
Ganglion-cell axon
Disc cupping is important for differential
diagnosis of glaucoma from other ocular
neuropathies. Functional changes include
progressive loss of visual field, short wavelength color sensitivity, spatial resolution,
and temporal contrast sensitivity.5 Damaged
ON fibers cannot be regenerated, and loss
of vision is irreversible.
CLINICAL FINDINGS
POAG is a chronic eye disease that is generally progressive. Typically, both eyes are
affected, although not necessarily to the same
extent. Because symptoms are minimal or
absent early in the disease process, a thorough
eye examination is essential. In establishing
Figure 3. A schematic representation of a normal (top panel) and glaucomatous (bottom a diagnosis of POAG, the clinician seeks
panel) optic disc. Elevated intraocular pressure causes posterior displacement of the gelatevidence of ON damage. Structural abnorinous lamina cribosa, resulting in degeneration of retinal ganglion cells (RGCs), RGC
axons, and surrounding structures. Progressive displacement of the lamina cribosa results malities in the optic disc or retinal nerve
bundle and/or loss of visual field confirm
in increased cup diameter. The increase in cup-to-disc ratio correlates with extent of
optic nerve damage. Reprinted with permission from Creighton University SPAHP.
damage. A dilated eye examination is preferred
54
3/31/10 1:43 PM

to properly assess the ON. Perimetry testing is used to
evaluate the visual field, the full visible range when the
eye is fixated straight ahead. In POAG, vision loss usually
begins peripherally and moves centrally. Most commonly,
structural defects precede vision deficits.1 Refer to TABLE
1 for other characteristic clinical findings.
Gonioscopy involves examination of the anterior chamber angle through a special contact lens (goniolens), while
IOP is measured via tonometry. IOP is often elevated above
the normal range (10-21 mmHg), but a significant portion
of patients with POAG have normal IOP levels.1 Conversely,
elevated IOP levels do not always indicate POAG. Patients
with above-normal IOP but no evidence of ON damage
are said to have ocular hypertension. These individuals may
or may not receive treatment to lower IOP, based on
patient-specific factors. However, they should be monitored
closely over time since IOP elevation constitutes a risk for
developing POAG. Of note, an IOP measurement only
provides a snapshot of the pressure at a given moment in
time. Diurnal fluctuation may mask elevated IOP. Tonometric assessment on different days or at varying times of
the day may help supply a more accurate measure of IOP.1
Assessment of the optic disc and visual-field testing are
also used to monitor for disease progression and efficacy
of therapeutic interventions. While lowering IOP is presumed to decrease disease progression, it is not a surrogate
measure of visual function.4
over 65 years, in whom significantly higher rates were

found.3 Other factors possibly related to POAG include
thinner central corneal thickness, diabetes, systemic hypertension, a history of ocular trauma, reduced blood flow
to the ON, myopia (nearsightedness), and vasospastic
conditions such as Raynauds disease or migraines.1-4
GOALS OF THERAPY
The primary purpose of therapy is to enhance the patients
quality of life by preserving vision and minimizing adverse
therapeutic effects.1,4 Goals that support therapeutic purpose include stabilizing ON/retinal nerve fiber status and
visual fields; controlling IOP; and educating and involving
the patient in disease management.1
TREATMENT STRATEGIES
All current treatment modalities aim to reduce IOP.1,4 Finding an IOP range that allows for stabilization of visual fields
and ON/retinal nerve fiber status is often a process of trial
and error. The upper limit of that range is referred to as the
target pressure. The clinician assumes pretreatment IOP
resulted in optic neuropathy and endeavors to reduce initial
IOP target pressure by at least 20%. Once therapy is initiated, IOP measurement and ON assessment guide therapeutic adjustments.1
Present options for managing glaucoma include pharmacologic therapy and surgical modalities such as laser
trabeculoplasty and filtering or cyclodestructive surgery.
Each has associated benefits and risks, and patient-specific
factors and preferences must be considered when selecting
appropriate initial therapy. Therapies may be combined
to achieve treatment goals. Topical medications are an
effective first approach in many patients, although laser
trabeculoplasty may be an acceptable option. In some
patients, filtering surgery may be preferred initially.1
RISK FACTORS
IOP is a significant risk factor in the pathogenesis of
glaucoma. There is evidence that an increase in IOP
is proportional to the prevalence of glaucoma.8 Large
variation in IOP is an additional risk factor for glaucoma. In nonglaucomatous eyes, IOP varies with
circadian rhythm by about 2 to 4 mmHg over a 24-hour
period, with peak values observed in the morning
hours.9 An increase in magnitude of variation above Surgical Management of Glaucoma
10 mmHg increases the risk of ON head (optic disc) Laser Trabeculoplasty: This procedure increases outflow
via the conventional pathway. Inflammation is the most
damage and is considered pathologic.10
In addition to elevated IOP,
common adverse effect. Pharincreasing age, family history
macologic therapy may be
Table 1. Characteristic
of glaucoma, and African or
necessary posttreatment, and
Clinical
Findings
in
POAG
Hispanic/Latino race are conbeneficial effects may dissipate
Evidence of optic nerve damage
sistently linked to an increased
over time, necessitating further
(from either or both categories)
risk of glaucoma.1-4,11 A metatreatment.4
1. Optic disc or retinal nerve fiber structural abnormality
analysis of population-based
2. Visual field abnormality
Filtering Surgery: Trabecudata identified three times the
Adult onset
Open anterior chamber angles
lotomy, which creates an alterprevalence of POAG in black
Absence of other reasons for glaucomatous changes
native pathway for AH drainas compared to white persons.
Elevated IOP (may or may not be present)
age, is often performed after
Prevalence in Hispanic/Latino
IOP:
intraocular
pressure;
POAG:
primary
open-angle
glaucoma.
medication and laser therapies
persons was similar to that in
have failed. Best results are
white persons except in those
55
3/31/10 1:43 PM

achieved in patients with no prior eye
surgeries. Cataracts, corneal problems,
intraocular inflammation, growth of
scar tissue, and infection are possible
adverse effects.1
Cyclodestructive Surgery: This method
for lowering IOP destroys the ciliary
body epithelial tissue, resulting in a
permanent reduction in AH production. Loss of visual acuity and blindness
may occur, so this treatment option is
usually reserved for patients with poor
visual acuity or those in whom standard
medical, laser, or surgical modalities
have failed.4
CASE STUDY: GLAUCOMA

M.M., a 52-year-old African American woman, presents to the clinic today for an
ophthalmic exam. Her last exam (5 years ago) indicated a normal IOP (10-21 mmHg).
Family History: Mother: cataracts; father: death from myocardial infarction at age 63
Social History: Nonsmoker, nondrinker, married with 2 daughters
Allergies: PCN (anaphylaxis)
Medications: None
Personal Medical History: Unremarkable
Vital Signs: BP 112/78, P 70, RR 14, T 36.9C, HT 168 cm, WT 59.3 kg
General: Healthy, ambulatory female
Eye Exam: Elevated IOP OU. IOP by tonometry is 25/25 mmHg. Optic disc shows mild
cupping, and gonioscopy reveals open angles in the anterior chambers OU. Visual
fields are normal, and visual acuity without correction is 20/20 OD and 20/40 OS. No
signs of cataract formation are evident.
Labs: None
Physicians Assessment: POAG
1. What signs in the visual examination are consistent with diagnosis of POAG?
Elevated IOP by tonometry25 mmHg OU.
Optic disc shows mild cupping.
Gonioscopy reveals open angles in anterior chambers OU.
2. What are the goals of therapy for this patient?
Reduce IOP to stop optic nerve damage.
Preserve vision.
Maintain patients quality of lifeselect cost-effective pharmacologic treatment
with minimal adverse effects.
3. What available ophthalmic medication would provide appropriate initial treatment
of POAG for this patient?
Since she does not have any other medical problems listed, a selective or
nonselective beta-blocker or a prostaglandin analogue is recommended first line.
4. What counseling should the pharmacist provide to this patient?
Discuss treatment plan and rationale, so patient understands its importance.
Discuss adherence/compliance with treatment plan. Explain that although
glaucoma may be asymptomatic, it can lead to blindness if inadequately
treated.
Discuss common transient adverse effectscontinue medication if possible.
Discuss possible (serious/frequent) adverse effectsreport to eye doctor.
NLO and closing eye to decrease risk of systemic effects and promote optimal
drug effect.
Appropriate interval between drops if more than one drop per eye is ordered.
Proper/aseptic technique to use with eye dropspreparation, administration,
and storage.
Shake bottle if it contains a suspension.
Pharmacologic
Management of Glaucoma
Medications used to manage POAG
decrease IOP by two primary mechanisms: decreasing AH production or
increasing AH outflow (through either
the conventional or unconventional
pathways). Glaucoma is a chronic diseasethere is no cure, and medical
management must be continued
throughout a persons life.
Currently, prostaglandin analogues
and beta-blockers are the most frequently
used topical medications. Sympathomimetics, topical and oral carbonic
anhydrase inhibitors, and cholinergics
are used to a lesser degree.1,4 Adverse
effects or inadequate clinical response
M.M. was treated with the recommended regimen. Her IOP normalized to 18 mmHg
may necessitate a therapeutic change,
within 3 months, following several dosage adjustments. Two years later her IOP
remains normal, and her visual fields and optic nerves are stable.
while drugs with different mechanisms
BP: blood pressure; HT: height; IOP: intraocular pressure; NLO: nasolacrimal occlusion;
of action may be used in combination
OD: right eye; OS: left eye; OU: each eye; P: pulse; PCN: penicillin; POAG: primary opento maximize IOP reduction.
angle glaucoma; RR: retinal reflex; T: temperature; WT: weight.
Many minor local adverse effects of
POAG medications are transient, and
Following instillation of topical medications, nasolacknowledge of this will encourage patients to continue
rimal occlusion (NLO) and closing the eyelid for 2
using prescribed medications. If an adverse effect does
minutes will prevent excess medication from draining
not subside, the patient should notify his or her eye
into the lacrimal ducts and greatly decrease the risk of
doctor before discontinuing use of a medication so that
systemic effects.4 Pharmacists should recommend these
another drug can be prescribed. Refer to TABLE 2 for a
summary of therapeutic and adverse effects of POAG
techniques to patients using POAG eye drops.
medications.
Instruct patients in aseptic technique to prevent conHere are some general guidelines for the pharmacist to
tamination of the container and product, and ultimately
remember when counseling patients with POAG:
the eye. The tip of the medication container must not
Systemic adverse effects are rare complications of topbe allowed to contact the patients eye or the hand of
ical glaucoma medications, but they can be serious.
whoever dispenses the drops.
56
3/31/10 1:43 PM
Table 2. Pharmacologic Agents for Glaucoma Management in the U.S.

Drug Name
Brand Name
Formulation
Betaxolol
hydrochloride
Carteolol
Levobunolol
hydrochloride
Metipranolol
Timolol
Betoptic
Betoptic S
Ocupress
Betagan
0.25%, 0.5% solution

0.25% suspension
1% solution
0.25%, 0.5% solution
Optipranolol
Betimol, Istalol,
Timoptic
Timolol-XE
0.3% solution
0.25%,0.5% solution
Dosage
0.25%,0.5%
gel-forming solution
Beta-blockers
1-2 drops BID
1 drop BID
1 drop BID
1-2 drops
Q day-BID
1 drop BID
1 drop
Q day-BID
1 drop Q day
Bimatoprost
Lumigan
0.03% solution
Prostaglandins
1 drop Q day
Latanoprost
Travoprost
Xalatan
Travatan,
Travatan Z
0.005% solution
0.004% solution
1 drop Q day
1 drop Q day
Acetazolamide
Diamox Sequels 250-mg, 500-mg

tablet/ER capsules
Azopt
1% susp
Trusopt
2% solution
Brinzolamide
Dorzolamide
hydrochloride
Methazolamide (none in U.S.)
25-mg,
50-mg tablets
Notes
Clinical effect: decreases production of AH

One of the most commonly used medications for treatment
Nonselective: timolol, levobunolol, metipranolol, carteolol
Beta1-selective: betaxolol
Contraindications:
1. All beta-blockers: sinus bradycardia, atrioventricular block
(second or third degree), heart failure, or cardiogenic shock
2. Nonselective beta-blockers: asthma, COPD
Clinical effect: increases uveoscleral outflow; bimatoprost may

have additional effect on outflow at trabecular meshwork
One of the most commonly used medications for treatment
Pigmentation of the eye and eyelid as the most common form
of adverse effects, eyelash effects
Avoid in those with active intraocular inflammation
Carbonic Anhydrase Inhibitors

Max: 1 g Q 24 h
1 drop TID
1 drop TID
50 mg-100 mg
BID-TID
Clinical effect: decreases production of AH

Topical: used as alternative to monotherapy or adjunctive therapy
Oral: used as adjunctive therapy
Caution in those with sulfonamide allergies, renal insufficiency
Avoid using concurrent ophthalmic and oral CAIs
Cholinergics
Direct-acting agonists
Carbachol
Miostat
0.01% solution
Pilocarpine
Pilopine HS
4% gel
1 mL to anterior
chamber of eye
1/2-in ribbon
on lower
conjunctiva
at bedtime
Clinical effect: increases AH outflow

Good efficacy, but not commonly used due to frequent
adverse effects and frequent dosing
Excessive miosis may induce angle-closure glaucoma
secondary to pupillary block
May produce systemic cholinergic effects
Cholinesterase inhibitor
Echothiophate
iodide
Phospholine
Iodide
0.03%, 0.06%, 0.125%,

0.25% solution
1 drop BID
Sympathomimetics
Alpha2-selective adrenergic agonists

Apraclonidine
Iopidine
0.5%, 1% solution
hydrochloride
Brimonidine
Alphagan P
0.1%, 0.15%,
tartrate
0.2% solution
Nonspecific adrenergic agonists
Dipivefrin
Propine
0.1% solution
hydrochloride
Epinephrine
(none in U.S.)
0.5%, 1%, 2% solution
1-2 drops TID

1 drop TID
1 drop BID
1-2 drops BID
Clinical effects: increases AH uveoscleral outflow

Apraclonidine efficacy wears off in <1 mo
Rate of allergic reactions limits use of apraclonidine
Clinical effects: increases conventional outflow (primary);
chronic use decreases AH production (secondary)
Epinephrine formulation no longer available in the U.S.
Dipivefrin is a prodrug of epinephrine
Limited use due to frequency of adverse effects
Monitor for angle-closure glaucoma, cardiovascular
and metabolic effects
AH: aqueous humor; CAIs: carbonic anhydrase inhibitors; COPD: chronic obstructive pulmonary disease; ER: extended release; Max: maximum.
57
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A patient using more than one POAG eye drop (multiple drops of the same medication or different medications) should wait at least 5 minutes between instillation
of the drops.4
If different ophthalmic formulations are being used,
solutions should always be used before other formulations, such as gels and suspensions, to optimize absorption of each medication.
Because POAG drugs pass through the placenta, women
should inform their health care provider if they are
pregnant or are trying to conceive.
Beta-Blockers: Medications in this class lower IOP via
decreased production of AH and are considered first-line

pharmacologic options.2,4,12 Nonselective (timolol, levobunolol, metipranolol, carteolol) and selective (betaxolol)
forms of beta-blockers are available in the U.S.
Minor, usually transient, ocular adverse affects include
blurred vision, irritation, burning, stinging, and tearing.
Additional local adverse affects that should be reported to
the eye doctor include loss of visual acuity, pain, inflammation, foreign body sensation, and erythema.
Systemic adverse effects are rarely reported for topical
beta-blockers, and their occurrence will be minimized by
NLO.
Nonselective beta-blockers are contraindicated in patients
with asthma or severe chronic obstructive pulmonary
disease (COPD) because they can cause bronchospasms,
although betaxolol may be used due to its receptor selectivity. Because beta-blockers can both mask the early
warning symptoms of hypoglycemia and prolong recovery
from low blood sugars, they should be used cautiously in
diabetes. All beta-blockers are contraindicated in patients
with cardiac diseases such as sinus bradycardia, second- or
third-degree atrioventricular block, heart failure, or cardiogenic shock.
Prostaglandin Analogues: Regarded as first-line therapeu-
tic agents, analogues of prostaglandins (bimatoprost,

latanoprost, travoprost) bind to prostanoid FP receptors
located on the iris, promoting uveoscleral outflow of AH,
which subsequently lowers IOP.13 Bimatoprost may also
significantly affect AH outflow through the trabecular

meshwork.
Common, frequently transient, adverse ocular effects
include blurred vision or other decreased visual acuity,
itching, burning or stinging, dry eyes, and excessive tearing. Patients have reported body aches, rash, upper respiratory infections, cold, and (rarely) flu. Systemic adverse
effects are very rare with prostaglandin analogues. Patients
with active intraocular inflammation should not be started
on ophthalmic prostaglandin analogues because these could
worsen their condition. Caution should be used in those
with a past history of ocular inflammation.
Darkening of the iris, particularly in patients with hazel
eyes, has been reported by persons using ophthalmic prostaglandins. In addition, these medications tend to darken
the periorbital tissues to a brownish color. These effects may
be permanent. A serendipitous side effect is darkening,
thickening, and lengthening of the eyelashes. The FDA has
approved Latisse, a form of bimatoprost, for the treatment
of hypotrichosis, or inadequate eyelashes.14
While the American Academy of Ophthalmology and
the American Optometric Association have not stated a
definitive preference for pharmacologic treatment of glaucoma, it has been argued that prostaglandin analogues are
preferable to beta-blockers because of a greater efficacy in
lowering IOP and producing fewer systemic effects.1,2,12,15
However, there are no generic formulations of prostaglandin analogues, so where cost is an important issue, generic
beta-blockers will more likely be used.
Carbonic Anhydrase Inhibitors (CAIs): This drug classification
is available in both ophthalmic (brinzolamide and dorzolamide)
and oral (acetazolamide and methazolamide) formulations.
CAIs lower IOP by decreasing production of AH.16
Topical CAIs are normally well tolerated and are considered second-line therapeutic alternatives. Bitter taste and
transient burning, stinging, blurred vision, and foreign body
sensation are commonly reported. Corneal inflammation and
ophthalmic allergic reactions occur rarely. Systemic adverse
effects, including headache, tingling in the extremities, fatigue,
liver disease, and kidney stones, are very rare with topical
CAIs but are more common with the oral formulations.
Table 3. Factors Associated With Decreased Adherence

Patient-Specific
Dexterity
Vision
Health literacy
Understanding of disease/treatment
Concern about vision loss
Comorbidities
Therapy
Doses per day
Cost
Adverse effects
Complexity of regimen
Provider
Rapport with patient
Patient perception of provider skill
Life Circumstances
Lack of support system
Traveling/vacation
Transportation
Complicated lifestyle

58
3/31/10 1:43 PM

While quite effective, oral CAIs are deemed third- or
fourth-line agents for POAG because they are not well
tolerated; thus, long-term use is uncommon.2 They are
approved for adjunctive use when maximum topical
therapy is inadequate, or for those persons who are intolerant of topicals.2 Metabolic acidosis is one of the most
common reasons for discontinuing systemic CAIs.
CAIs are sulfonamides, but are structurally different
from bacteriostatic sulfonamides. They may be used cautiously in patients with bacteriostatic sulfonamide allergy,
but CAIs should be discontinued if reactions suggestive
of sulfonamide hypersensitivity emerge.17 Patients at risk
for acidosis, electrolyte imbalance, or kidney or liver dysfunction should avoid systemic CAIs.
Cholinergics: Direct-acting (pilocarpine and carbachol)
and indirect-acting (cholinesterase inhibitor, echothiophate

iodide) parasympathomimetics exert a miotic effect. As the
pupil constricts, channels in the trabecular meshwork open,
reducing resistance to outflow of AH.1 These third- or
fourth-line glaucoma medications are rarely used today
because of the need for frequent dosing and significant
adverse effects such as blurred vision, cataracts, and retinal
detachment.2,12,16 It is important to note that excessive
miosis may severely restrict the flow of AH from the posterior to the anterior chamber. Thus, patients should be
closely monitored for pupillary block leading to ACG.
Systemic cholinergic adverse effects are also possible. Newer,
safer drugs have generally eclipsed the need for cholinergics.
Sympathomimetics: The alpha-adrenergic agonists brimonidine and apraclonidine, first-line sympathomimetic
agents, are selective to alpha2-receptors that increase uveoscleral outflow of AH, thereby decreasing IOP.2 In addition,
brimonidine reduces the production of AH. The efficacy
of apraclonidine typically wears off in less than a month,
so it is used specifically for short-term adjunctive therapy.
Common ocular adverse effects include burning, stinging, irritation, tearing, and eyelid edema. Mild ocular
allergic reactions, such as itching, are common with alphaadrenergic agonists. More serious allergic reactions may
develop over time and should be reported. Dizziness and
drowsiness occur rarely, so patients should be cautious
when performing hazardous activities that require alertness.
These drugs can potentiate the effects of depressants, such
as alcohol, barbiturates, and sedatives.
The nonspecific sympathomimetics epinephrine and
dipivefrin (a prodrug of epinephrine) increase the outflow
of AH through both the trabecular meshwork and uveoscleral route. If used long-term, they also decrease AH
production.12,16 Ophthalmic epinephrine is no longer
available in the U.S., and dipivefrin is rarely used because
of frequent local adverse effects and significant systemic

effects, including elevated blood pressure and irregular
heartbeat.12 It must be used cautiously in the elderly and
in persons with hypertension, diabetes, hypothyroidism,
and heart disease. Dipivefrin produces mydriasis and may
increase IOP by blocking outflow via the conventional
pathway. This situation may lead to ACG. Dipivefrin is
used primarily as an alternative treatment for those who
respond inadequately to other, safer medications.
ADHERENCE TO MEDICAL THERAPY

Poor adherence to therapy is a common problem with
chronic diseases. Patients with glaucoma face many challenges as they attempt to lower IOP and preserve their
vision through medical therapy regimens. Many studies
have attempted to identify obstacles to adherence and
define strategies for improving therapeutic outcomes.18-23
Some of the most common factors associated with poor
therapeutic adherence are listed in TABLE 3.
Failure to follow recommended therapeutic regimens
may lead to continued optic neuropathy and vision loss.
Health care professionals diagnose and educate about
glaucoma, prescribe and dispense medication, and monitor therapy, but the patient is ultimately responsible for
daily ongoing disease management. Home diagnostics
allow patients with many chronic diseases to monitor for
therapeutic efficacy: blood pressure readings (hypertension),
blood glucose levels (diabetes), peak flow measurement
(asthma). This valuable feedback allows patients to selfadjust behaviors or recognize the need to contact their
health care providers. No day-to-day self-monitoring is
available for patients with glaucoma. Moreover, because
glaucoma is largely asymptomatic, few cues alert patients
to disease progression.
Pharmacists are widely regarded as the most accessible
health care providers, and they enjoy the publics trust and
respect. They are ideally positioned to serve as teachers
and coaches for patients with glaucoma. Patients must be
educated about the disease process and the significance of
untreated or inadequately treated glaucoma. Therapeutic
regimens must be clearly explained to patients, including
the desired effect of therapy, possible side effects, and when
to contact a health care provider. Careful counseling,
augmented by periodic dialoguing, may help pharmacists
identify barriers to adherence and offer solutions to improve
outcomes. Pharmacists should assess patients understanding by asking questions and offering further explanation
or clarification as necessary.20
NEW HORIZONS
Visual function can be preserved by reducing IOP and
protecting RGCs from degeneration through pharmaco-
59
3/31/10 1:43 PM

logic and surgical therapies previously described. Unfortunately, in some patients, loss of RGCs progresses in
spite of well-controlled IOP. It appears RGC degeneration
could also be attributed to vascular insufficiency, axonal
transport blockade, diffusion of toxic agents into nerve
cells, initiation of apoptosis (programmed cell death),
and other causes.24
The concept of neuroprotection, preserving existing
RGCs, and rescuing damaged RGCs and their axons has
been proposed as superior to treatment modalities aimed
at lowering IOP because it would be effective irrespective
of disease etiology.25
Several groups of compounds, including the antioxidant
alpha-tocopherol, phenytoin, aminoguanidine, and the
N-methyl-d-aspartate receptor antagonist memantine, have
been proposed as possible candidates for RGC neuroprotection.26 Memantine showed promise in Phase I and II
trials but failed to pass Phase III clinical trials.24 The quest
for treatment modalities that can stop loss of vision remains
a subject of intense investigation.
CONCLUSION
Glaucoma, strongly associated with aging and vision loss,
is a serious public health concern in the U.S. because the
proportion of elderly persons in the population is rapidly
growing. Elevated IOP, along with other as yet unidentified
factors, contributes to optic neuropathy and vision loss. All
current treatment modalities are aimed at lowering IOP,
and adherence to medical therapy is important in preserving vision. Pharmacists may positively impact outcomes by
providing education about glaucoma, describing proper use
of prescribed medications, identifying barriers to treatment
adherence, and developing strategies to help patients overcome obstacles to successful management of glaucoma.
The authors gratefully acknowledge the editorial assistance of
Janet Shea, BSN, MPA.
Disclosure Statements:
Drs. OBrien, Chock, and Opere have no actual or potential conflicts of
interest in relation to this activity.
U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the
activity was planned to be balanced, objective, and scientifically rigorous.
Occasionally, authors express opinions that represent their own viewpoint.
Conclusions drawn by participants should be derived from objective analysis
of scientific data.
Disclaimer:
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The
information presented in this activity is not meant to serve as a guideline for
patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by
clinicians without evaluation of their patients conditions and possible contraindications or dangers in use, review of any applicable manufacturers product
information, and comparison with recommendations of other authorities.
EXAMINATION
Select one correct answer for each question and record your responses
on the examination answer sheet. Mail it to U.S. Pharmacist, address
shown on the answer sheet (photocopies are acceptable). Please allow
four weeks for processing. Alternatively, this exam can be taken online
at www.uspharmacist.com. Please contact CE Customer Service at
(800) 825-4696 or cecustomerservice@jobson.com with any questions.
2 CE Credits
Management for Pharmacists
1. Which medication class may be used orally as

adjunctive therapy for glaucoma?
A. Beta-blockers
C. Cholinergics
B. Carbonic anhydrase
D. Prostaglandins
inhibitors
2. Which medication may increase outflow of aqueous
humor through the trabecular meshwork?
A. Acetazolamide
C. Brimonidine
B. Bimatoprost
D. Timolol
3. Which treatment option results in permanent
reduction of aqueous humor production?
A. Cyclodestructive surgery C. Laser trabeculoplasty
B. Filtering surgery
D. Medication
4. Which is a patient-specific factor associated with
decreased adherence to therapy?
A. Complexity of regimen
C. Health literacy
B. Complicated lifestyle
D. Lack of support system
5. All current glaucoma treatment strategies aim to:
A. Decrease aqueous humor production
B. Decrease intraocular pressure
C. Increase aqueous humor outflow
D. Increase aqueous humor production
6. Optic nerve damage in primary open-angle
glaucoma is typically evidenced by:
A. Central field vision deficit
B. Intraocular pressure above 15 mmHg
C. Increased cup-to-disc ratio
D. Narrow anterior chamber angles
7. Which of the following is a prodrug of epinephrine?
A. Alphagan P
C. Iopidine
B. Betoptic
D. Propine
8. Structures of the conventional pathway include:
A. Aqueous humor, vitreous
B. Lens, cornea
C. Trabecular meshwork, Schlemms canal
D. Uvea, sclera
9. Which is an important risk factor for glaucoma?
A. Asian heritage
C. Myopia
B. Increasing age
D. Systemic hypertension
60
4/1/10 1:10 PM
10. Which is true of primary open-angle glaucoma?

A. Acute disease presentation
B. Disease is progressive
C. Typically only one eye is affected
D. Visual acuity decreases early in the disease process
11. Patients should wait at least ___ minutes between
instillation of eye drops:
A. 2
B. 5
C. 7
D. 10
12. Which medication is a sulfonamide?
A. Brimonidine
C. Carbachol
B. Brinzolamide
D. Carteolol
13. The two most commonly prescribed classes of
primary open-angle glaucoma medications are:
A. Alpha-adrenergic agonists and beta-blockers
B. Alpha-adrenergic agonists and cholinergics
C. Beta-blockers and prostaglandin analogs
D. Carbonic anhydrase inhibitors and prostaglandin
analogues
14. Which drug class causes darkening of the iris and
periorbital tissues?
A. Alpha-adrenergic agonists C. Cholinergics
B. Beta-blockers
D. Prostaglandin analogues
15. Metabolic acidosis is a common reason for
discontinuing:
A. Acetazolamide
C. Latanoprost
B. Apraclonidine
D. Metipranolol
16. Common, frequently transient adverse effects
associated with prostaglandin analogues include:
A. Body aches, dry eyes, excessive tearing
B. Blurred vision, dry eyes, excessive tearing
C. Dry eyes, periorbital discoloration, stinging
D. Intraocular inflammation, itching, rash
AN OVERVIEW OF GLAUCOMA
Examination Answer Sheet
Credits: 2.0 hours (0.20 ceu)

Expires: April 30, 2012
This exam can be taken online at www.uspharmacist.com. Upon passing, you can
print out your statement immediately and view your test history. Alternatively, you
can mail this answer sheet to the address below. Please contact CE Customer
Service at (800) 825-4696 or cecustomerservice@jobson.com with any questions.
Management for Pharmacists
Directions: Select one answer for each question in the exam and completely darken
the appropriate circle. A minimum score of 70% is required to earn credit. An identifier
is required to process your exam. This is used for internal processing purposes only.
Mail to: U.S. PharmacistCE, PO Box 487, Canal Street Station, New York, NY 10013
Check one:
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1 = Excellent 2 = Very Good 3 = Good

6 = N/A for Pharmacy Technicians
Rate the effectiveness of how well the activity:
21. Met objective 1:*
24. Met objective 4:
4 = Fair
5 = Poor
25. Related to your educational needs:
26. The active learning strategies

(questions, cases, discussions) were
appropriate and effective learning tools:
27. Avoided commercial bias:
28. How would you rate the overall

usefulness of the material presented?
29. How would you rate the quality of the faculty? 1
30. How would you rate the appropriateness

of the examination for this activity?
31. Comments on this activity:
* Also applies to pharmacy technicians.
Please retain a copy for your records. Please print clearly.

You must choose and complete ONE of the following three identifier types:
1 SS #
2 Last 4 digits of your SS # and date of birth
3 State Code and License #
17. Medications from which class of primary open-angle

glaucoma drugs are contraindicated in patients with
asthma and chronic obstructive pulmonary disease?
A. Beta-blockers
C. Cholinergics
inhibitors
18. Which class of drugs has no generic formulations?
A. Beta-blockers
C. Cholinergics
inhibitors
19. Which ophthalmic medication could cause
pupillary block leading to angle-closure glaucoma?
A. Brimonidine
C. Latanoprost
B. Levobunolol hydrochloride D. Pilocarpine
20. Aqueous humor is produced in the:
A. Ciliary body
C. Trabecular meshwork
B. Iris
D. Zonules
(Example: FL12345678)
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The following is your:
Home Address
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Profession:
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By submitting this answer sheet, I certify that I have read the lesson in its entirety and
completed the self-assessment exam personally based on the material presented.
I have not obtained the answers to this exam by any fraudulent or improper means.
Signature
Date
Postgraduate Healthcare Education, LLC is accredited by the
Accreditation Council for Pharmacy Education as a provider
of continuing pharmacy education.
61
Lesson 106698
Type of Activity: Knowledge
0430-0000-10-007-H01-P
0430-0000-10-007-H01-T
4/1/10 1:11 PM
U.S. Pharmacist Classifieds

CAREER OPPORTUNITIES
We are currently hiring for the following positions:
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Director of Pharmacy
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IL Sparta
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Shift F/T, 1 PRN);
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Together we are
Essential to care
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ATTN:PHARMACY TECHNICIANS
DISCOVER NPTA...the largest
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U.S. Pharmacist Classifieds


Toll Free: (800) 983-7737
Phone: (610) 854-3770
Fax: (610) 854-3780
AD INDEX
National
National
New Products - National
Actavis . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Reckitt Benckiser, Inc. . . . . . . . . . . . . . . 19
Combe, Inc. . . . . . . . . . . . . . . . . . . . . . . . 43
Sandoz Inc. . . . . . . . . . . . . . . . . . . . . . . . 16
Authorized Generics /
Greenstone LLC . . . . . . . . . . . . . . . . .51
Dr. Reddy's . . . . . . . . . . . . . . . . . . . . . . . 25
Santarus. . . . . . . . . . . . . . . . . . . . . . . . . . 27
Eli Lilly and Company. . . . . . . . . . . . . . . 38
Takeda Pharmaceuticals
North America, Inc. . . . . . . . . . . . . . . . CV2
Falcon Pharmaceuticals . . . . . . . . . . . . 21
Brimonidine /
Falcon Pharmaceuticals . . . . . . . . . .21
Teva Pharmaceuticals . . . . . . . . . . . . CV4
Dexilant / Takeda Pharmaceuticals

North America, Inc.. . . . . . . . . . . . . CV2
Health Systems
Imiquimod Cream / Fougera . . . . . . . .5
GlaxoSmithKline . . . . . . . . . . . . . . . . . . . 33
Amgen . . . . . . . . . . . . . . . . . . . HS17
New Products - Health Systems
Greenstone LLC . . . . . . . . . . . . . . . . . . . 51
Eli Lilly and Company . . . . . . . HS12
Humalog / Eli Lilly and Company . . HS12
Mylan Pharmaceuticals Inc. . . . . . . . . . . 3
Mylan Pharmaceuticals Inc. . . HS05
Injectables / Pfizer Injectables . . . . . HS01
Novo Nordisk. . . . . . . . . . . . . . . . . . . . . . 35
Pfizer Injectables . . . . . . . . . . . HS01
QS/1 Data System . . . . . . . . . . . . . . . . . 31
Waste Management - Segments . . HS21
Forest Labs, Inc. . . . . . . . . . . . . . . . . . . . . 7

Fougera . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Gallipot . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
Pharmacy Law
Steroid Marketing
Convictions
The illegal distribution
of anabolic steroids and
human growth hormone
can cost pharmacists
their licenses and more.
wo recently decided cases

illustrate the point that pharmacists can easily step over
the boundaries of legal behavior by
pursuing business opportunities that,
while profitable, are also illegal. Both
cases involve compounding pharmacies that employed questionable habits of distributing steroids, hormones, and other specialty products
that landed the pharmacist-owners
and several other individuals in jail,
with stiff fines and loss of their
licenses to practice.
Case #1: Operation Which Doctor

A pharmacist-owner of a compounding pharmacy was recently convicted
in Mobile, Alabama, on charges of
illegal distribution of anabolic steroids and other drugs.1 The investigation alleged that illegal activities
began in 2006. After a month-long
trial and 4 days of deliberations, a
federal jury also convicted the supervising pharmacist, two partial owners, and the corporate secretary of
the pharmacy, along with the owner
Jesse C. Vivian, RPh, JD
Professor, Department of Pharmacy Practice
College of Pharmacy and Health Sciences
Wayne State University
Detroit, Michigan
of a Colorado Internet anti-aging

clinic, guilty of conspiracy in the
same case. Acquitted were three
employee pharmacists and an investor in the clinic. The investor was a
Colorado sheriffs deputy who
started out as a customer.
Another individual, identified as
an alternative medicine practitioner
and a naturopathic medical doctor
from Arizona, was indicted as a
coconspirator and will be tried separately later this year. This Arizona
physician fled to Latin America after
he was indicted.2 He made contact
with the U.S. Embassy in Costa
Rica and returned to Florida in
October 2009, where he was apprehended by federal authorities. This
physician is charged with distribution of controlled substances, conspiracy to distribute, money laundering, and criminal forfeiture.
According to prosecutors, he used
steroids himself and conspired with
the Alabama pharmacists to dispense
and sell anabolic steroids for no
legitimate medical purpose.
Earlier in the same case, a Colorado Springs business owner pled
guilty to related charges of conspiracy to distribute steroids and money
laundering in a scheme that netted
$4 million.3 At least 17 physicians
and executives of this business, who
previously had pleaded guilty to steroids charges, testified that they colluded with the anti-aging clinic to
supply steroids to bodybuilders, athletes, and other healthy customers.
In addition, 12 other individuals
from Alabama, Colorado, and Tennessee were indicted after a long-
term investigation into the distribution of anabolic steroids to

physicians, gyms, and workout clubs
nationwide. The convicted pharmacist-owner from Alabama was identified as a ringleader in the plot. Federal prosecutors filed a 198-count
indictment against the individuals
charged with these crimes.4 Each
person who pled or was found guilty
faces imprisonment of 5 to 12 years.
The pharmacists who filled the
steroid prescriptions in Alabama
claimed that they thought the orders
were legitimate because they were
signed by licensed physicians. The
pharmacy profited in the millions of
dollars from the conspiracy ring that
included physicians writing fraudulent prescriptions during its operation from 2003 to 2006.5
Some of the drugs that were dispensed have been approved by the
FDA only for use in fattening veterinary livestock and not for use in
humans. The anabolic steroids that
were dispensed included boldenone
undecylenate (Equipoise); fluoxymesterone (Halotestin); nandrolone
(Deca); nandrolone decanoate (Durabolin); nandrolone decanoate/testosterone undecanoate (Nandrotest);
oxandrolone (Anavar); oxymetholone
(Anadrol); stanozolol capsules (Winstrol), injectable (Winstrol-V), and
gel; and trenbolone acetate (Fina).
Forms of testosterone that were dispensed include testosterone cypionate,
testosterone decanoate, testosterone
enanthate, testosterone ICED, testosterone isocaproate, testosterone
phenylpropionate, testosterone propionate, and testosterone suspension.6
64
64 Law 3_30bosc.indd 64
3/31/10 1:43 PM
STEROID MARKETING CONVICTIONS

Records obtained by the Drug
Enforcement Agency (DEA) during
a raid of the pharmacy in 2006
showed that customers included
baseball players Jose Canseco and
John Rocker, professional boxer
Evander Holyfield, and more than a
dozen other athletes.7 This investigation later became known among law
enforcement agencies as Operation
Which Doctor.
Evidence showed that the clinic
advertised in gyms, health clubs, and
other spots to entice clientele across
the country. One of the defendants
boasted that he had customers in 41
states. The clinic recruited prescribers to issue the steroid prescriptions
without ever seeing the patient in
most cases. The clinic faxed the
orders to the Alabama pharmacy,
which was shipping as many as 250
packages per day. Many of the customers were under 21 and at least
three teenagers obtained steroids
from the pharmacy.8
Case #2: Fall of a Pioneer in

Prescription Compounding
In a separate case taking place at
almost the same time and involving
similar charges, another compounding pharmacist, also from Colorado
Springs, was convicted in federal
court on 31 charges of illegally
importing and distributing anabolic
steroids and human growth hormone
(hGH, sometimes called somatotropin) manufactured in China.9,10
The trial took nearly a month to
complete, and jurors deliberated for
3 days before convicting the pharmacist.11 The jury determined that
he should forfeit $4.8 million in
assets and the land where the pharmacy was located. The sentence
could include up to 20 years in a
federal prison and a criminal fine of
$250,000. Sentencing is scheduled
to take place on April 29, 2010.
The pharmacy was once hailed as
a pioneer in prescription compounding.12 At one time it employed 15

pharmacists and another 15 to 20
technicians who worked in the pharmacys laboratories. Physicians, primarily dermatologists, sought out
the pharmacy for its ability to make
custom compounds. The pharmacy
specialized in making special orders
from raw chemicals, a talent that
was unique to the area at the time.
Spurred by a book published in the
early 1980s by Katharina Dalton on
the use of progesterone in treating
PMS,13 the pharmacist-owner took
special interest in the emerging treatment of female health issues. As a
result, he began to produce custommade progesterone suppositories.
Soon, physicians from all over the
country were sending in prescriptions to be compounded, with over
90% of the hormone-compounding
business originating from out-oftown prescribers. By 2003, the pharmacy employed an administrative
staff of five and dozens of customer
service representatives. The pharmacist began traveling the world lecturing physician and nursing groups on
emerging therapies. Womens health
continued to be the prime focus. A
chief operating officer and marketing
director were hired to lead in strategic planning, finance, marketing,
promotion, customer service, and
client education. The goal was to
double the business in a short time,
but then things started to sour.
According to the indictment, the
pharmacist-owner, along with two
accomplices, intended to devise a
scheme to defraud physicians to
whom they marketedand the
patients of those physiciansby
means of materially false and fraudulent pretenses and representations.14
The pharmacy was alleged to have
combined FDA-approved medications with unapproved drugs for a
new regimen specific to a patient.
According to one organization,

Pharmwatch, The pharmacy is one
of several that supply nonstandard
products to offbeat physicians who
do chelation therapy, mesotherapy,
and other dubious treatments.15
The jury also found the pharmacist guilty of two counts of conspiracy. In this case, testosterone was
sold to bodybuilders who had no
legitimate relationship with physicians. One of those counts charged
that the pharmacist and others conspired to facilitate the sale of the
Chinese-made hGH, which was
misbranded and was not approved
by the FDA, knowing it had been
imported into the U.S. in violation
of the law. The other conspiracy
count charged that the pharmacist
engaged in an illegal conspiracy to
manufacture, distribute, dispense,
and possess with intent to distribute
anabolic steroids.
Included in the guilty verdict are
27 counts of distributing hGH, with
23 counts of selling the hormone to
minors. The jury also found the
pharmacist guilty of one count of
facilitating the sale of smuggled
hGH and one count of possessing
with intent to distribute hGH. He
was found not guilty of the single
charge of receiving smuggled goods.
The jury disagreed with the pharmacists contention that the illegal
drugs he distributed were not subject
to FDA approval due to the lax
restrictions on particular compounded drugs. The evidence
revealed that the pharmacist had
managed to distribute the drugs to
physicians in Florida, Georgia, Illinois, and Indiana between April
2004 and February 2007.16
The pharmacy had claimed in
advertisements that it is one of the
largest, most comprehensive compounding centers in North America.17 It had been in trouble with
the law on prior occasions. In 2005,
65
3/31/10 1:43 PM
STEROID MARKETING CONVICTIONS

the pharmacy was placed on probation by the Colorado Board of Pharmacy as a result of complaints that
its pharmacists incorrectly dispensed
medications as far back as 2002. The
pharmacy was fined $50,000 and
required to report how many prescriptions it dispensed to patients,
physicians, and other pharmacies on
a quarterly basis for 4 years.18 In
2004, it was fined $1,000 for failing
to report a change in managers as
required by state law. The Colorado
Board of Pharmacy has revoked the
pharmacist-owners license.19
Anabolic Steroids
According to the DEA, anabolic steroids are a class of drugs with a basic
steroid ring structure that produce
anabolic and androgenic effects. The
chemicals are synthetically produced
variants of the naturally occurring
male hormone testosterone. Both
males and females produce testosterone in their bodies: males in the testes and females in the ovaries and
other tissues. The full name for this
class of drugs is androgenic (promoting masculine characteristics) anabolic (tissue-building) steroids (the
class of drugs).20 Athletes, bodybuilders, and others abuse anabolic
REFERENCES
1. Kirby B. Jury finds 5 guilty in Mobile steroids conspiracy
case. Alabama Live LLC. February 8, 2010.
http://blog.al.com/live/2010/02/jury_convicts_owners_of_
applie.html. Accessed February 17, 2010.
2. Vinton N, OKeeffe M. Arizona naturopath Jesse Haggard
faces music in steroid prosecution. NY Daily News. October 7,
2009. www.nydailynews.com/sports/2009/10/07/2009-10-07_
steroids.html. Accessed February 24, 2010.
3. Associated Press. Mobile business owner pleads guilty to
steroid distribution. October 19, 2009.
http://wkrg.com/460434. Accessed February 17, 2010.
4. Baker M. Political grandstanding in Applied Pharmacy Services indictment for steroid distribution. MesoRx. January 23,
2010. www.mesomorphosis.com/blog/2009/01/23/indictmentagainst-applied-pharmacy-services-steroid-distribution-network/.
5. Kirby B. Mobile steroids trial nearing end; Applied Pharmacy
charged with supplying star athletes. Alabama Live LLC.
February 2, 2010. http://blog.al.com/live/2010/02/lawyers_
debate_steroids_sales.html. Accessed February 17, 2010.
6. See Note 4, supra.
7. OKeeffe M. Pharmacy owners indicted for role in performance-enhancing drug ring. NY Daily News. January 24, 2009.
www.nydailynews.com/sports/2009/01/23/2009-01-23_
pharmacy_owners_indicted_for_role_in_per.html.
steroids with the intent to improve

athletic performance, muscle
strength, and appearance.21
Anabolic steroid abuse has been
associated with a wide range of
adverse side effects ranging from
those that are physically unattractive,
such as acne and breast development
in men, to others that are life threatening, such as heart attacks and liver
cancer. Most of the effects are reversible if the abuser stops taking the
drug, but some can be permanent.
In addition to the physical effects,
anabolic steroids can cause increased
irritability and aggression.22 Currently, there are more than 100 different types of anabolic steroids that
have been developed, and each
requires a prescription to be used
legally in the U.S.23 The Anabolic
Steroid Control Act of 2004 placed
32 additional steroids in Schedule
III and expanded the DEAs regulatory and enforcement authority.
The possession or sale of anabolic
steroids without a valid prescription
is illegal. Simple possession of illicitly
obtained anabolic steroids carries a
maximum penalty of 1 year in
prison and a minimum $1,000 fine
if this is an individuals first drug
offense. The maximum penalty for
trafficking is 5 years in prison and a

fine of $250,000 if this is the individuals first felony drug offense. If
this is the second felony drug
offense, the maximum period of
imprisonment and the maximum
fine both double. While the above
listed penalties are for federal
offenses, individual states have also
implemented fines and penalties for
illegal use of anabolic steroids.24

9. See, e.g., The Anabolic Network. www.steroid.com/HumanGrowth-Hormone.php; and Somatotropin. www.answers.com/
topic/somatotropin. Accessed February 24, 2010
10. Springs pharmacist convicted of importing, distributing
steroids. The Denver Channel. February 2, 2010.
www.thedenverchannel.com/news/22416726/detail.html.
11. Springs pharmacist convicted of dealing steroids. KRDO.
February 9, 2010. www.krdo.com/Global/story.asp?S=11922419.
12. Hurley B. College pharmacy pioneers prescription compounding. Colorado Springs Business J. February 21, 2003.
http://findarticles.com/p/articles/mi_qn4190/is_20030221/ai_
n10044518/. Accessed February 24, 2010.
13. Interview: Katharina Dalton, MD: progesterone and related
topics. Int J Pharm Compound. Sept/Oct 1999.
www.natural-progesterone-advisory-network.com/PDFs/dalton.pdf.
Accessed March 2, 2010.
14. McSwane D. Thomas Bader, Colorado Springs pharmacist,
made millions in illegal steroid distribution to docs and
minorsuntil a jury popped the bubble. Denver Westword
Blogs. February 3, 2010. http://blogs.westword.com/latestword/2010/02/springs_pharmacist_thomas_bade.php.
15. Barrett S. Compounding pharmacy indicted for illegal

hormone sales. Pharmwatch. October 16, 2007.
www.pharmwatch.org/comp/college/indictment.shtml.
16. Spring pharmacist gets 31 counts related to steroids and
HGH distribution. Steroid Sources. February 8, 2010.
www.steroidsources.com/Steroid-Information/2010/02/springspharmacist-gets-31-counts-related-to-steroids-and-hgh-distribution/.
19. Barrett S. Compounding pharmacy operators charged with
illegal growth hormone sales. Casewatch. June 24, 2009.
www.casewatch.org/doj/college/indictment.shtml. Accessed
February 24, 2010.
20. Anabolic steroids: hidden dangers. DEA. March 2004.
www.justice.gov/dea/concern/steroids.html. Accessed
March 2, 2010.
21. Drugs and chemicals of concern: anabolic steroids. DEA. June
2009. www.deadiversion.usdoj.gov/drugs_concern/anabolic.htm.
Accessed March 2, 2010.
22. National Institute on Drug Abuse Research Report Series.
Anabolic Steroid Abuse. Revised August 2006.
www.nida.nih.gov/PDF/RRSteroids.pdf. Accessed March 2, 2010.
23. Id.
Analysis
Steroids, growth hormones, and
related drugs all have legitimate therapeutic uses, and compounding of
specialty products for unique situations is at the core of good pharmacy practice. But, as demonstrated
by the above cases, there are limits
that cannot be exceeded, lest the
power of law come knocking on
your door. Compounding medications requires a prescription that
comes from a licensed prescriber acting in the normal course of practice
for an individual with whom the
prescriber has a legitimate patient
relationship, and is issued for a legal
medical purpose. Staying within
these guidelines will ensure that
pharmacists are engaged in useful,
valid practices.
66
3/31/10 1:43 PM
BRIEF SUMMARY
PRAMIPEXOLE DIHYDROCHLORIDE TABLETS

CONTRAINDICATIONS
Pramipexole dihydrochloride tablets are contraindicated in patients
who have demonstrated hypersensitivity to the drug or its ingredients.
WARNINGS
Falling Asleep During Activities of Daily Living
Patients treated with pramipexole dihydrochloride tablets have
reported falling asleep while engaged in activities of daily living,
including the operation of motor vehicles which sometimes resulted
in accidents. Although many of these patients reported somnolence
while on pramipexole dihydrochloride tablets, some perceived
that they had no warning signs such as excessive drowsiness, and
believed that they were alert immediately prior to the event. Some
of these events have been reported as late as one year after the
initiation of treatment.
Somnolence is a common occurrence in patients receiving
pramipexole dihydrochloride tablets at doses above 1.5 mg/day
(0.5 mg TID) for Parkinsons disease. Many clinical experts believe
that falling asleep while engaged in activities of daily living always
occurs in a setting of preexisting somnolence, although patients
may not give such a history. For this reason, prescribers should
continually reassess patients for drowsiness or sleepiness,
especially since some of the events occur well after the start of
treatment. Prescribers should also be aware that patients may not
acknowledge drowsiness or sleepiness until directly questioned
about drowsiness or sleepiness during specic activities.
Before initiating treatment with pramipexole dihydrochloride
tablets, patients should be advised of the potential to develop
drowsiness and specically asked about factors that may increase
the risk with pramipexole dihydrochloride tablets such as
concomitant sedating medications, the presence of sleep disorders,
and concomitant medications that increase pramipexole plasma
levels (e.g., cimetidine see PRECAUTIONS, Drug Interactions).
If a patient develops signicant daytime sleepiness or episodes
of falling asleep during activities that require active participation
(e.g., conversations, eating, etc.), pramipexole dihydrochloride
tablets should ordinarily be discontinued. If a decision is made
to continue pramipexole dihydrochloride tablets, patients should
be advised to not drive and to avoid other potentially dangerous
activities. While dose reduction clearly reduces the degree of
somnolence, there is insufcient information to establish that dose
reduction will eliminate episodes of falling asleep while engaged
in activities of daily living.
Symptomatic Hypotension
Dopamine agonists, in clinical studies and clinical experience, appear
to impair the systemic regulation of blood pressure, with resulting
orthostatic hypotension, especially during dose escalation. Parkinsons
disease patients, in addition, appear to have an impaired capacity to
respond to an orthostatic challenge. For these reasons, Parkinsons
disease patients being treated with dopaminergic agonists ordinarily
require careful monitoring for signs and symptoms of orthostatic
hypotension, especially during dose escalation, and should be
informed of this risk (see PRECAUTIONS, Information for Patients).
In clinical trials of pramipexole, however, and despite clear orthostatic
effects in normal volunteers, the reported incidence of clinically
signicant orthostatic hypotension was not greater among those
assigned to pramipexole dihydrochloride tablets than among those
assigned to placebo. This result, especially with the higher doses used
in Parkinsons disease, is clearly unexpected in light of the previous
experience with the risks of dopamine agonist therapy.
While this nding could reect a unique property of pramipexole, it
might also be explained by the conditions of the study and the nature
of the population enrolled in the clinical trials. Patients were very
carefully titrated, and patients with active cardiovascular disease or
signicant orthostatic hypotension at baseline were excluded.
Hallucinations
In the three double-blind, placebo-controlled trials in early
Parkinsons disease, hallucinations were observed in 9% (35 of 388)
of patients receiving pramipexole dihydrochloride tablets, compared
with 2.6% (6 of 235) of patients receiving placebo. In the four doubleblind, placebo-controlled trials in advanced Parkinsons disease,
where patients received pramipexole dihydrochloride tablets and
concomitant levodopa, hallucinations were observed in 16.5% (43
of 260) of patients receiving pramipexole dihydrochloride tablets
compared with 3.8% (10 of 264) of patients receiving placebo.
Hallucinations were of sufcient severity to cause discontinuation of
treatment in 3.1% of the early Parkinsons disease patients and 2.7%
of the advanced Parkinsons disease patients compared with about
0.4% of placebo patients in both populations.
Age appears to increase the risk of hallucinations attributable to
pramipexole. In the early Parkinsons disease patients, the risk of
hallucinations was 1.9 times greater than placebo in patients younger
than 65 years and 6.8 times greater than placebo in patients older than
65 years. In the advanced Parkinsons disease patients, the risk of
hallucinations was 3.5 times greater than placebo in patients younger
than 65 years and 5.2 times greater than placebo in patients older
than 65 years.
PRECAUTIONS
Rhabdomyolysis
A single case of rhabdomyolysis occurred in a 49 year-old male
with advanced Parkinsons disease treated with pramipexole
dihydrochloride tablets. The patient was hospitalized with an elevated
CPK (10,631 IU/L). The symptoms resolved with discontinuation of
the medication.
Renal
Since pramipexole is eliminated through the kidneys, caution
should be exercised when prescribing pramipexole dihydrochloride
tablets to patients with renal insufciency (see DOSAGE AND
ADMINISTRATION).
Dyskinesia
Pramipexole dihydrochloride tablets may potentiate the dopaminergic
side effects of levodopa and may cause or exacerbate preexisting
dyskinesia. Decreasing the dose of levodopa may ameliorate this side
effect.
Retinal Pathology in Albino Rats
Pathologic changes (degeneration and loss of photoreceptor cells)
were observed in the retina of albino rats in the 2 year carcinogenicity
study. While retinal degeneration was not diagnosed in pigmented
rats treated for 2 years, a thinning in the outer nuclear layer of the
retina was slightly greater in rats given drug compared with controls.
Evaluation of the retinas of albino mice, monkeys, and minipigs did
not reveal similar changes. The potential signicance of this effect in
humans has not been established, but cannot be disregarded because
disruption of a mechanism that is universally present in vertebrates

(i.e., disk shedding) may be involved (see ANIMAL TOXICOLOGY).
Events Reported with Dopaminergic Therapy
Although the events enumerated below may not have been reported in
association with the use of pramipexole in its development program,
they are associated with the use of other dopaminergic drugs. The
expected incidence of these events, however, is so low that even if
pramipexole caused these events at rates similar to those attributable
to other dopaminergic therapies, it would be unlikely that even a
single case would have occurred in a cohort of the size exposed to
pramipexole in studies to date.
Withdrawal-Emergent Hyperpyrexia and Confusion
Although not reported with pramipexole in the clinical development
program, a symptom complex resembling the neuroleptic malignant
syndrome (characterized by elevated temperature, muscular rigidity,
altered consciousness, and autonomic instability), with no other
obvious etiology, has been reported in association with rapid dose
reduction, withdrawal of, or changes in antiparkinsonian therapy.
Fibrotic Complications
Although not reported with pramipexole in the clinical development
program, cases of retroperitoneal brosis, pulmonary inltrates, pleural
effusion, and pleural thickening, pericarditis, and cardiac valvulopathy
have been reported in some patients treated with ergot derived
dopaminergic agents. While these complications may resolve when the
drug is discontinued, complete resolution does not always occur.
Although these adverse events are believed to be related to the
ergoline structure of these compounds, whether other, nonergot
derived dopamine agonists can cause them is unknown.
A small number of reports have been received of possible brotic
complications, including peritoneal brosis, pleural brosis, and
pulmonary brosis, in the postmarketing experience for pramipexole.
While the evidence is not sufcient to establish a causal relationship
between pramipexole and these brotic complications, a contribution
of pramipexole cannot be completely ruled out in rare cases.
Melanoma
Epidemiological studies have shown that patients with Parkinsons
disease have a higher risk (2- to approximately 6-fold higher) of
developing melanoma than the general population. Whether the
increased risk observed was due to Parkinsons disease or other
factors, such as drugs used to treat Parkinsons disease, is unclear.
For the reasons stated above, patients and providers are advised
to monitor for melanomas frequently and on a regular basis when
using pramipexole dihydrochloride tablets for any indication. Ideally,
periodic skin examinations should be performed by appropriately
qualied individuals (e.g., dermatologists).
Information for Patients (also see available Patient Package Insert)
Patients should be instructed to take pramipexole dihydrochloride
tablets only as prescribed.
Patients should be alerted to the potential sedating effects associated
with pramipexole dihydrochloride tablets, including somnolence and
the possibility of falling asleep while engaged in activities of daily
living. Since somnolence is a frequent adverse event with potentially
serious consequences, patients should neither drive a car nor engage
in other potentially dangerous activities until they have gained sufcient
experience with pramipexole dihydrochloride tablets to gauge whether
or not it affects their mental and/or motor performance adversely.
Patients should be advised that if increased somnolence or new
episodes of falling asleep during activities of daily living (e.g., watching
television, passenger in a car, etc.) are experienced at any time during
treatment, they should not drive or participate in potentially dangerous
activities until they have contacted their physician. Because of possible
additive effects, caution should be advised when patients are taking
other sedating medications or alcohol in combination with pramipexole
dihydrochloride tablets and when taking concomitant medications that
increase plasma levels of pramipexole (e.g., cimetidine).
Patients should be informed that hallucinations can occur and that
the elderly are at a higher risk than younger patients with Parkinsons
disease.
There have been reports of patients experiencing intense urges
to gamble, increased sexual urges, and other intense urges and
the inability to control these urges while taking one or more of
the medications that increase central dopaminergic tone, that are
generally used for the treatment of Parkinsons disease, including
pramipexole dihydrochloride. Although it is not proven that the
medications caused these events, these urges were reported to have
stopped in some cases when the dose was reduced or the medication
was stopped. Prescribers should ask patients about the development
of new or increased gambling urges, sexual urges or other urges
while being treated with pramipexole dihydrochloride. Patients should
inform their physician if they experience new or increased gambling
urges, increased sexual urges or other intense urges while taking
pramipexole dihydrochloride. Physicians should consider dose
reduction or stopping the medication if a patient develops such urges
while taking pramipexole dihydrochloride.
Patients may develop postural (orthostatic) hypotension, with or
without symptoms such as dizziness, nausea, fainting or blackouts,
and sometimes, sweating. Hypotension may occur more frequently
during initial therapy. Accordingly, patients should be cautioned
against rising rapidly after sitting or lying down, especially if they have
been doing so for prolonged periods and especially at the initiation of
treatment with pramipexole dihydrochloride tablets.
Because the teratogenic potential of pramipexole has not been
completely established in laboratory animals, and because experience
in humans is limited, patients should be advised to notify their
physicians if they become pregnant or intend to become pregnant
during therapy (see PRECAUTIONS, Pregnancy).
Because of the possibility that pramipexole may be excreted in breast
milk, patients should be advised to notify their physicians if they
intend to breast-feed or are breast-feeding an infant.
If patients develop nausea, they should be advised that taking
pramipexole with food may reduce the occurrence of nausea.
Laboratory Tests
During the development of pramipexole dihydrochloride tablets,
no systematic abnormalities on routine laboratory testing were
noted. Therefore, no specic guidance is offered regarding routine
monitoring; the practitioner retains responsibility for determining how
best to monitor the patient in his or her care.
Drug Interactions
Carbidopa/levodopa
Carbidopa/levodopa did not inuence the pharmacokinetics of
pramipexole in healthy volunteers (N=10). Pramipexole did not
alter the extent of absorption (AUC) or the elimination of carbidopa/
levodopa, although it caused an increase in levodopa Cmax by about
40% and a decrease in Tmax from 2.5 to 0.5 hours.
Selegiline
In healthy volunteers (N=11), selegiline did not inuence the
pharmacokinetics of pramipexole.
Amantadine
Population pharmacokinetic analysis suggests that amantadine may
slightly decrease the oral clearance of pramipexole.
Cimetidine
Cimetidine, a known inhibitor of renal tubular secretion of organic
bases via the cationic transport system, caused a 50% increase in
pramipexole AUC and a 40% increase in half-life (N=12).
Probenecid
Probenecid, a known inhibitor of renal tubular secretion of organic
acids via the anionic transporter, did not noticeably inuence
pramipexole pharmacokinetics (N=12).
Other Drugs Eliminated Via Renal Secretion
Population pharmacokinetic analysis suggests that coadministration
of drugs that are secreted by the cationic transport system (e.g.,
cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine,
and quinine) decreases the oral clearance of pramipexole by about
20%, while those secreted by the anionic transport system (e.g.,
cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and
chlorpropamide) are likely to have little effect on the oral clearance
of pramipexole.
CYP Iinteractions
Inhibitors of cytochrome P450 enzymes would not be expected to
affect pramipexole elimination because pramipexole is not appreciably
metabolized by these enzymes in vivo or in vitro. Pramipexole does
not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and
CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of
30 M, indicating that pramipexole will not inhibit CYP enzymes at
plasma concentrations observed following the clinical dose of 4.5 mg/
day (1.5 mg TID).
Dopamine Antagonists
Since pramipexole is a dopamine agonist, it is possible that
dopamine antagonists, such as the neuroleptics (phenothiazines,
butyrophenones, thioxanthenes) or metoclopramide, may diminish
the effectiveness of pramipexole dihydrochloride tablets.
Drug/Laboratory Test Interactions
There are no known interactions between pramipexole dihydrochloride
tablets and laboratory tests.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Two year carcinogenicity studies with pramipexole have been
conducted in mice and rats. Pramipexole was administered in the diet
to Chbb:NMRI mice at doses of 0.3, 2, and 10 mg/kg/day (0.3, 2.2,
and 11 times the maximum recommended human dose [MRHD of
1.5 mg TID on a mg/m2 basis). Pramipexole was administered in the
diet to Wistar rats at 0.3, 2, and 8 mg/kg/day (plasma AUCs were 0.3,
2.5, and 12.5 times the AUC in humans at the MRHD). No signicant
increases in tumors occurred in either species.
Pramipexole was not mutagenic or clastogenic in a battery of assays,
including the in vitro Ames assay, V79 gene mutation assay for
HGPRT mutants, chromosomal aberration assay in Chinese hamster
ovary cells, and in vivo mouse micronucleus assay.
In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5
times the MRHD on a mg/m2 basis), prolonged estrus cycles and
inhibited implantation. These effects were associated with reductions
in serum levels of prolactin, a hormone necessary for implantation
and maintenance of early pregnancy in rats.
Pregnancy
Teratogenic Effects
Pregnancy Category C
When pramipexole was given to female rats throughout pregnancy,
implantation was inhibited at a dose of 2.5 mg/kg/day (5 times the
maximum recommended human dose [MRHD] on a mg/m2 basis).
Administration of 1.5 mg/kg/day of pramipexole to pregnant rats
during the period of organogenesis (gestation days 7 through 16)
resulted in a high incidence of total resorption of embryos. The plasma
AUC in rats at this dose was 4 times the AUC in humans at the MRHD.
These ndings are thought to be due to the prolactin lowering effect
of pramipexole, since prolactin is necessary for implantation and
maintenance of early pregnancy in rats (but not rabbits or humans).
Because of pregnancy disruption and early embryonic loss in these
studies, the teratogenic potential of pramipexole could not be
adequately evaluated. There was no evidence of adverse effects on
embryo fetal development following administration of up to 10 mg/
kg/day to pregnant rabbits during organogenesis (plasma AUC was 71
times that in humans at the MRHD). Postnatal growth was inhibited
in the offspring of rats treated with 0.5 mg/kg/day (approximately
equivalent to the MRHD on a mg/m2 basis) or greater during the latter
part of pregnancy and throughout lactation.
There are no studies of pramipexole in human pregnancy. Because
animal reproduction studies are not always predictive of human
response, pramipexole should be used during pregnancy only if the
potential benet outweighs the potential risk to the fetus.
Nursing Mothers
A single-dose, radio-labeled study showed that drug-related materials
were excreted into the breast milk of lactating rats. Concentrations of
radioactivity in milk were three to six times higher than concentrations
in plasma at equivalent time points.
Other studies have shown that pramipexole treatment resulted in an
inhibition of prolactin secretion in humans and rats.
It is not known whether this drug is excreted in human milk. Because
many drugs are excreted in human milk and because of the potential
for serious adverse reactions in nursing infants from pramipexole, a
decision should be made as to whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug
to the mother.
Pediatric Use
The safety and efcacy of pramipexole dihydrochloride tablets in
pediatric patients has not been established.
Geriatric Use
Pramipexole total oral clearance was approximately 30% lower
in subjects older than 65 years compared with younger subjects,
because of a decline in pramipexole renal clearance due to an agerelated reduction in renal function. This resulted in an increase in
elimination half-life from approximately 8.5 hours to 12 hours. In
clinical studies with Parkinsons disease patients, 38.7% of patients
were older than 65 years. There were no apparent differences in
efcacy or safety between older and younger patients, except that the
relative risk of hallucination associated with the use of pramipexole
dihydrochloride tablets was increased in the elderly.
ADVERSE REACTIONS
Parkinsons Disease
During the premarketing development of pramipexole, patients with
either early or advanced Parkinsons disease were enrolled in clinical
trials. Apart from the severity and duration of their disease, the two
populations differed in their use of concomitant levodopa therapy.
Patients with early disease did not receive concomitant levodopa
therapy during treatment with pramipexole; those with advanced

Parkinsons disease all received concomitant levodopa treatment.
Because these two populations may have differential risks for various
adverse events, this section will, in general, present adverse event
data for these two populations separately.
Because the controlled trials performed during premarketing
development all used a titration design, with a resultant confounding
of time and dose, it was impossible to adequately evaluate the effects
of dose on the incidence of adverse events.
Early Parkinsons Disease
In the three double-blind, placebo-controlled trials of patients with
early Parkinsons disease, the most commonly observed adverse
events (>5%) that were numerically more frequent in the group treated
with pramipexole dihydrochloride tablets were nausea, dizziness,
somnolence, insomnia, constipation, asthenia, and hallucinations.
Approximately 12% of 388 patients with early Parkinsons disease and
treated with pramipexole dihydrochloride tablets who participated in
the double-blind, placebo-controlled trials discontinued treatment due
to adverse events compared with 11% of 235 patients who received
placebo. The adverse events most commonly causing discontinuation
of treatment were related to the nervous system (hallucinations
[3.1% on pramipexole dihydrochloride tablets vs 0.4% on placebo];
dizziness [2.1% on pramipexole dihydrochloride tablets vs 1% on
placebo]; somnolence [1.6% on pramipexole dihydrochloride tablets
vs 0% on placebo]; extrapyramidal syndrome [1.6% on pramipexole
dihydrochloride tablets vs 6.4% on placebo]; headache and confusion
[1.3% and 1.0%, respectively, on pramipexole dihydrochloride tablets
vs 0% on placebo]); and gastrointestinal system (nausea [2.1% on
pramipexole dihydrochloride tablets vs 0.4% on placebo]).
Adverse-Event Incidence in Controlled Clinical Studies in Early
Parkinsons Disease
Table 1 lists treatment-emergent adverse events that occurred in the
double-blind, placebo-controlled studies in early Parkinsons disease
that were reported by 1% of patients treated with pramipexole
dihydrochloride tablets and were numerically more frequent than
in the placebo group. In these studies, patients did not receive
concomitant levodopa. Adverse events were usually mild or moderate
in intensity.
The prescriber should be aware that these gures cannot be used
to predict the incidence of adverse events in the course of usual
medical practice where patient characteristics and other factors
differ from those that prevailed in the clinical studies. Similarly, the
cited frequencies cannot be compared with gures obtained from
other clinical investigations involving different treatments, uses, and
investigators. However, the cited gures do provide the prescribing
physician with some basis for estimating the relative contribution of
drug and nondrug factors to the adverse-event incidence rate in the
population studied.
Table 1: Treatment-Emergent Adverse-Event* Incidence

in Double-Blind, Placebo-Controlled Trials in Early
Parkinsons Disease (Events 1% of Patients Treated
With Pramipexole Dihydrochloride Tablets and
Numerically More Frequent Than in the Placebo Group)
Body System/
Pramipexole
Placebo
Adverse Event
dihydrochloride
N=235
N=388
Body as a Whole
Asthenia
14
12
General Edema
Malaise
Reaction unevaluable
Fever
Nausea
28
18
Constipation
14
4
2
2
0
Disgestive System
Anorexia
Dysphagia
Metabolic &
Nutritional System
Peripheral edema
Decreased weight
reported equally or more frequently in the placebo group were

infection, accidental injury, headache, pain, tremor, back pain, syncope,
postural hypotension, hypertonia, depression, abdominal pain, anxiety,
dyspepsia, atulence, diarrhea, rash, ataxia, dry mouth, extrapyramidal
syndrome, leg cramps, twitching, pharyngitis, sinusitis, sweating,
rhinitis, urinary tract infection, vasodilation, u syndrome, increased
saliva, tooth disease, dyspnea, increased cough, gait abnormalities,
urinary frequency, vomiting, allergic reaction, hypertension, pruritis,
hypokinesia, increased creatine PK, nervousness, dream abnormalities,
chest pain, neck pain, paresthesia, tachycardia, vertigo, voice alteration,
conjunctivitis, paralysis, accommodation abnormalities, tinnitus,
diplopia, and taste perversions.
In a xed-dose study in early Parkinsons disease, occurrence of the
following events increased in frequency as the dose increased over the
range from 1.5 mg/day to 6 mg/day: postural hypotension, nausea,
constipation, somnolence, and amnesia. The frequency of these events
was generally 2-fold greater than placebo for pramipexole doses
greater than 3 mg/day. The incidence of somnolence with pramipexole
at a dose of 1.5 mg/day was comparable to that reported for placebo.
Advanced Parkinsons Disease
In the four double-blind, placebo-controlled trials of patients with
advanced Parkinsons disease, the most commonly observed adverse
events (> 5%) that were numerically more frequent in the group
treated with pramipexole dihydrochloride tablets and concomitant
levodopa were postural (orthostatic) hypotension, dyskinesia,
extrapyramidal syndrome, insomnia, dizziness, hallucinations,
accidental injury, dream abnormalities, confusion, constipation,
asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry
mouth, amnesia, and urinary frequency.
Approximately 12% of 260 patients with advanced Parkinsons
disease who received pramipexole dihydrochloride tablets and
concomitant levodopa in the double-blind, placebo-controlled trials
discontinued treatment due to adverse events compared with 16%
of 264 patients who received placebo and concomitant levodopa.
The events most commonly causing discontinuation of treatment
were related to the nervous system (hallucinations [2.7% on
pramipexole dihydrochloride tablets vs 0.4% on placebo]; dyskinesia
[1.9% on pramipexole dihydrochloride tablets vs 0.8% on placebo];
extrapyramidal syndrome [1.5% on pramipexole dihydrochloride
tablets vs 4.9% on placebo]; dizziness [1.2% on pramipexole
dihydrochloride tablets vs 1.5% on placebo]; confusion [1.2% on
pramipexole dihydrochloride tablets vs 2.3% on placebo]); and
cardiovascular system (postural [orthostatic] hypotension [2.3% on
pramipexole dihydrochloride tablets vs 1.1% on placebo]).
Adverse-Event Incidence in Controlled Clinical Studies in Advanced
Parkinsons Disease
Table 2 lists treatment-emergent adverse events that occurred in the
double-blind, placebo-controlled studies in advanced Parkinsons
disease that were reported by 1% of patients treated with
pramipexole dihydrochloride tablets and were numerically more
frequent than in the placebo group. In these studies, pramipexole
dihydrochloride tablets or placebo was administered to patients who
were also receiving concomitant levodopa. Adverse events were
usually mild or moderate in intensity.
The prescriber should be aware that these gures cannot be used to
predict the incidence of adverse events in the course of usual medical
practice where patient characteristics and other factors differ from those
that prevailed in the clinical studies. Similarly, the cited frequencies
cannot be compared with gures obtained from other clinical
investigations involving different treatments, uses, and investigators.
However, the cited gures do provide the prescribing physician with
some basis for estimating the relative contribution of drug and nondrug
factors to the adverse-events incidence rate in the population studied.

in Double-Blind, Placebo-Controlled Trials in Advanced
with Pramipexole Dihydrochloride Tablets and
Placebo
Body System/
Pramipexole
N=264
Adverse Event
dihydrochloride
N=260
Body as a Whole
Accidental injury
17
Asthenia
10
General edema
Chest pain
53
48
10
Dizziness
25
Somnolence
22
Malaise
Cardiovascular
System
Postural hypotension
Insomnia
17
12
Digestive System
Hallucinations
Confusion
Amnesia
Hypesthesia
Dystonia
Akathisia
Thinking
Abnormalities
Decreased libido
Myoclonus
Nervous System
24
Special Senses
Vision abnormalities
Urogenital System
Impotence
2
1
*Patients may have reported multiple adverse experiences
during the study or at discontinuation; thus, patients may
be included in more than one category.
Other events reported by 1% or more of patients with early Parkinsons
disease and treated with pramipexole dihydrochloride tablets but
Constipation
Dry mouth
Metabolic &
Nutritional System
Peripheral edema
Increased creatine
PK
Musculoskeletal
System
Arthritis
15
Twitching
Bursitis
Myasthenia
47
31
28
26
27
26
22
25
Nervous System
Dyskinesia
Extrapyramidal
syndrome
Insomnia
Dizziness
(contd)

in Double-Blind, Placebo-Controlled Trials in Advanced
with Pramipexole Dihydrochloride Tablets and
Placebo
Body System/
Pramipexole
N=264
Adverse Event
dihydrochloride
N=260
Nervous System
(continued)
Hallucinations
17
4
Dream abnormalities
11
10
Confusion
10
Somnolence
Dystonia
Gait abnormalities
Hypertonia
Amnesia
Akathisia
Thinking
abnormalities
Paranoid reaction
Delusions
Sleep disorders
Dyspnea
Rhinitis
Pneumonia
Respiratory System
Skin & Appendages

Skin disorders
Special Senses
Accommodation
abnormalities
Vision abnormalities
Diplopia
Urogenital System
Urinary frequency
Urinary tract
infection
Urinary incontinence
*Patients may have reported multiple adverse experiences during the

study or at discontinuation; thus, patients may be included in more
than one category.
Patients received concomitant levodopa.

Other events reported by 1% or more of patients with advanced
Parkinsons disease and treated with pramipexole dihydrochloride
tablets but reported equally or more frequently in the placebo
group were nausea, pain, infection, headache, depression, tremor,
hypokinesia, anorexia, back pain, dyspepsia, atulence, ataxia, u
syndrome, sinusitis, diarrhea, myalgia, abdominal pain, anxiety,
rash, paresthesia, hypertension, increased saliva, tooth disorder,
apathy, hypotension, sweating, vasodilation, vomiting, increased
cough, nervousness, pruritus, hypesthesia, neck pain, syncope,
arthralgia, dysphagia, palpitations, pharyngitis, vertigo, leg cramps,
conjunctivitis, and lacrimation disorders.
General
Adverse Events; Relationship to Age, Gender, and Race
Among the treatment-emergent adverse events in patients treated
with pramipexole dihydrochloride tablets, hallucination appeared
to exhibit a positive relationship to age in patients with Parkinsons
disease. Although no gender-related differences were observed in
Parkinsons disease patients. Less than 4% of patients enrolled were
noncaucasian, therefore, an evaluation of adverse events related to
race is not possible.
Other Adverse Events Observed During Phase 2 and 3 Clinical Trials
Pramipexole dihydrochloride tablets have been administered to
1,620 Parkinsons disease patients in Phase 2 and 3 clinical trials.
During these trials, all adverse events were recorded by the clinical
investigators using terminology of their own choosing; similar
types of events were grouped into a smaller number of standardized
categories using MedDRA dictionary terminology. These categories
are used in the listing below. Adverse events which are not listed
above but occurred on at least two occasions (one occasion if the
event was serious) in the 2,509 individuals exposed to pramipexole
dihydrochloride tablets are listed below. The reported events below
are included without regard to determination of a causal relationship
to pramipexole dihydrochloride tablets.
Blood and lymphatic system disorders
anemia, iron de ciency anemia, leukocytosis, leukopenia,
lymphadenitis,
lymphadenopathy,
thrombocythaemia,
thrombocytopenia
Cardiac disorders
angina pectoris, arrhythmia supraventricular, atrial brillation,
atrioventricular block rst degree, atrioventricular block second
degree, bradycardia, bundle branch block, cardiac arrest, cardiac
failure, cardiac failure congestive, cardiomegaly, coronary artery
occlusion, cyanosis, extrasystoles, left ventricular failure, myocardial
infarction, nodal arrhythmia, sinus arrhythmia, sinus bradycardia,
sinus tachycardia, supraventricular extrasystoles, supraventricular
tachycardia, tachycardia, ventricular brillation, ventricular
extrasystoles, ventricular hypertrophy
Congenital, familial and genetic disorders
atrial septal defect, congenital foot malformation, spine malformation
Ear and labyrinth disorders
deafness, ear pain, hearing impaired, hypoacusis, motion sickness,
vestibular ataxia
Endocrine disorders
goiter, hyperthyroidism, hypothyroidism
Eye disorders
amaurosis
fugax,
blepharitis,
blepharospasm,
cataract,
dacryostenosis acquired, dry eye, eye hemorrhage, eye irritation,
eye pain, eyelid edema, eyelid ptosis, glaucoma, keratitis, macular
degeneration, myopia, photophobia, retinal detachment, retinal
vascular disorder, scotoma, vision blurred, visual acuity reduced,
vitreous oaters
Gastrointestinal disorders
abdominal discomfort, abdominal distension, aphthous stomatitis,
ascites, cheilitis, colitis, colitis ulcerative, duodenal ulcer, duodenal
ulcer hemorrhage, enteritis, eructation, fecal incontinence, gastric
ulcer, gastric ulcer hemorrhage, gastritis, gastrointestinal hemorrhage,
gastroesophageal reux disease, gingivitis, haematemesis,
haematochezia, hemorrhoids, hiatus hernia, hyperchlorhydria, ileus,
inguinal hernia, intestinal obstruction, irritable bowel syndrome,
esophageal spasm, esophageal stenosis, esophagitis, pancreatitis,
periodontitis, rectal hemorrhage, reux esophagitis, tongue edema,
tongue ulceration, toothache, umbilical hernia
General disorders
chest discomfort, chills, death, drug withdrawal syndrome, face
edema, feeling cold, feeling hot, feeling jittery, gait disturbance,
impaired healing, inuenza-like illness, irritability, localized edema,
edema, pitting edema, thirst
Hepatobiliary disorders
biliary colic, cholecystitis, cholecystitis chronic, cholelithiasis
Immune system disorders
drug hypersensitivity
Infections and infestations
abscess, acute tonsillitis, appendicitis, bronchiolitis, bronchitis,
bronchopneumonia, cellulitis, cystitis, dental caries, diverticulitis,
ear infection, eye infection, folliculitis, fungal infection, furuncle,
gangrene, gastroenteritis, gingival infection, herpes simplex,
herpes zoster, hordeolum, intervertebral discitis, laryngitis, lobar
pneumonia, nail infection, onychomycosis, oral candidiasis, orchitis,
osteomyelitis, otitis externa, otitis media, paronychia, pyelonephritis,
pyoderma, sepsis, skin infection, tonsillitis, tooth abscess, tooth
infection, upper respiratory tract infection, urethritis, vaginal
candidiasis, vaginal infection, viral infection, wound infection
Injury, poisoning and procedural complications
accidental falls, drug toxicity epicondylitis, road trafc accident,
sunburn, tendon rupture
Metabolism and nutrition disorders
cachexia, decreased appetite, dehydration, diabetes mellitus, uid
retention, gout, hypercholesterolemia, hyperglycemia, hyperlipidemia,
hyperuricemia,
hypocalcemia,
hypoglycemia,
hypokalemia,
hyponatremia, hypovitaminosis, increased appetite, metabolic alkalosis
Musculoskeletal and connective tissue disorders
bone pain, fasciitis, ank pain, intervertebral disc disorder,
intervertebral disc protrusion, joint effusion, joint stiffness,
joint swelling, monarthritis, muscle rigidity, muscle spasms,
musculoskeletal stiffness, myopathy, myositis, nuchal rigidity,
osteoarthritis, osteonecrosis, osteoporosis, polymyalgia, rheumatoid
arthritis, shoulder pain, spinal osteoarthritis, tendonitis, tenosynovitis
Neoplasms benign, malignant and unspecied
abdominal neoplasm, adenocarcinoma, adenoma benign, basal cell
carcinoma, bladder cancer, breast cancer, breast neoplasm, chronic
lymphocytic leukemia, colon cancer, colorectal cancer, endometrial
cancer, gallbladder cancer, gastric cancer, gastrointestinal neoplasm,
hemangioma, hepatic neoplasm, hepatic neoplasm malignant, lip
and/or oral cavity cancer, lung neoplasm malignant, lung cancer
metastatic, lymphoma, malignant melanoma, melanocytic naevus,
metastases to lung, multiple myeloma, oral neoplasm benign,
neoplasm, neoplasm malignant, neoplasm prostate, neoplasm skin,
neuroma, ovarian cancer, prostate cancer, prostatic adenoma, pseudo
lymphoma, renal neoplasm, skin cancer, skin papilloma, squamous
cell carcinoma, thyroid neoplasm, uterine leiomyome
Nervous system disorders
ageusia, akinesia, anticholinergic syndrome, aphasia, balance
disorder, brain edema, carotid artery occlusion, carpal tunnel
syndrome, cerebral artery embolism, cerebral hemorrhage, cerebral
infarction, cerebral ischemia, chorea, cognitive disorder, coma,
convulsion, coordination abnormal, dementia, depressed level
of consciousness, disturbance in attention, dizziness postural,
dysarthria, dysgraphia, facial palsy, grand mal convulsion,
hemiplegia,
hyperaesthesia,
hyperkinesia,
hyperreexia,
hyporeexia, hypotonia, lethargy, loss of consciousness, memory
impairment, migraine, muscle contractions involuntary, narcolepsy,
neuralgia, neuropathy, nystagmus, parosmia, psychomotor
hyperactivity, sciatica, sedation, sensory disturbance, sleep phase
rhythm disturbance, sleep talking, stupor, syncope vasovagal,
tension headache
Psychiatric disorders
affect lability, aggression, agitation, bradyphrenia, bruxism, suicide,
delirium, delusional disorder persecutory type, disorientation,
dissociation, emotional distress, euphoric mood, hallucination
auditory, hallucination visual, initial insomnia, libido increased, mania,
middle insomnia, mood altered, nightmare, obsessive thoughts,
obsessive-compulsive disorder, panic reaction, parasomnia,
personality disorder, psychotic disorder, restlessness, sleep walking,
suicidal ideation
Renal and urinary disorders
chromaturia, dysuria, glycosuria, hematuria, urgency, nephrolithiasis,
neurogenic bladder, nocturia, oliguria, pollaciuria, proteinuria, renal
artery stenosis, renal colic, renal cyst, renal failure, renal impairment,
urinary retention
Reproductive system and breast disorders
amenorrhea, breast pain, dysmenorrhea, epididymitis, gynaecomastia,
menopausal symptoms, menorrhagia, metrorrhagia, ovarian cyst,
priapism, prostatitis, sexual dysfunction, uterine hemorrhage, vaginal
discharge, vaginal hemorrhage
Respiratory, thoracic and mediastinal disorders
apnea, aspiration, asthma, choking, chronic obstructive pulmonary
disease, dry throat, dysphonia, dyspnea exertional, epistaxis,
haemoptysis, hiccups, hyperventilation, increased bronchial
secretion, laryngospasm, nasal dryness, nasal polyps, obstructive
airways disorder, pharyngolaryngeal pain, pleurisy, pneumonia
aspiration, pneumothorax, postnasal drip, productive cough,
pulmonary embolism, pulmonary edema, respiratory alkalosis,
respiratory distress, respiratory failure, respiratory tract congestion,
rhinitis allergic, rhinorrhea, sinus congestion, sleep apnea syndrome,
sneezing, snoring, tachypnea, wheezing
Skin and subcutaneous tissue disorders
acne, alopecia, cold sweat, dermal cyst, dermatitis, dermatitis
bullous, dermatitis contact, dry skin, ecchymosis, eczema, erythema,
hyperkeratosis, livedo reticularis, night sweats, periorbital edema,
petechiae, photosensitivity allergic reaction, psoriasis, purpura, rash
erythematous, rash maculo-papular, rash papular, rosacea, seborrhea,

seborrheic dermatitis, skin burning sensation, skin discoloration, skin
exfoliation, skin hyperpigmentation, skin hypertrophy, skin irritation,
skin nodule, skin odor abnormal, skin ulcer, urticaria
Vascular disorders
aneurysm, angiopathy, arteriosclerosis, circulatory collapse, deep
vein thrombosis, embolism, hematoma, hot ush, hypertensive crisis,
lymphoedema, pallor, phlebitis, Raynauds phenomenon, shock,
thrombophlebitis, thrombosis, varicose vein
Falling Asleep During Activities of Daily Living
Patients treated with pramipexole dihydrochloride tablets have
reported falling asleep while engaged in activities of daily living,
including operation of a motor vehicle which sometimes resulted in
accidents (see bolded WARNING).
Post-Marketing Experience
In addition to the adverse events reported during clinical trials, the
following adverse reactions have been identied during post-approval
use of pramipexole dihydrochloride tablets, primarily in Parkinsons
disease patients. Because these reactions are reported voluntarily
from a population of uncertain size, it is not always possible to
reliably estimate their frequency or establish a causal relationship
to drug exposure. Decisions to include these reactions in labeling
are typically based on one or more of the following factors: (1)
seriousness of the reaction, (2) frequency of reporting, or (3) strength
of causal connection to pramipexole tablets. Similar types of events
were grouped into a smaller number of standardized categories
using the MedDRA dictionary: abnormal behavior, abnormal dreams,
accidents (including fall), blackouts, fatigue, hallucinations (all kinds),
headache, hypotension (including postural hypotension), increased
eating (including binge eating, compulsive eating, and hyperphagia),
libido disorders (including increased and decreased libido, and
hypersexuality), pathological gambling, syncope, and weight increase.
DOSAGE AND ADMINISTRATION
Dosing in Patients With Renal Impairment
Table 4: Pramipexole Dosage in
Parkinsons Disease Patients With Renal Impairment
Renal Status
Normal to mild impairment
(creatinine Cl > 60 mL/min)
Moderate impairment
(creatinine Cl = 35 to 59 mL/
min)
Severe impairment
(creatinine Cl = 15 to 34 mL/
min)
Very severe impairment
(creatinine Cl < 15 mL/min and
hemodialysis patients)
Starting Dose
(mg)
Maximum Dose
(mg)
0.125 tid
1.5 tid
0.125 bid
1.5 bid
0.125 qd
1.5 qd
The use of pramipexole

dihydrochloride tablets has not
been adequately studied in this
group of patients.
ANIMAL TOXICOLOGY
Retinal Pathology in Albino Rats
Pathologic changes (degeneration and loss of photoreceptor cells)
were observed in the retina of albino rats in the 2 year carcinogenicity
study with pramipexole. These ndings were rst observed during
week 76 and were dose dependent in animals receiving 2 or 8 mg/kg/
day (plasma AUCs equal to 2.5 and 12.5 times the AUC in humans that
received 1.5 mg tid). In a similar study of pigmented rats with 2 years
exposure to pramipexole at 2 or 8 mg/kg/day, retinal degeneration
was not diagnosed. Animals given drug had thinning in the outer
nuclear layer of the retina that was only slightly greater than that seen
in control rats utilizing morphometry.
Investigative studies demonstrated that pramipexole reduced the
rate of disk shedding from the photoreceptor rod cells of the retina
in albino rats, which was associated with enhanced sensitivity to the
damaging effects of light. In a comparative study, degeneration and
loss of photoreceptor cells occurred in albino rats after 13 weeks of
treatment with 25 mg/kg/day of pramipexole (54 times the highest
clinical dose on a mg/m2 basis) and constant light (100 lux) but not in
pigmented rats exposed to the same dose and higher light intensities
(500 lux). Thus, the retina of albino rats is considered to be uniquely
sensitive to the damaging effects of pramipexole and light. Similar
changes in the retina did not occur in a 2 year carcinogenicity study
in albino mice treated with 0.3, 2, or 10 mg/kg/day (0.3, 2.2 and 11
times the highest clinical dose on a mg/m2 basis). Evaluation of the
retinas of monkeys given 0.1, 0.5, or 2 mg/kg/day of pramipexole
(0.4, 2.2, and 8.6 times the highest clinical dose on a mg/m2 basis) for
12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole
for 13 weeks also detected no changes.
The potential signicance of this effect in humans has not been
established, but cannot be disregarded because disruption of a
mechanism that is universally present in vertebrates (i.e., disk
shedding) may be involved.
Fibro-osseous Proliferative Lesions in Mice
An increased incidence of bro-osseous proliferative lesions occurred
in the femurs of female mice treated for 2 years with 0.3, 2, or 10 mg/
kg/day (0.3, 2.2, and 11 times the highest clinical dose on a mg/m2
basis). Lesions occurred at a lower rate in control animals. Similar
lesions were not observed in male mice or rats and monkeys of either
sex that were treated chronically with pramipexole. The signicance
of this lesion to humans is not known.
Manufactured By:
BARR LABORATORIES, INC.
Pomona, NY 10970
Manufactured For:
TEVA PHARMACEUTICALS USA
Sellersville, PA 18960
Iss. 8/2009
PATIENT INFORMATION ABOUT PRAMIPEXOLE DIHYDROCHLORIDE
TABLETS
Read the Patient Information that comes with pramipexole before you
start taking it and each time you get a rell. There may be some new
information. This leaet does not take the place of talking with your
doctor about your medical condition or your treatment.
What is the most important information I should know about
pramipexole?
Pramipexole may cause you to fall asleep while you are doing daily
activities such as driving, talking with other people, watching TV,
or eating.
Some people taking pramipexole have had car accidents because

they fell asleep while driving.
Some patients did not feel sleepy before they fell asleep while
driving. You could fall asleep without any warning.
Do not drive a car, operate a machine, or do anything that needs
you to be alert until you know how pramipexole affects you.
Tell your doctor right away if you fall asleep while you are doing
activities such as talking with people, watching TV, eating, or
driving, or if you feel sleepier than is normal for you.
What is pramipexole?
Pramipexole is a prescription medicine to treat
signs and symptoms of Parkinsons disease.
Pramipexole has not been studied in children.
Who should not take pramipexole?
Do not take pramipexole if you are allergic to pramipexole or any of
the inactive ingredients of pramipexole. See the end of this leaet for
a complete list of ingredients in pramipexole.
What should I tell my doctor before taking pramipexole?
Tell your doctor about all of your medical conditions, including if you
feel sleepy during the day from a sleep problem.
have low blood pressure, or if you feel dizzy or faint, especially
when getting up from a lying or sitting position.
have trouble controlling your muscles (dyskinesia).
have kidney problems.
are pregnant or plan to become pregnant. It is not known if
pramipexole will harm your unborn baby.
are breast-feeding. It is not known if pramipexole will pass into
your breast milk. You and your doctor should decide if you will
take pramipexole or breast-feed. You should not do both.
drink alcohol. Alcohol can increase the chance that pramipexole
will make you feel sleepy or fall asleep when you should be awake.
Tell your doctor about all the medicines you take, including
prescription and non-prescription medicines, vitamins, and herbal
supplements. Especially tell your doctor if you take any other
medicines that make you sleepy. Pramipexole and other medicines
may interact with each other causing side effects. Pramipexole may
affect the way other medicines work, and other medicines may affect
how pramipexole works.
How should I take pramipexole?
Take pramipexole exactly as your doctor tells you to. Your doctor
will tell you how many pramipexole tablets to take and when to
take them.
Your doctor may change your dose until you are taking the right
amount of medicine to control your symptoms. Do not take more
or less pramipexole than your doctor tells you to.
Pramipexole can be taken with or without food. Taking pramipexole
with food may lower your chances of getting nausea.
If you miss a dose, do not double your next dose. Skip the dose
you missed and take your next regular dose.
Be sure to tell your doctor right away if you stop taking pramipexole
for any reason. Do not start taking pramipexole again before
speaking with your doctor. If you have Parkinsons disease and
are stopping pramipexole, you should stop pramipexole slowly
over 7 days.
What should I avoid while taking pramipexole?
Do not drive a car, operate a machine, or do anything that needs
you to be alert until you know how pramipexole affects you.
See What is the most important information I should know about
pramipexole? at the beginning of this leaet.
Do not drink alcohol while taking pramipexole. It can increase your
chances of feeling sleepy or falling asleep when you should be
awake.
What are the possible side effects of pramipexole?
Pramipexole can cause serious side effects, including
falling asleep during normal daily activities. See What is the most
important information I should know about pramipexole?
low blood pressure when you sit or stand up quickly. You may
have dizziness, nausea, fainting, or sweating. Sit and stand up
slowly after you have been sitting or lying down for a while.
hallucinations. You may see, hear, feel, or taste something that
isnt there. You have a higher chance of having hallucinations if
you are over 65 years old.
The most common side effects in people taking pramipexole for
Parkinsons disease are nausea, dizziness, sleepiness, constipation,
hallucinations, insomnia, muscle weakness, confusion, and abnormal
movements.
These are not all the possible side effects of pramipexole. For more
information ask your doctor or pharmacist.
Be sure to talk to your doctor about any side effects that bother you
or that do not go away.
Other Information about pramipexole
Studies of people with Parkinsons disease show that they may be
at an increased risk of developing melanoma, a form of skin cancer,
when compared to people without Parkinsons disease. It is not
known if this problem is associated with Parkinsons disease or the
medicines used to treat Parkinsons disease. Pramipexole is one of the
medicines used to treat Parkinsons disease, therefore, patients being
treated with pramipexole should have periodic skin examinations.
There have been reports of patients taking certain medicines to
treat Parkinsons disease, including pramipexole, that have reported
problems with gambling, compulsive eating, and increased sex drive.
It is not possible to reliably estimate how often these behaviors occur
or to determine which factors may contribute to them. If you or your
family members notice that you are developing unusual behaviors,
talk to your doctor.
How should I store pramipexole?
Store at 20 to 25C (68 to 77F) [See USP Controlled Room
Temperature].
Protect from light.
Keep pramipexole and all medicines out of the reach of children.
General information about pramipexole
Medicines are sometimes prescribed for purposes other than those
listed in this Patient Information Leaet. Do not take pramipexole for
a condition for which it was not prescribed. Do not share pramipexole
with other people, even if they have the same symptoms you do. It
may harm them.
This Patient Information Leaet summarizes the most important
information about pramipexole. For more information, talk with
your doctor or pharmacist. They can give you information about
pramipexole that is written for healthcare professionals.
What are the ingredients in pramipexole?
Active Ingredient: pramipexole dihydrochloride monohydrate
Inactive Ingredients: corn starch, hydrogenated vegetable oil,
mannitol, povidone and pregelantinized corn starch.
Tevas
Pramipexole Dihydrochloride
Tablets
AB Rated and Bioequivalent to
Mirapex* Tablets
To place your order,

call your wholesaler
or distributor today.
Please see brief summary
of prescribing information
on adjacent page.
Pramipexole Dihydrochloride Tablets

STRENGTH
SIZE
NDC#
0.125 mg
63
00555-0617-62
0.25 mg
90
00555-0612-14
0.5 mg
90
00555-0613-14
1 mg
90
00555-0614-14
1.5 mg
90
00555-0615-14
*Mirapex is a registered trademark of Boehringer Ingelheim Pharma.

2010, Teva Pharmaceuticals USA
1090 Horsham Road North Wales, PA 19454

800.545.8800 www.tevausa.com
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