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February 2017

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Volume 42 Number 2

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A Peer-Reviewed Journal for Managed Care
and Formulary Management Decision-Makers

New Pharmacotherapies in VISIT US ONLINE AT WWW.PTCOMMUNITY.COM

Chronic Lymphocytic Leukemia
J. L. Olin, MS, PharmD, BCPS, CDE, FASHP, FCCP;
K. Canupp, BS, PharmD Candidate; and M. B. Smith,
PharmD, BCOP

Experts Provide a Glimpse of the New

Post-SPRINT Era of Hypertension
S. L. Worley

FDA Flags Inconsistent Hospital Reporting

Of Medical Device Problems
Hazy Reporting Rules Beget Confusion
S. Barlas

Effect of Intravenous Acetaminophen on

Post-Anesthesia Care Unit Length of Stay,
Opioid Consumption, Pain, and Analgesic
Drug Costs After Ambulatory Surgery
M. A. Khobrani, PharmD; J. M. Camamo, PharmD; and
A. E. Patanwala, PharmD

MEETING HIGHLIGHTS PIPELINE PLUS

American Society of Hematology New Schizophrenia Treatments
Annual Meeting and Exposition Address Unmet Clinical Needs
W. Alexander C. Fellner

DRUG FORECAST
Brivaracetam (Briviact)
A Novel Adjunctive Therapy for Partial-Onset Seizures
F. Khaleghi, PharmD Candidate; and E. C. Nemec II,
PharmD, BCPS
When it clicks, members with
type 2 diabetes have an option
to progress beyond orals alone
to improve glycemic control*1
Do your members struggle with the challenges of adding an injectable? If so, consider Trulicity
as an option. Designed with patients like them in mind, this is the first once-weekly glucagon-like
peptide-1 receptor agonist (GLP-1 RA) to require no mixing and come in a pen with a pre-attached
needle.1-3. Talk to your Lilly account manager about an option that may make it click for your members.

Recommended starting dose is 0.75 mg. Dose can be
increased to 1.5 mg for additional A1C reduction.
*In clinical studies, the range of A1C reduction from
baseline was 0.7% to 1.6% for the 0.75 mg dose and
0.8% to 1.6% for the 1.5 mg dose; the percentage of
patients achieving A1C <7% ranged from 37% to 69%
for 0.75 mg and 53% to 78% for 1.5 mg.1,4-7
Trulicity is indicated as an adjunct to diet and exercise
to improve glycemic control in adults with type 2
diabetes mellitus.
Limitations of Use: Not recommended as first-line therapy
for patients inadequately controlled on diet and exercise
because of the uncertain relevance of rodent C-cell tumor
findings to humans. Prescribe only if potential benefits
outweigh potential risks. Has not been studied in patients
with a history of pancreatitis; consider another antidiabetic
therapy. Not for the treatment of type 1 diabetes mellitus
or diabetic ketoacidosis. Not a substitute for insulin.
Has not been studied in patients with severe gastrointestinal
disease, including severe gastroparesis. Not for patients
with pre-existing severe gastrointestinal disease. Has not
been studied in combination with basal insulin.
Select Important Safety Information
WARNING: RISK OF THYROID C-CELL TUMORS
In male and female rats, dulaglutide causes a
dose-related and treatment-duration-dependent
increase in the incidence of thyroid C-cell tumors
(adenomas and carcinomas) after lifetime exposure.
It is unknown whether Trulicity causes thyroid
C-cell tumors, including medullary thyroid
carcinoma (MTC), in humans as human relevance
of dulaglutide-induced rodent thyroid C-cell
tumors has not been determined.
Trulicity is contraindicated in patients with a
personal or family history of MTC and in patients
with Multiple Endocrine Neoplasia syndrome type 2
(MEN 2). Counsel patients regarding the potential
risk of MTC with use of Trulicity and inform them
of symptoms of thyroid tumors (eg, mass in the
neck, dysphagia, dyspnea, persistent hoarseness).
Routine monitoring of serum calcitonin or using
thyroid ultrasound is of uncertain value for early
detection of MTC in patients treated with Trulicity.

Please see Important Safety Information for Trulicity,

including Boxed Warning about possible thyroid tumors
including thyroid cancer, on the following page and
accompanying Brief Summary of Prescribing Information.
Please see Instructions for Use included with the pen.
Important Safety Information
WARNING: RISK OF THYROID C-CELL TUMORS
In male and female rats, dulaglutide causes a dose-
related and treatment-duration-dependent increase in
the incidence of thyroid C-cell tumors (adenomas and
carcinomas) after lifetime exposure. It is unknown whether
Trulicity causes thyroid C-cell tumors, including medullary
thyroid carcinoma (MTC), in humans as human relevance
of dulaglutide-induced rodent thyroid C-cell tumors has
not been determined.
Trulicity is contraindicated in patients with a personal or
family history of MTC and in patients with Multiple
Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel
patients regarding the potential risk of MTC with use of
Trulicity and inform them of symptoms of thyroid tumors
(eg, mass in the neck, dysphagia, dyspnea, persistent
hoarseness). Routine monitoring of serum calcitonin or
using thyroid ultrasound is of uncertain value for early
detection of MTC in patients treated with Trulicity.
Trulicity is contraindicated in patients with a personal or family
history of MTC or in patients with MEN 2, and in patients with
a prior serious hypersensitivity reaction to dulaglutide or any
of the product components.
Risk of Thyroid C-cell Tumors: Cases of MTC in patients treated
with liraglutide, another GLP-1 receptor agonist (GLP-1 RA),
have been reported in the postmarketing period; the data in
these reports are insufcient to establish or exclude a causal
relationship between MTC and GLP-1 RA use in humans.
If serum calcitonin is measured and found to be elevated or
thyroid nodules are noted on physical examination or neck
imaging, the patient should be further evaluated.
Pancreatitis: Has been reported in clinical trials. Observe
patients for signs and symptoms including persistent severe
abdominal pain. If pancreatitis is suspected, discontinue
Trulicity promptly. Do not restart if pancreatitis is conrmed.
Consider other antidiabetic therapies in patients with a history
of pancreatitis.
Hypoglycemia: The risk of hypoglycemia is increased when
Trulicity is used in combination with insulin secretagogues
(eg, sulfonylureas) or insulin. Patients may require a lower dose
of the sulfonylurea or insulin to reduce the risk of hypoglycemia.
Hypersensitivity Reactions: Systemic reactions were observed
in patients receiving Trulicity in clinical trials. Instruct patients
who experience symptoms to discontinue Trulicity and promptly
seek medical advice.
Renal Impairment: In patients treated with GLP-1 RAs, there
have been postmarketing reports of acute renal failure
and worsening of chronic renal failure, sometimes requiring
hemodialysis. A majority of reported events occurred in
patients who had experienced nausea, vomiting, diarrhea,
or dehydration. In patients with renal impairment, use caution
when initiating or escalating doses of Trulicity and monitor
renal function in patients experiencing severe adverse
gastrointestinal reactions.
Severe Gastrointestinal Disease: Use of Trulicity may be
associated with gastrointestinal adverse reactions, sometimes
severe. Trulicity has not been studied in patients with severe
gastrointestinal disease, including severe gastroparesis, and
is therefore not recommended in these patients.
PP-DG-US-0696 12/2016 Lilly USA, LLC 2016. All rights reserved.
Macrovascular Outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction
with Trulicity or any other antidiabetic drug.
The most common adverse reactions reported in 5% of
Trulicity-treated patients in placebo-controlled trials (placebo,
Trulicity 0.75 mg, and Trulicity 1.5 mg) were nausea (5.3%, 12.4%,
21.1%), diarrhea (6.7%, 8.9%, 12.6%), vomiting (2.3%, 6.0%,
12.7%), abdominal pain (4.9%, 6.5%, 9.4%), decreased appetite
(1.6%, 4.9%, 8.6%), dyspepsia (2.3%, 4.1%, 5.8%), and fatigue
(2.6%, 4.2%, 5.6%).
Gastric emptying is slowed by Trulicity, which may impact
absorption of concomitantly administered oral medications.
Use caution when oral medications are used with Trulicity.
Drug levels of oral medications with a narrow therapeutic
index should be adequately monitored when concomitantly
administered with Trulicity. In clinical pharmacology studies,
Trulicity did not affect the absorption of the tested, orally
administered medications to a clinically relevant degree.
Pregnancy: There are no adequate and well-controlled studies
of Trulicity in pregnant women. Use only if potential benet
outweighs potential risk to fetus.
Nursing Mothers: It is not known whether Trulicity is excreted in
human milk. A decision should be made whether to discontinue
nursing or to discontinue Trulicity, taking into account the
importance of the drug to the mother.
Pediatric Use: Safety and effectiveness of Trulicity have not
been established and use is not recommended in patients
less than 18 years of age.
Please see Brief Summary of Prescribing Information, including
Boxed Warning about possible thyroid tumors including
thyroid cancer, on following page.
Please see Instructions for Use included with the pen.
DG HCP ISI 20APR2015
Trulicity is a registered trademark owned or licensed by Eli Lilly and Company,
its subsidiaries, or affiliates. Trulicity is available by prescription only.
References
1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015.
2. Trulicity [Instructions for Use]. Indianapolis, IN: Lilly USA, LLC; 2014.
3. Glaesner W, Vick AM, Millican R, et al. Engineering and characterization
of the long-acting glucagon-like peptide-1 analogue LY2189265, an
Fc fusion protein. Diabetes Metab Res Rev. 2010;26(4):287-296.
4. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus
once-daily liraglutide in metformin-treated patients with type 2 diabetes
(AWARD-6): a randomised, open-label, phase 3, non-inferiority trial
[published correction appears in Lancet. 2014;384:1348]. Lancet.
2014;384:1349-1357.
5. Umpierrez G, Tof Povedano S, Prez Manghi F, et al. Efcacy and
safety of dulaglutide monotherapy versus metformin in type 2
diabetes in a randomized controlled trial (AWARD-3). Diabetes Care.
2014;37:2168-2176.
6. Giorgino F, Benroubi M, Sun JH, et al. Efcacy and safety of once-weekly
dulaglutide versus insulin glargine in patients with type 2 diabetes on
metformin and glimepiride (AWARD-2). Diabetes Care. 2015;38(12):2241-
2249.
7. Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus
bedtime insulin glargine, both in combination with prandial insulin lispro,
in patients with type 2 diabetes (AWARD-4): a randomised, open-label,
phase 3, non-inferiority study. Lancet. 2015;385:2057-2066.
TrulicityTM (dulaglutide)
Brief Summary: Consult the package insert for complete prescribing information.
WARNING: RISK OF THYROID C-CELL TUMORS
In male and female rats, dulaglutide causes a dose-related and treatment-
duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas
and carcinomas) after lifetime exposure. It is unknown whether Trulicity causes
thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as
human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been
determined.
Trulicity is contraindicated in patients with a personal or family history of MTC
and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel
patients regarding the potential risk of MTC with use of Trulicity and inform them of
symptoms of thyroid tumors (eg, mass in the neck, dysphagia, dyspnea, persistent
hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of
uncertain value for early detection of MTC in patients treated with Trulicity.
INDICATIONS AND USAGE
Trulicity is indicated as an adjunct to diet and exercise to improve glycemic control in
adults with type2diabetes mellitus.
Limitations of Use:
Not recommended as a first-line therapy for patients who have inadequate glycemic
control on diet and exercise because of the uncertain relevance of rodent C-cell tumor
findings to humans. Prescribe Trulicity only to patients for whom the potential benefits
outweigh the potential risk. Has not been studied in patients with a history of pancreatitis.
Consider other antidiabetic therapies in patients with a history of pancreatitis. Should not be
used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
It is not a substitute for insulin. Has not been studied in patients with severe gastrointestinal
disease, including severe gastroparesis. Not recommended in patients with pre-existing
severe gastrointestinal disease. The concurrent use of Trulicity and basal insulin has not
been studied.
CONTRAINDICATIONS
Do not use in patients with a personal or family history of MTC or in patients with MEN 2.
Do not use in patients with a prior serious hypersensitivity reaction to dulaglutide or to any
of the product components.
WARNINGS AND PRECAUTIONS
Risk of Thyroid C-cell Tumors: In male and female rats, dulaglutide causes a dose-
related and treatment-duration-dependent increase in the incidence of thyroid C-cell
tumors (adenomas and carcinomas) afterlifetime exposure. Glucagon-like peptide (GLP-1)
receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and
rats at clinically relevant exposures. It is unknown whether Trulicity will cause thyroid
C-cell tumors, including MTC, in humans, as the human relevance of dulaglutide-induced
rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a
patient treated with Trulicity. This patient had pretreatment calcitonin levels approximately
8times the upper limit of normal (ULN). Cases of MTC in patients treated with liraglutide,
another GLP-1 receptor agonist, have been reported in the postmarketing period; the data
in these reports are insufficient to establish or exclude a causal relationship between MTC
and GLP-1 receptor agonist use in humans. Trulicity is contraindicated in patients with a
personal or family history of MTC or in patients with MEN 2. Counsel patients regarding
the potential risk for MTC with the use of Trulicity and inform them of symptoms of thyroid
tumors (eg, a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine
monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early
detection of MTC in patients treated with Trulicity. Such monitoring may increase the risk
of unnecessary procedures, due to the low test specificity for serum calcitonin and a high
background incidence of thyroid disease. Significantly elevated serum calcitonin value may
indicate MTC and patients with MTC usually have calcitonin values >50ng/L. If serum
calcitonin is measured and found to be elevated, the patient should be further evaluated.
Patients with thyroid nodules noted on physical examination or neck imaging should also
be further evaluated. Pancreatitis: In Phase 2 and Phase 3 clinical studies, 12(3.4 cases
per 1000patientyears) pancreatitis-related adverse reactions were reported in patients
exposed to Trulicity versus 3 in non-incretin comparators (2.7 cases per 1000 patient years).
An analysis of adjudicated events revealed 5cases ofconfirmed pancreatitis in patients
exposed to Trulicity (1.4 cases per 1000 patient years) versus 1 case in non-incretin
comparators (0.88 cases per 1000 patient years). After initiation of Trulicity, observe
patients carefully for signs and symptoms of pancreatitis, including persistent severe
abdominal pain. If pancreatitis is suspected, promptly discontinue Trulicity. If pancreatitis
is confirmed, Trulicity should not be restarted. Trulicity has not been evaluated in patients
with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a
history of pancreatitis. Hypoglycemia with Concomitant Use of Insulin Secretagogues
or Insulin: The risk of hypoglycemia is increased when Trulicity is used in combination with
TrulicityTM (dulaglutide) DG HCP BS 20APR2015
insulin secretagogues (eg, sulfonylureas) or insulin. Patients may require a lower dose of
sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting. Hypersensitivity
Reactions: Systemic hypersensitivity reactions were observed in patients receiving
Trulicity in clinical trials. If a hypersensitivity reaction occurs, the patient should discontinue
Trulicity and promptly seek medical advice. Renal Impairment: In patients treated with
GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and
worsening of chronic renal failure, which may sometimes require hemodialysis. Some of
these events were reported in patients without known underlying renal disease. A majority
of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or
dehydration. Because these reactions may worsen renal failure, use caution when initiating
or escalating doses of Trulicity in patients with renal impairment. Monitor renal function
in patients with renal impairment reporting severe adverse gastrointestinal reactions.
Severe Gastrointestinal Disease: Use of Trulicity may be associated with gastrointestinal
adverse reactions, sometimes severe. Trulicity has not been studied in patients with severe
gastrointestinal disease, including severe gastroparesis, and is therefore not recommended
in these patients. Macrovascular Outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction with Trulicity or any other
antidiabetic drug.
ADVERSE REACTIONS
Clinical Studies 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. Pool of Placebo-controlled Trials: These data reflect exposure of
1670 patients to Trulicity and a mean duration of exposure to Trulicity of 23.8weeks. Across
the treatment arms, the mean age of patients was 56 years, 1% were 75 years or olderand
53% were male. The population in these studies was 69% White, 7% Black or African
American, 13% Asian; 30% were of Hispanic or Latino ethnicity. At baseline, the population
had diabetes for an average of 8.0years and had a mean HbA1c of 8.0%. At baseline,
2.5%of the population reported retinopathy. Baseline estimated renal function was normal
or mildly impaired (eGFR 60mL/min/1.73 m2) in 96.0% of thepooled study populations.
Adverse Reactions in Placebo-Controlled Trials Reported in 5% of Trulicity-Treated
Patients: Placebo (N=568), Trulicity 0.75mg (N=836), Trulicity 1.5 mg (N=834) (listed as
placebo, 0.75 mg, 1.5 mg): nausea (5.3%, 12.4%, 21.1%), diarrheaa (6.7%, 8.9%, 12.6%),
vomitingb (2.3%,6.0%, 12.7%), abdominal painc (4.9%, 6.5%, 9.4%), decreased appetite
(1.6%, 4.9%, 8.6%), dyspepsia (2.3%, 4.1%, 5.8%), fatigued (2.6%, 4.2%, 5.6%). (a Includes
diarrhea, fecal volume increased, frequent bowel movements. bIncludes retching, vomiting,
vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower,
abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue,
asthenia, malaise.) Note: Percentages reflect the number of patients that reported at least
1treatment-emergent occurrence of the adverse reaction. Gastrointestinal Adverse
Reactions: In the pool of placebo-controlled trials, gastrointestinal adverse reactions
occurred more frequently among patients receiving Trulicity than placebo (placebo 21.3%,
0.75mg 31.6%, 1.5mg 41.0%). More patients receiving Trulicity 0.75 mg (1.3%) and
Trulicity 1.5 mg (3.5%) discontinued treatment due to gastrointestinal adverse reactions
than patients receiving placebo (0.2%). Investigators graded the severity of gastrointestinal
adverse reactions occurring on 0.75 mg and 1.5 mg of Trulicity as mild in 58% and 48%
of cases, respectively, moderate in 35% and 42%of cases, respectively, or severe in 7%
and 11% of cases, respectively. In addition to the adverse reactions 5% listed above, the
following adverse reactions were reported more frequently in Trulicity-treated patients than
placebo (frequencies listed, respectively, as: placebo; 0.75mg;1.5mg): constipation (0.7%;
3.9%; 3.7%), flatulence (1.4%; 1.4%; 3.4%), abdominal distension(0.7%; 2.9%; 2.3%),
gastroesophageal reflux disease (0.5%; 1.7%; 2.0%), and eructation (0.2%;0.6%; 1.6%).
Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactionswasalso
evaluated in a larger pool of patients with type 2 diabetes participating in 6 placebo- and
active-controlled trials evaluating the use of Trulicity as monotherapy and add-on therapy to
oral medications or insulin. In this pool, a total of 3342 patients with type 2 diabetes were
treated with Trulicity for a mean duration 52 weeks. The mean age of patients was 56 years,
2% were 75years or older and 51% were male. The population in these studies was
71%White, 7% Black or African American, 11% Asian; 32% were of Hispanic or Latino
ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a
mean HbA1c of 7.6-8.5%. At baseline, 5.2% of the population reported retinopathy. Baseline
estimated renal function was normal or mildly impaired (eGFR 60 ml/min/1.73 m2) in
95.7% of the Trulicity population. In the pool of placebo- and active-controlled trials, the
types and frequency of common adverse reactions, excluding hypoglycemia, were similar to
those listed as 5% above. Other Adverse Reactions: Hypoglycemia: Incidence (%) of
Documented Symptomatic (70mg/dL Glucose Threshold) and Severe Hypoglycemia
in Placebo-Controlled Trials: Add-on to Metformin at 26 weeks, Placebo (N=177), Trulicity
0.75 mg (N=302), Trulicity 1.5 mg (N=304), Documented symptomatic: Placebo: 1.1%,
0.75mg: 2.6%, 1.5mg: 5.6%; Severe: all0. Add-on to Metformin + Pioglitazone at
26weeks, Placebo (N=141), Trulicity 0.75 mg (N=280), Trulicity1.5 mg (N=279),
Documented symptomatic: Placebo: 1.4%, 0.75mg: 4.6%, 1.5 mg: 5.0%; Severe: all 0.
Hypoglycemia was more frequent when Trulicity was used in combination with a
sulfonylurea or insulin. Documented symptomatic hypoglycemia occurred in 39% and 40%
of patients when Trulicity 0.75 mg and 1.5mg, respectively, was co-administered with a
sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7%of patients when Trulicity
0.75mg and 1.5mg, respectively, was co-administered with a sulfonylurea. Documented
symptomatic hypoglycemia occurred in 85% and 80% of patients when Trulicity 0.75 mg
TrulicityTM (dulaglutide) DG HCP BS 20APR2015
and 1.5mg, respectively, was co-administered with prandial insulin. Severe hypoglycemia
occurred in 2.4% and 3.4% of patients when Trulicity 0.75 mg, and 1.5 mg, respectively,
was co-administered with prandial insulin. Heart Rate Increase and Tachycardia Related
Adverse Reactions: Trulicity 0.75 mg and 1.5 mg resulted in a mean increase in heart rate
(HR) of 2-4 beats per minute (bpm). The long-term clinical effects of the increase in HR have
not been established. Adverse reactions of sinus tachycardia were reported more frequently
in patients exposed to Trulicity. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of
patients treated with placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg, respectively.
Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%,
0.4%, and 1.6% of patients treated with placebo, Trulicity 0.75mgand Trulicity 1.5 mg,
respectively. Episodes of sinus tachycardia, associated with a concomitant increase from
baseline in heart rate of 15 beats per minute, were reported in 0.7%, 1.3%, and 2.2% of
patients treated with placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg, respectively.
Immunogenicity : Across four Phase 2 and five Phase 3 clinical studies, 64(1.6%) Trulicity-
treated patients developed anti-drug antibodies (ADAs) to the active ingredient in Trulicity
(ie, dulaglutide). Of the 64dulaglutide-treated patients that developed dulaglutide ADAs,
34patients (0.9% of the overall population) had dulaglutide-neutralizing antibodies, and
36patients (0.9% of the overall population) developed antibodies against native GLP-1. The
detection of antibody formation is highly dependent on the sensitivity and specificity of the
assay. Additionally, the observed incidence of antibody (including neutralizing antibody)
positivity in an assay may be influenced by several factors including assay methodology,
sample handling, timing of sample collection, concomitant medications, and underlying
disease. For these reasons, the incidence of antibodies to dulaglutide cannot be directly
compared with the incidence of antibodies of other products. Hypersensitivity : Systemic
hypersensitivity adverse reactions sometimes severe (eg, severe urticaria, systemic rash,
facial edema, lip swelling) occurred in 0.5% of patients on Trulicity in the four Phase 2 and
Phase 3 studies. Injection-site Reactions: In the placebo-controlled studies, injection-site
reactions (eg, injection-site rash, erythema) were reported in 0.5% of Trulicity-treated
patients and in 0.0% of placebo-treated patients. PR Interval Prolongation and Adverse
Reactions of First Degree Atrioventricular (AV) Block: A mean increase from baseline in PR
intervalof 2-3 milliseconds was observed in Trulicity-treated patients in contrast to a mean
decrease of 0.9millisecond in placebo-treated patients. The adverse reaction of first degree
AV block occurred more frequently in patients treated with Trulicity than placebo (0.9%,
1.7%, and 2.3% for placebo, Trulicity 0.75mg,and Trulicity 1.5 mg, respectively). On
electrocardiograms, a PR interval increase to at least 220milliseconds was observed in
0.7%, 2.5%, and 3.2% of patients treated with placebo, Trulicity 0.75mg,and Trulicity
1.5mg, respectively. Amylase and Lipase Increase: Patients exposed to Trulicity had mean
increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-
treated patients had mean increases of up to 3%.
DRUG INTERACTIONS
Trulicity slows gastric emptying and thus has the potential to reduce the rate of absorption
of concomitantly administered oral medications. Caution should be exercised when oral
medications are concomitantly administered with Trulicity. Drug levels of oral medications
with a narrow therapeutic index should be adequately monitored when concomitantly
administered with Trulicity. In clinical pharmacology studies, Trulicity did not affect the
absorption of the tested, orally administered medications to any clinically relevantdegree.
USE IN SPECIFIC POPULATIONS
Pregnancy - Pregnancy Category C: There are no adequate and well-controlled studies
of Trulicity in pregnantwomen. The risk of birth defects, loss, or other adverse outcomes
is increased in pregnancies complicated by hyperglycemia and may be decreased with
good metabolic control. It is essential for patients with diabetes to maintain good metabolic
control before conception and throughout pregnancy. Trulicity should be used during
pregnancy only if the potential benefit justifies the potential risk to the fetus. In rats and
rabbits, dulaglutide administered during the major period of organogenesis produced
fetal growth reductions and/or skeletal anomalies and ossification deficits in association
with decreased maternal weight and food consumption attributed to the pharmacology of
dulaglutide. Nursing Mothers: It is not known whether Trulicity is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential for clinical
adverse reactions from Trulicity in nursing infants, a decision should be made whether
to discontinue nursing or to discontinue Trulicity, taking into account the importance of
the drug to the mother. Pediatric Use: Safety and effectiveness of Trulicity have not been
established in pediatric patients. Trulicity is not recommended for use in pediatric patients
younger than 18 years. Geriatric Use: In the pool of placebo- and active-controlled trials,
620 (18.6%) Trulicity-treated patients were 65 years of age and over and 65 Trulicity-treated
patients (1.9%) were 75 years of age and over. No overall differences in safety or efficacy
were detected between these patients and younger patients, but greater sensitivity of
some older individuals cannot be ruled out. Hepatic Impairment: There is limited clinical
experience in patients with mild, moderate, or severe hepatic impairment. Therefore,
Trulicity should be used with caution in these patient populations. In a clinical pharmacology
study in subjects with varying degrees of hepatic impairment, no clinically relevant change
in dulaglutide pharmacokinetics (PK) was observed. Renal Impairment: In the four Phase 2
and five Phase 3 randomized clinical studies, at baseline, 50 (1.2%) Trulicity-treated patients
had mild renal impairment (eGFR60 but <90 mL/min/1.73 m2), 171 (4.3%) Trulicity-
treated patients had moderate renal impairment (eGFR 30 but <60 mL/min/1.73m2) and
no Trulicity-treated patients had severe renal impairment (eGFR<30mL/min/1.73 m2).
TrulicityTM (dulaglutide) DG HCP BS 20APR2015
No overall differences in safety or effectiveness were observed relative to patients with
normal renal function, though conclusions are limited due to small numbers. In a clinical
pharmacology study in subjects with renal impairment including end-stage renal disease
(ESRD), no clinically relevant change in dulaglutide PK was observed. There is limited clinical
experience in patients with severe renal impairment or ESRD. Trulicity should be used with
caution, and if these patients experience adverse gastrointestinal side effects, renal function
should be closely monitored. Gastroparesis: Dulaglutide slows gastric emptying. Trulicity
has not been studied in patients with pre-existing gastroparesis.
OVERDOSAGE
Overdoses have been reported in clinical studies. Effects associated with these overdoses
were primarily mild or moderate gastrointestinal events (eg, nausea, vomiting) and non-
severe hypoglycemia. In the event of overdose, appropriate supportive care (including
frequent plasma glucose monitoring) should be initiated according to the patients clinical
signs and symptoms.
PATIENT COUNSELING INFORMATION See FDA-approved Medication Guide
Inform patients that Trulicity causes benign and malignant thyroid C-cell tumors in rats
and that the human relevance of this finding has not been determined. Counsel patients
to report symptoms of thyroid tumors (eg,a lump in the neck, persistent hoarseness,
dysphagia, or dyspnea) to their physician. Inform patients that persistent severe
abdominal pain, that may radiate to the back and which may (or may not) be accompanied
by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue
Trulicity promptly, and to contact their physician, if persistent severe abdominal pain occurs.
The risk of hypoglycemia may be increased when Trulicity is used in combination with
a medicine that can cause hypoglycemia, such as a sulfonylurea or insulin. Review and
reinforce instructions for hypoglycemia management when initiating Trulicity therapy,
particularly when concomitantly administered with a sulfonylurea or insulin. Patients
treated with Trulicity should be advised of the potential risk of dehydration due to
gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Inform
patients treated with Trulicity of the potential risk for worsening renal function and explain
the associated signs and symptoms of renal impairment, as well as the possibility of
dialysis as a medical intervention if renal failure occurs. Inform patients that serious
hypersensitivity reactions have been reported during postmarketing use of GLP-1 receptor
agonists. If symptoms of hypersensitivity reactions occur, patients must stop taking Trulicity
and seek medical advice promptly. Advise patients to inform their healthcare provider if
they are pregnant or intend to become pregnant. Prior to initiation of Trulicity, train patients
on proper injection technique to ensure a full dose is delivered. Refer to the accompanying
Instructions for Use for complete administration instructions with illustrations. Inform
patients of the potential risks and benefits of Trulicity and of alternative modes of therapy.
Inform patients about the importance of adherence to dietary instructions, regular physical
activity, periodic blood glucose monitoring and HbA1c testing, recognition and management
of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During
periods of stress such as fever, trauma, infection, or surgery, medication requirements may
change and advise patients to seek medical advice promptly. Each weekly dose of Trulicity
can be administered at any time of day, with or without food. The day of once-weekly
administration can be changed if necessary, as long as the last dose was administered 3
or more days before. If a dose is missed and there are at least 3 days (72 hours) until the
nextscheduled dose, it should be administered as soon as possible. Thereafter, patients can
resume theirusual once-weekly dosing schedule. If a dose is missed and the next regularly
scheduled dose is due in 1 or 2 days, the patient should not administer the missed dose and
instead resume Trulicity with the next regularly scheduled dose. Advise patients treated
with Trulicity of the potential risk of gastrointestinal side effects. Instruct patients to read
the Medication Guide and the Instructions for Use before starting Trulicity therapy and
review them each time the prescription is refilled. Instruct patients to inform their doctor
or pharmacist if they develop any unusual symptom, or if any known symptom persists
or worsens. Inform patients that response to all diabetic therapies should be monitored
by periodic measurements of blood glucose and HbA1c levels, with a goal of decreasing
these levels towards the normal range. HbA1c is especially useful for evaluating long-term
glycemic control.
Eli Lilly and Company, Indianapolis, IN 46285, USA
US License Number 1891
Copyright 2014, 2015, Eli Lilly and Company. All rights reserved.
Additional information can be found at www.trulicity.com
DG HCP BS 20APR2015
TrulicityTM (dulaglutide) DG HCP BS 20APR2015
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Vol. 42 No. 2 February 2017 P&T

65

Cover: Scanning electron micrograph
of a white blood cell from a patient
with chronic lymphocytic leukemia
(CLL). A review of the latest treatment
strategies for CLL starts on page 106.
(Credit: Aaron Polliack/Science Source)
DEPARTMENTS
Medication Errors 74
The impact of disrespectful
workplace behavior and how
to address it
Prescription: Washington 76
21st Century Cures bill may
lead to faster drug/device
approvals
Drug and Device News 78
Approvals, new indications,
regulatory activities, and more
Pharmaceutical
Approval Update 90
Prasterone (Intrarosa) for the
treatment of dyspareunia due
to menopause; crisaborole
(Eucrisa) for the topical
treatment of atopic dermatitis;
and tenofovir alafenamide
(Vemlidy) for once-daily
treatment of chronic hepatitis
B virus infection
Drug Forecast 92
Brivaracetam (Briviact):
a novel adjunctive therapy
for partial-onset seizures
Author Guidelines 124
Research Briefs 140
Back issues are available on
the PubMed Central archive.
Visit www.pubmedcentral.nih.gov
The digital edition does not contain some of the advertising pages that appear in the print edition.
CONTENTS
February 2017
FEATURES
FDA Flags Inconsistent Hospital Reporting
Of Medical Device Problems 97
Hazy Reporting Rules Beget Confusion
The National Evaluation System for Health Technology will be developed over the
next ve years to upgrade and improve the reporting of medical device adverse
events. However, participants using the new system will incur signicant capital costs.
Stephen Barlas
New Pharmacotherapies in Chronic Lymphocytic Leukemia 106
The authors present the clinical outcomes and therapeutic application of
newly approved pharmacotherapies for chronic lymphocytic leukemia and
highlight emerging investigational therapeutic options.
Jacqueline L. Olin, MS, PharmD, BCPS, CDE, FASHP, FCCP; Katherine Canupp, BS,
PharmD Candidate; and Morgan B. Smith, PharmD, BCOP
Experts Provide a Glimpse of the
New Post-SPRINT Era of Hypertension 118
In advance of the new guidelines being published this year, the author discusses
treatment targets, diagnostics, and public policy with three hypertension experts.
Susan L. Worley
Effect of Intravenous Acetaminophen on Post-Anesthesia Care
Unit Length of Stay, Opioid Consumption, Pain, and Analgesic
Drug Costs After Ambulatory Surgery 125
A retrospective cohort study conducted in adult patients nds that intravenous
acetaminophen use in certain ambulatory procedures is not associated with
decreased PACU length of stay, but it may decrease postoperative pain.
Moteb A. Khobrani, PharmD; James M. Camamo, PharmD; and
Asad E. Patanwala, PharmD
PIPELINE PLUS
New Schizophrenia Treatments
Address Unmet Clinical Needs 130
We present several novel drugs in development for enhancing cognition, treating
negative symptoms, and providing improved options for treatment-resistant patients.
Drug makers aim to enhance safety proles and increase patient compliance to therapy.
Chris Fellner
MEETING HIGHLIGHTS
American Society of Hematology
Annual Meeting and Exposition 135
Key sessions on pharmacotherapy clinical trials across a wide span of disease states,
including leukemia, graft-versus-host disease, myelobrosis, multiple myeloma, and
sickle cell disease, are reviewed.
Walter Alexander
Editor-in-Chief
David B. Nash, MD, MBA
Dr. Raymond C. and
Doris N. Grandon Professor
The Jefferson College of Population Health
Philadelphia, Pennsylvania
Richard Afable, MD, MPH
President and Chief Executive Ofcer
Hoag Memorial Hospital Presbyterian
Newport Beach, California
Robert L. Barkin, MBA, PharmD
Professor, Faculty of Anesthesiology,
Family Medicine, and Pharmacology
Rush Medical College of Rush University
Chicago, Illinois
Clinical Pharmacologist
North Shore University Health System
Pain Centers
Skokie and Evanston, Illinois
Mark J. Baumel, MD, MS
President/Chief Executive Ofcer
Colon Health Centers of America, LLC
Mendenhall, Pennsylvania
Thomas Biancaniello, MD
Clinical Professor of Pediatrics
Columbia University
College of Physicians and Surgeons
Division of Pediatric Cardiology
New York, New York
Joseph E. Biskupiak, PhD, MBA
Research Associate Professor
Department of Pharmacy Practice
Director, Pharmacotherapy Outcomes
Research Center
College of Pharmacy, University of Utah
Salt Lake City, Utah
David A. Casey, MD
Vice Chairman, Department of Psychiatry
University of Louisville
Louisville, Kentucky
Alan Caspi, PhD, PharmD, MBA
President, Caspi & Associates
New York, New York
Burke A. Cunha, MD
Professor of Medicine
State University of New York at Stony Brook
Chief, Infectious Disease Division
Winthrop-University Hospital
Mineola, New York
Joseph C. English III, MD
Professor of Dermatology
Clinical Vice Chairman
for Quality and Innovation
Founding Director of Teledermatology
University of Pittsburgh
Department of Dermatology
Pittsburgh, Pennsylvania
EDITORIAL BOARD
Marvin M. Goldenberg, PhD, RPh, MS
President, Pharmaceutical and Scientic
Services
Marvin M. Goldenberg, LLC
Westeld, New Jersey
Nancy Greengold, MD, MBA
Chief Medical Ofcer
Sharp Grossmont Hospital/Sharp
HealthCare
La Mesa, California
Matthew Grissinger, RPh, FASCP
Director, Error Reporting Programs
Institute for Safe Medication Practices
Horsham, Pennsylvania
Rusty Hailey, PharmD, DPh, MBA, FAMCP
President, Pharmaceutical Operations
Senior Vice President, HealthSpring, Inc.
Nashville, Tennessee
Steven D. Hanks, MD, MMM, FACP
Executive Vice President
and Chief Medical Ofcer
The Hospital of Central Connecticut
New Britain, Connecticut
Michele B. Kaufman, PharmD, BCGP, RPh
Pharmacist, New YorkPresbyterian
Lower Manhattan Hospital, Pharmacy
Department
New York, New York
Grant D. Lawless, RPh, MD
Associate Professor of Clinical Pharmacy,
Pharmaceutical Economics and Policy
Director, Master of Science Program in
Healthcare Decision Analysis
School of Pharmacy
University of Southern California
Los Angeles, California
Burton Orland, BS, RPh
President
BioCaRe Consultants
Westport, Connecticut
Fred Joseph Pane, RPh, BS, FASHP, FABC
Senior Director, Customer Engagement
The Medicines Company
Parsippany, New Jersey
Lawrence Charles Parish, MD
Dermatologist, Editor-in-Chief
Clinics in Dermatology
Philadelphia, Pennsylvania
Associate Editor-in-Chief
Karl A. Matuszewski, MS, PharmD
Vice President
First Databank, Inc.
Clinical and Editorial
Knowledge Base Services
South San Francisco, California
Luke A. Probst, PharmD, BCPS
Director of Pharmacy Services
Upstate University Hospital/
Downtown Campus
Clinical Assistant Professor, Departments
of Pediatrics and Medicine
SUNY Upstate Medical University
Syracuse, New York
Sheldon M. Retchin, MD, MSPH
Executive Vice President of Health
Sciences, The Ohio State University
Chief Executive Ofcer, OSU Wexner
Medical Center
Columbus, Ohio
Vitalina Rozenfeld, PharmD, BCPS
Medical Affairs
AstraZeneca
Wilmington, Delaware
Fadia T. Shaya, PhD, MPH
Professor and Vice-Chair for Academic
Affairs
University of Maryland School of Pharmacy
Associate Director
Center on Drugs and Public Policy
Baltimore, Maryland
Arthur F. Shinn, PharmD, FASCP
President
Managed Pharmacy Consultants, LLC
Palm City, Florida
Brian Swift, PharmD, MBA
Vice President/Chief of Pharmacy
and Accreditation
Thomas Jefferson University Hospital
Associate Dean of Professional Affairs
Jefferson College of Pharmacy
Philadelphia, Pennsylvania
F. Randy Vogenberg, RPh, PhD
Partner
Access Market Intelligence and National
Institute of Collaborative Healthcare
Greenville, South Carolina
Scott W. Yates, MD, MBA, MS
Center for Executive Medicine
Plano, Texas
Vol. 42 No. 2 February 2017 P&T
73
MEDICATION ERRORS
Disrespectful Behavior in Health Care
Its Impact, Why It Arises and Persists,
And How to Address ItPart 2
Matthew Grissinger, RPh, FASCP
Mr. Grissinger, an editorial
board member of P&T, is
Director of Error Reporting
Programs at the Institute for
Safe Medication Practices
(ISMP) in Horsham, Penn-
sylvania (www.ismp.org).
In our last column, we published the
results of an Institute for Safe Medication
Practices (ISMP) survey, which clearly
exposed health cares continued tolerance
of and indifference to disrespectful behav-
ior.1 Widespread disrespectful behavior
in health care persists unchecked and
is found at all levels of the organization
and among all disciplines of staff. The
stubborn strength of this problem lies
in its quiet ability to undermine critical
conversations.2 In Part 2, we delve into the
impact of disrespectful behavior, why it
arises and persists, and how to address it.
Impact of Disrespectful Behavior
Disrespectful behavior chills communi-
cation and collaboration, undercuts indi-
vidual contributions to care, undermines
staff morale, increases staff resignations
and absenteeism, creates an unhealthy or
hostile work environment, causes some to
abandon their profession, and ultimately
harms patients. These behaviors have
been linked to adverse events, medical
errors, compromises in patient safety, and
even patient mortality.3,4 Disrespect causes
the recipient to experience fear, anger,
shame, confusion, uncertainty, isolation,
self-doubt, depression, and a whole host
of physical ailments, such as insomnia,
fatigue, nausea, and hypertension.5 These
feelings diminish a persons ability to think
clearly, make sound judgments, and speak
up regarding questions or concerns. Dis-
respectful behavior is also at the root of
difculties encountered in developing
team-based approaches to improving
care.5 Patient condence has also been
undermined by disrespectful behaviors,
making patients less likely to ask questions
or provide important information.
74 P&T February 2017 Vol. 42 No. 2
Why Disrespectful Behavior Arises
Disrespectful behavior can arise in
any health care setting, and both the
stressful nature of the environment and
human nature play roles in this destruc-
tive behavior. We are driven to function in
survival mode when forced to cope with
difcult personal frustrations and system
failures. Disrespectful behavior is often
survival behavior gone awry.2 Although
personal frustrations and system failures
do not excuse disrespectful behavior,
they often create a tipping point by which
an individual is pushed over the edge
into full-blown disrespectful behavior.
Characteristics of the individual, such as
insecurity, anxiety, depression, aggres-
siveness, and narcissism, can also kick
in and serve as a form of self-protection
against feelings of inadequacy.5 Cul-
tural, generational, and gender biases,
and current events inuencing mood,
attitude, and actions, also contribute to
disrespectful behavior.4
Differences in communication styles
and power dynamics can also play a
role.5,6 For example, physicians may get
frustrated when nurses present informa-
tion in more detail than they believe is
necessary. Nurses may get frustrated
when physicians do not seem interested
in the information provided. These differ-
ences in communication styles can lead
to disrespectful behavior. The hierarchi-
cal nature of health care and a sense of
privilege and status can lead those at the
top of a hierarchy to treat others lower on
the hierarchy with disrespect.
Why Disrespectful Behavior Persists
Health care organizations have fed
the problem of disrespectful behavior
for years by ignoring it, thereby tacitly
accepting such behaviors.2 The health
care culture has permitted a certain
degree of disrespect while considering
this a normal style of communication.5
Studies have shown that disrespectful
behaviors are tolerated most often in
unfavorable work environments, but it is
unclear whether poor working conditions
create an environment where the behav-
iors are tolerated or if the disrespectful
behaviors create the unfavorable
environment.7,8
Organizations have largely failed to
address disrespectful behavior for a
variety of reasons. First, the behavior
typically occurs daily but often goes
unreported due to fear of retaliation
and the stigma associated with whistle
blowing. Disrespectful behaviors are
difcult to measure, so without robust
systems of environmental scanning to
uncover the behavior, leaders may be
ignorant of the problem.9 Leaders may
also be unaware of the behavior if man-
agers shield them from this informa-
tion because they view it as a personal
failure.9 If disrespectful behaviors are
known, leaders may be reluctant to con-
front individuals if they are powerful or
high-revenue producers, or they may not
know how to handle the problem. Its not
a topic taught in training programs, so
leaders may hesitate to take on a problem
for which there is no obvious solution.9
Addressing Disrespectful Behavior
1. Set the Stage
Establish a steering committee of
trustees, senior leaders, middle manag-
ers, physicians, pharmacists, nurses, and
other staff. Have the committee educate
itself about disrespectful behavior, dene
the behavior, list examples of the many
forms it can take, and establish an action
plan that species how to identify dis-
respectful behavior, respond to it, and
measure the success of organizational
efforts. Responsibility for addressing the
problem belongs to the leaders, who need
to raise awareness of the problem, inspire
others to change, communicate respect
as a core value, articulate their commit-
ment to achieving it, and create a sense
of urgency around doing so.
Establish a no retribution policy for
those who report disrespectful behavior.
This policy must be established at the

very onset of organizational efforts to
reduce disrespectful behaviors.
Open the dialogue about disrespect-
ful behavior by surveying staff about
the issue using surveys from ISMP
(www.ismp.org/survey/disrespectful)
or the Agency for Healthcare Research
and Quality (www.ismp.org/sc?id=343).
Incorporate questions about disrespect-
ful behavior in safety rounds. Hold focus
groups where frank discussions can be
held with objective facilitators to keep
the conversation productive. However
uncomfortable, dialogue on this issue is
crucial to the development of more effec-
tive and respectful ways of interacting
with each other.
2. Establish a Code of Conduct
Create a code of conduct (or code of
professionalism) that serves as a model
of interdisciplinary collegial relationships
(different but equal) and collaboration
(mutual trust and respect that produces
willing cooperation).10 Clearly articulate
the standard of behavior desired as well
as unacceptable behaviorsdont assume
staff know this, so be clear.9 Addressing
disrespectful behavior must start with
an absolute belief by all staff that no one
deserves to be treated with disrespect.
Furthermore, the code of conduct should
not allow any exemptions. As long as
those who generate the most revenue
are excused from responsibility for their
actions, the code of conduct will have
little impact on anyone elses behavior.11
3. Establish a Communication
Strategy
Establish a standard, assertive com-
munication process for health care staff
who must convey important informa-
tion. Stating the problem along with its
rationale and a potential solution can
improve assertive communication.
Numerous communication techniques
are available to help staff accomplish this,
including:
SBAR (www.ismp.org/sc?id=344):
the person communicating the
crucial information covers the situa-
tion, background, assessment, and
recommendations
D-E-S-C script (www.ismp.org/
sc?id=345): Describe in objective
terms what you observed, heard, or
perceived; express concerns using
I statements and nonjudgmental
terminology; specify or inquire
about an alternate course of action;
discuss both positive and negative
consequences
TeamSTEPPS (http://teamstepps.
ahrq.gov): Team Strategies and
Tools to Enhance Performance and
Patient Safety, an evidence-based
teamwork system to improve com-
munication and teamwork skills
among health care professionals.
4. Manage Conicts
An escalation policy must be estab-
lished to manage conicts about the
safety of an order when the standard
communication process fails to resolve
an issue. Staff must know whom to call
to aid in getting a satisfactory resolution.
Be sure the process provides an avenue
for resolution outside the typical chain of
command in case the conict involves a
subordinate and his or her supervisor.
5. Establish Interventions
Develop an intervention policy that has
full leadership support to consistently
address disrespectful behaviors. An
effective policy includes zero tolerance
for disrespectful behaviors regardless of
the offenders standing in the organiza-
tion, fairness to all parties, consistency in
enforcement, a tiered response to infrac-
tions, a restorative process to help people
change their behavior, and surveillance
mechanisms.12 Levels of interventions
might start with coaching and proceed
to progressive discipline as warranted.
The intervention policy should clearly
articulate the behaviors or repeated
behaviors that will be referred for dis-
ciplinary action, and how and when the
disciplinary process will start.13 The focus
of an intervention should be on building
trust and holding staff accountable for
making better behavioral choices. The
importance of a prompt, predictable, and
appropriate response to an alleged viola-
tion cannot be overemphasized.10 In all
cases, those who report or cooperate in
the investigation should be protected
against retaliation.12
The intervention policy should also
require addressing any system issues that
amplify and perpetuate the disrespectful
behavior. Common system problems
include issues that affect workloads,
stafng, budgeting, education, commu-
MEDICATION ERRORS
nication, hand-offs, physical hazards,
and environmental stressors. Individual
behaviors can also be altered through
system improvements.2
6. Train Staff
Provide mandatory hospital-wide
education for all staff about the impact of
disrespectful behavior and appropriate
professional behavior as dened by the
code of conduct.12,14 Provide skill-based
training in communication methods,
relationship building, business etiquette,
behavioral techniques to confront and
address disrespect, conict resolution,
assertiveness training, team training, and
how to report disrespectful behaviors.
Use role-playing, vignettes, or aggression
scenarios to strengthen skills associated
with assertive communication, conict
resolution, and interpersonal interactions.
One health system provides leaders with a
toolkit that includes talking points regard-
ing the impact of disrespectful behavior,
the code of conduct, denitions, surveys,
communication/teamwork guides, key
articles and intranet resources, no retri-
bution policy, and a letter from the chief
executive ofcer outlining full leadership
support.9
7. Encourage Reporting/
Surveillance
Implement a condential reporting/
surveillance program for detecting dis-
ruptive behavior and measuring compli-
ance with the code of conduct. A formal
reporting program and an informal
process for unwritten reports should be
offered, and anyone who experiences or
witnesses disruptive behavior should be
encouraged to report the event.13 The no
retribution policy for reporting should
be well known to staff and upheld. Peri-
odic updates should be provided to those
who make reports about addressing
disrespectful behaviors, but individual
details should remain condential.
No organization should assume that
the absence of reports of disrespectful
behavior means it is not occurring. Other
means of surveillance to identify dis-
respectful behaviors should be employed,
including feedback from patients and
families, staff and patient surveys, focus
groups, informal dialogue, peer and team
evaluations, and making direct inquiries
at routine intervals (e.g., during safety
rounds).
continued on page 77
Vol. 42 No. 2 February 2017 P&T
75
PRESCRIPTION: WASHINGTON
21st Century Cures Bill May Lead
To Faster Drug/Device Approvals
But Moving Away from Clinical Trials Worries Some
Stephen Barlas
Mr. Barlas is a freelance
writer in Washington,
D.C., who covers issues
inside the Beltway. Send
ideas for topics and your
comments to sbarlas@
verizon.net.
cynic might say that it is hard to
A take the mammoth 21st Century
Cures bill seriously. It passed
Congress at the very end of the session in
December, the culmination of four years
of discussion. So in one sense, many of its
provisions were vetted, at least politically,
which is another way of saying they didnt
raise serious objections in any quarter.
The votes in the House (39226) and
Senate (945) were testimony to that. It
can often be said that, when it comes to
congressional legislation, no controversy
equals minimal signicance.
The nearly 1,000-page bill is a hodge-
podge of loosely worded speculative
provisions across many health care/
federal programs, most of them at the
Food and Drug Administration (FDA)
and National Institutes of Health (NIH).1
When the House Energy and Commerce
Committee began holding hearings on
the bill four years ago, the legislation was
viewed as a vehicle for allowing, or, if one
prefers, forcing the FDA to permit phar-
maceutical companies to gain approval of
new indications for existing drugs with
evidence assembled short of expensive
clinical trials and short of conventional
endpoints. Over the years, the vehicle
was expanded to include funding for the
Cancer Moonshot supported by Vice
President Joe Biden and some other pro-
grams at the NIH. As the bill lumbered
toward passage in early December, it was
larded with new provisions in areas such
as mental health and opioid addiction.
The FDA provisions are the most
ballyhooed and are where the bill started.
Here, the legislation encourages the
FDA to approve new drugs based on
76 P&T February 2017 Vol. 42 No. 2
real-world evidence (RWE) and surro-
gate endpoints, such as biomarkers. The
term RWE refers to ndings about a drug
that are gleaned by looking at patient
health records, whether obtained in a
clinical trial or not, and marrying them
with health insurance claims data and/or
product registries to reach a conclusion
about whether an already-approved drug
should be approved for a new indication.
The FDA already issued a guidance docu-
ment on RWE used for medical device
approval in 2016,2 so it is not clear what
the bill requires the FDA to do that it
is not already doing. Moreover, the top
leaders of the FDA published an article in
the New England Journal of Medicine on
December 8, 2016,3 committing to move
forward with the use of RWE, including
publishing draft guidance on pharma-
ceuticals as a follow-on to its guidance
on medical devices. The provision in the
bill simply requires the FDA to evaluate
the use of RWE.
The bill denes RWE as data regard-
ing the usage, or the potential benets
or risks, of a drug derived from sources
other than randomized clinical trials.1
The implication that randomized clinical
trials can be done away with concerns
some health researchers, such as Sanket
Dhruva, MD, FACC, a cardiologist and
health services researcher at the Yale
University School of Medicine. Speci-
cally saying that clinical trials, the gold
standard in drug and medical device
approval, do not have to be used takes
a step in the wrong direction, he says.
There certainly is tremendous poten-
tial with RWE, but we must validate the
evidence as being rigorously collected
and reliable.
Dr. Dhruva worries about the bills
endorsement of the use of drug develop-
ment tools in the drug approval process.
Here, the bill denes those tools as: a) a
biomarker; b) a clinical outcome assess-
ment; and c) any other method, mate-
rial, or measure that the [Department of
Health and Human Services] Secretary
determines aids drug development and
regulatory review for purposes of this
section.1 Dr. Dhruva also worries about
the FDA moving away from requiring
drug manufacturers to prove that a drug
actually benets a patient by making
his or her life longer and/or better. He
cites the controversial use of endpoints
in the recent FDA approval of eteplirsen
(Exondys 51, Sarepta Therapeutics)
based on the use of a surrogate measure
(in this case, muscle dystrophin levels).
In an article published by the Journal of
the American Medical Association, Aaron
S. Kesselheim, MD, JD, MPH, of the
Program on Regulation, Therapeutics,
and Law (PORTAL) at Harvard Medical
School, and similarly situated colleague
Jerry Avorn, MD, wrote:
However, the accelerated approval pathway
through which eteplirsen was authorized
requires that a surrogate endpoint must be
reasonably likely to predict clinical benet
of the drug, and this standard is challenged
by the minimal changes seen in the dys-
trophin levels. Speeding drugs to market
based on such biomarker outcomes can
actually lead to a worse outcome for patients,
even those with life-threatening diseases, if
a product confers no meaningful benet
and carries a risk of adverse effects and a
high cost. Immediately after approval, the
manufacturer announced a price of $300,000
per year for eteplirsen.4
The FDA approval process measures
were sought by the Pharmaceutical
Research and Manufacturers of America
(PhRMA) and the Advanced Medical Tech-
nology Association, the drug and medical
device manufacturers trade groups, and
some patient groups, too. The PhRMA
released a statement saying:
The legislation includes pro-patient, science-
based reforms, which enhance the com-
petitive market for biopharmaceuticals and
drive greater efciency in drug develop-
ment. It also increases FDAs regulatory
PRESCRIPTION: WASHINGTON
capabilities to foster the timely review and
approval of new treatments for patients.
A PhRMA spokeswoman was unable to
cite specic provisions that either allow
or force the FDA to do something more
than it is already doing.
To help the FDA hire new staff to
implement the Cures provisions, the
bill creates an FDA Innovation Account
and funds it to the tune of $500 million
over 10 years. That is guaranteed money,
over and above what Congress will
appropriate annually for the agency. The
Alliance for a Stronger FDA points out
that it is entirely possible that Congress
will subtract each years guaranteed
Cures money from the agencys non-
guaranteed base budget appropriation.
Were this done, FDA would acquire a
large number of new responsibilities,
but the agency would not receive net
additional funds, the Alliance says. Seen
another way, FDA might nd itself with a
signicant budget cut imposed upon the
agencys non-Cures activities.
There might be a similar scenario affect-
ing funding for the NIH. The Cures bill
provides $4.8 billion in new funding for
the NIH over the next 10 years to pursue
a moonshot to cure cancer, investi-
gate brain chemistry, and develop indi-
vidualized or precision medicine. Even if
Congress continues to increase annual
appropriations for the NIH at approxi-
mately the same rate it has beenbetween
1% and 2% per yearthe extra $4.8 billion
over 10 years probably wont keep NIH
spending increases even with ination.
Many other provisions are worth
noting, though it will not be clear for some
time whether they are signicant or not.
The Academy of Managed Care Pharmacy
was glad to see a provision included in the
bill that it says will be a plus for formulary
decision-makers. Specically, it loosens
the current FDA standard dictating what
kind of health care economic information
a manufacturer can share with a health
insurers P&T committee. The intention is
to allow drug companies to share informa-
tion about a drug beyond what is on the
drugs label. The bill denes health care
economic information as:
... any analysis, including the clinical data,
inputs, clinical or other assumptions,
methods, results, and other components
underlying or comprising the analysis
that identies, measures, or describes the
economic consequences, which may be
based on the separate or aggregated clini-
cal consequences of the represented health
outcomes, of the use of a drug.1
It may turn out that the Cures bill
results in deep culture changes in the
FDA drug and medical device approval
processes. Certainly, the Trump admin-
istration will be more expansive in its
interpretations of the provisions than
the Clinton administration would have
been where rulemakings are required.
But the vagueness of some of the pro-
visions and the general public concern
about out-of-control drug prices, shared
by Republicans and President Trump,
probably mitigate against the Cures bill
bestowing too many of what might be
viewed as rich gifts on the drug industry.
MEDICATION ERRORS
continued from page 75
8. Create a Positive Environment
Certain aspects of the workplace envi-
ronment are key to combatting disrespect,
including a fair and just culture, respectful
management of serious adverse events,
and transparency so staff members feel
safe talking about disrespectful behavior
without fear of reprisal.12 Another factor
is visible leadership commitment to a
respectful culture, which requires leading
by example. Leaders should set the tone
with an attitude of mutual respect for the
contributions of all staff, remain open to
questions and new ideas, and reward
outstanding examples of collaborative
teamwork, respectful communication,
and positive interpersonal skills. Using
key communication tools, such as email
blasts, leaders can maintain an ongoing
dialogue about respectful behaviors with
the entire organization to help assure
staff that leadership commitment to a
respectful culture is not eeting.2
REFERENCES
1. Grissinger M. Unresolved disrespect-
ful behavior in health care: practi-
tioners speak up (again)part 1.
P T 2017;42(1):45,23.
2. Zimmerman T, Amori G. The silent
organizational pathology of insidious
intimidation. J Healthc Risk Manag 2011;
30(3):56,815.
3. Rosenstein AH, ODaniel M. A survey
of the impact of disruptive behaviors
REFERENCES
1. Bonamici S. H.R.3421st Century
Cures Act. 114th Congress (20152016).
December 13, 2016, became Public Law
No: 114255. Available at: www.congress.
gov/114/bills/hr34/BILLS-114hr34enr.
pdf. Accessed December 28, 2016.
2. Food and Drug Administration. Use of
real-world evidence to support regulatory
decision-making for medical devices: draft
guidance for industry and Food and Drug
Administration staff. September 16, 2016.
Available at: www.fda.gov/ucm/groups/
fdagov-public/@fdagov-meddev-gen/
documents/document/ucm513027.pdf.
Accessed December 28, 2016.
3. Sherman RE, Anderson SA, Dal Pan GJ,
et al. Real-world evidencewhat is it and
what can it tell us? N Engl J Med 2016;
375(23):22932297.
4. Kesselheim AS, Avorn J. Approving a
problematic muscular dystrophy drug:
implications for FDA policy. JAMA 2016;
316(22):23572358. Q
and communication defects on patient
safety. Jt Comm J Qual Patient Saf 2008;
34(8):464471.
4. McNamara SA. Incivility in nursing:
unsafe nurse, unsafe patients. AORN J
2012;95(4):535540.
5. Leape LL, Shore MF, Dienstag JL, et al.
Perspective: a culture of respect, part 1:
the nature and causes of disrespectful
behavior by physicians. Acad Med 2012;
87(7):845852.
6. Gessler R, Rosenstein A, Ferron L. How
to handle disruptive physician behavior.
Am Nurse Today 2012;7(11):810.
7. Lamontagne C. Intimidation: a concept
analysis. Nurs Forum 2010;45(1):5465.
8. Budin WC, Brewer CS, Chao YY, et al.
Verbal abuse from nurse colleagues
and work environment of early career
registered nurses. J Nurs Scholarsh
2013;45(3):308316.
9. Porto G, Deen J. Drawing the line. Effec-
tive management strategies for disruptive
behavior. Patient Saf and Qual Healthcare
2008 Nov/Dec:2024,2628.
10. Kramer M, Schmalenberg C. Securing
good nurse physician relationships.
Nurs Manage 2003; 34(7):3438.
11. Leape LL, Shore MF, Dienstag JL, et al.
Perspective: a culture of respect, part 2:
creating a culture of respect. Acad Med
2012;87(7):853858.
12. Pennsylvania Patient Safety Author-
ity. Chain of command: when disruptive
behavior affects communication and
teamwork. Pa Patient Saf Advis 2010;16(7)
(suppl 2):S4S13.
13. DuPree E, Anderson R, McEvoy MD,
et al. Professionalism: a necessary ingredi-
ent in a culture of safety. Jt Comm J Qual
Patient Saf 2011;37(10):447455.
14. The Joint Commission. Behaviors that
undermine a culture of safety. Sentinel
Event Alert 2008;40:13. Q
Vol. 42 No. 2 February 2017 P&T
77
 NEW DRUG APPROVALS
Rubraca for Ovarian Cancer
The FDA has granted accelerated
approval to rucaparib (Rubraca, Clovis
Oncology) to treat women with advanced
ovarian cancer who have been treated
with two or more chemotherapies and
whose tumors have a specic gene muta-
tion (deleterious BRCA), as identied by
an FDA-approved companion diagnostic
test.
The agency also approved the
FoundationFocus CDxBRCA (Founda-
tion Medicine, Inc.) companion diagnos-
tic for use with rucaparib. The test detects
the presence of deleterious BRCA gene
mutations in the tumor tissue of ovar-
ian cancer patients. If one or more of the
mutations are detected, the patient may
be eligible for treatment with rucaparib.
Source: FDA, December 19, 2016
Spinraza for Spinal
Muscular Atrophy
Nusinersen (Spinraza, Biogen/Ionis
Pharmaceuticals) has received FDA
approval as the rst drug to treat children
and adults with spinal muscular atrophy
(SMA), a rare and often fatal genetic
disease affecting muscle strength and
movement. Nusinersen is an injection
administered into the uid surrounding
the spinal cord.
The efcacy of nusinersen was inves-
tigated in a study of 121 patients with
infantile-onset SMA who were diagnosed
before 6 months of age and who were less
than 7 months old at the time of their
rst dose. The FDA asked the sponsor to
conduct an interim analysis as a way to
evaluate the study results as early as pos-
sible; 82 patients were eligible for this
analysis. Forty percent of the patients
treated with nusinersen achieved
improvements in motor milestones as
dened in the study, whereas none of the
control patients did.
Source: Biogen, December 27, 2016
78 P&T February 2017 Vol. 42 No. 2
Synjardy ER for Diabetes
The FDA has given the green light
to Synjardy XR (empagliozin and met-
formin hydrochloride extended-release
tablets, Boehringer Ingelheim/Eli Lilly)
for the treatment of adults with type-2
diabetes (T2D). When used along with
diet and exercise, Synjardy XR is indi-
cated to improve blood sugar in adults
with T2D when both empagliflozin
and metformin can be taken. Standard
Synjardy tablets were approved in 2015.
Empagliflozin, a sodium-glucose
cotransporter 2 inhibitor, removes excess
glucose through the urine by blocking
glucose reabsorption in the kidney. Met-
formin, a commonly prescribed initial treat-
ment forT2D, lowers glucose production by
the liver and its absorption in the intestine.
Source: Eli Lilly, December 12, 2016
Adynovate Antihemophilic Factor
The FDA has approved Adynovate
(antihemophilic factor [recombinant],
PEGylated, Shire), an extended circulating
half-life recombinant factor VIII treatment
for pediatric patients under 12 years of age
with hemophilia A. The FDA also approved
Adynovate for use in surgical settings in
both adult and pediatric patients. Adyno-
vate is built on the full-length Advate (anti-
hemophilic factor [recombinant]) mole-
cule, a leading treatment for patients with
hemophilia A, with more than 13 years of
real-world patient experience.
Source: Shire, December 27, 2016
Eucrisa Ointment for Eczema
Crisaborole ointment (Eucrisa, Ana-
cor Pharmaceuticals) has secured
FDA approval to treat mild-to-moderate
eczema (atopic dermatitis) in patients
2 years of age and older. Crisaborole,
applied topically twice daily, is a phos-
phodiesterase 4 inhibitor, although its
specic mechanism of action in atopic
dermatitis is not known.
Source: FDA, December 14, 2016
NEW BIOLOGIC APPROVAL
Maci for the Repair of
Knee Cartilage Defects
The FDA has approved Maci (auto-
logous cultured chondrocytes on a
porcine collagen membrane, Vericel
Corporation) for the repair of symptom-
atic, full-thickness cartilage defects of
the knee in adults. Maci is the rst FDA-
approved product that applies the process
of tissue engineering to grow cells on
scaffolds using healthy cartilage tissue
from the patients own knee.
Each Maci implant consists of a small
cellular sheet containing 500,000 to
1,000,000 cells per square centimeter
(approximately 0.16 square inches). The
amount of Maci administered depends
on the size of the cartilage defect, and
the membrane is trimmed to ensure that
the damaged area is completely covered.
Multiple implants may be used if there is
more than one defect.
Source: FDA, December 13, 2016
Generic Approvals and Launches
Epinephrine Injection
Mylan has launched an authorized
generic for the EpiPen autoinjector (epi-
nephrine injection, USP) at a wholesale
acquisition cost (WAC) of $300 per epi-
nephrine injection two-pack, which is
more than 50% lower than the WAC of
the companys EpiPen 2-Pak autoinjec-
tors. The authorized generic has the same
drug formulation and device functionality
as the EpiPen autoinjector and is admin-
istered the same way.
Source: Mylan, December 16, 2016
Oseltamivir Phosphate Capsules
Alvogen has launched the rst generic
equivalent to Tamiu (oseltamivir phos-
phate capsules, HoffmanLa-Roche) in
the United States. The product is available
in 30-mg, 45-mg, and 75-mg strengths.
Alvogen expects this generic equivalent
to Tamiu to deliver savings for patients
and health providers of up to $500 million
during the 20162017 u season.
Source: Alvogen, December 12, 2016
NEW INDICATIONS
Lucentis for Eye Disorder
The FDA has approved ranibizumab
(Lucentis, Genentech) 0.5-mg injec-
tion for the treatment of patients with
myopic choroidal neovascularization
(mCNV), a complication of severe near-
sightedness that can lead to blindness.
In the United States, ranibizumab was
previously approved for the treatment
of patients with wet age-related macu-
lar degeneration; macular edema after
retinal vein occlusion; diabetic macular
edema (DME); and diabetic retinopathy
in people with DME.
The new approval was based on results
from the phase 3, randomized, double-
blind, active-controlled RADIANCE trial,
which compared the efcacy and safety
of ranibizumab injection (0.5 mg) with
that of verteporn photodynamic therapy
(vPDT) in 276 patients with visual impair-
ment due to mCNV. At month 3, two
ranibizumab groups had a mean change
in best corrected visual acuity (BCVA)
of +12.1 and +12.5 letters from baseline,
respectively, compared with a mean BCVA
change of +1.4 letters in the vPDT group.
Source: Genentech, January 5, 2017
Jardiance for Diabetic CV Risk
The FDA has approved a new indication
for empagliozin (Jardiance, Boehringer
Ingelheim/Eli Lilly) to reduce the risk of
cardiovascular (CV) death in adults with
type-2 diabetes (T2D) and established
CV disease. Empagliozin is the rst T2D
treatment with this additional indication
and the only oral T2D medication shown
in a clinical trial to provide a life-saving CV
benet, according to the manufacturers.
In the EMPA-REG OUTCOME trial,
empagliozin signicantly reduced the
combined primary endpoint (the time
to the rst occurrence of CV death, non-
fatal heart attack, or nonfatal stroke) by
14% compared with placebo (hazard ratio
[HR], 0.86); the absolute risk reduction
was 1.6% for empagliozin compared with
placebo. This primary nding was driven
by a signicant 38% reduction in the risk
of CV death (HR, 0.62); the absolute risk
reduction was 2.2% for patients treated
with empagliozin compared with those
given placebo. There was no change in
the risk of nonfatal heart attack (HR, 0.87)
or nonfatal stroke (HR, 1.24).
Source: Boehringer Ingelheim,
January 5, 2017
FDA REVIEW ACTIVITIES
Priority Review Designations
Niraprib for Ovarian Cancer
The FDA has granted priority review
of the new drug application for niraparib
(Tesaro, Inc.). Niraparib is a poly(ADP-
ribose) polymerase inhibitor that is
being evaluated as a potential new treat-
ment option for patients with recurrent
epithelial ovarian, fallopian tube, or
primary peritoneal cancer after respond-
ing to platinum-based chemotherapy. The
FDA has established a target action date
of June 30, 2017.
The niraparib application was sup-
ported by data from a phase 3, double-
blind, placebo-controlled, international
trial that enrolled 553 patients with recur-
rent ovarian cancer who had achieved
either a partial response or a complete
response to their most-recent platinum-
based chemotherapy. Among patients
who were germline BRCA mutation car-
riers, median progression-free survival
(PFS) for those treated with niraparib was
21.0 months compared with 5.5 months
for control (P < 0.0001). Among patients
in the nongermline BRCA mutant cohort,
the median PFS for patients treated with
niraparib was 9.3 months compared with
3.9 months for control (P < 0.0001).
Source: Tesaro, December 20, 2016
Stivarga for Liver Cancer
The FDA has granted priority review
status to a supplemental new drug
application for regorafenib (Stivarga,
Bayer) for the second-line treatment of
patients with unresectable hepatocellular
carcinoma (uHCC).
The regulatory submission was based
on data from the phase 3 RESORCE
trial, which investigated regorafenib
in patients with uHCC whose disease
had progressed during treatment
with sorafenib (Nexavar, Bayer/Onyx
Pharmaceuticals). Regorafenib signi-
cantly improved overall survival (OS)
compared with placebo (hazard ratio,
0.63; P < 0.001), which represented a
37% reduction in the risk of death for
patients who received regorafenib plus
best supportive care (BSC) compared
with patients treated with placebo plus
BSC. The median OS was 10.6 months
in patients treated with regorafenib
plus BSC compared with 7.8 months in
patients who received placebo plus BSC.
Source: Bayer, January 4, 2017
Betrixaban for VTE
The FDA has accepted a new drug
application granting priority review for
betrixaban (Portola Pharmaceuticals),
an oral, once-daily factor Xa-inhibitor
anticoagulant, for extended-duration
prophylaxis of venous thromboembolism
(VTE) in acute medically ill patients with
risk factors for VTE. The application for
betrixaban, an FDA-designated fast-
track investigational drug, has a Prescrip-
tion Drug User Fee Act action date of
June 24, 2017.
Source: Portola Pharmaceuticals,
December 23, 2016
Durvalumab for Bladder Cancer
The FDA has accepted a biolog-
ics license application for durvalumab
(AstraZeneca/MedImmune) and has
granted the medication priority review
Vol. 42 No. 2 February 2017 P&T
79
status, with the Prescription Drug User
Fee Act action date set for the second
quarter of 2017.
Durvalumab is an investigational
human monoclonal antibody directed
against programmed death ligand-1
(PD-L1). PD-L1 is expressed by tumors
to evade detection by the immune system
through binding to programmed death-1
(PD-1) proteins on cytotoxic T lympho-
cytes. Durvalumab blocks the PD-L1 inter-
action with PD-1, thereby countering the
tumors immune-evading tactics.
Source: AstraZeneca, December 9, 2016
Fast-Track Designations
APL-2 for PNH
The FDA has granted a fast-track
designation to the development program
for APL-2 (Apellis Pharmaceuticals), a
complement C3 inhibitor, for the treat-
ment of patients with paroxysmal noctur-
nal hemoglobinuria (PNH) who continue
to experience hemolysis and require
transfusions of red blood cells despite
receiving therapy with eculizumab.
PNH is a rare, acquired, potentially life-
threatening disease characterized by
complement-mediated hemolytic ane-
mia. APL-2 is a synthetic cyclic peptide
that binds specically to C3 and C3b,
effectively blocking all three pathways
of complement activation.
Source: Apellis Pharmaceuticals,
December 20, 2016
ASP0892 Vaccine forPeanut Allergy
The drug candidate ASP0892 (Astellas
Pharma/Immunomic Therapeutics), a
DNA vaccine for the mitigation of severe
hypersensitivity reactions due to peanut
allergy, has been granted FDA fast-track
status. A phase 1 clinical trial has been
initiated to evaluate the safety, tolerabil-
ity, and immune response of ASP0892 in
adults who are allergic to peanuts.
Source: Astellas Pharma, December
20, 2016
80 P&T February 2017 Vol. 42 No. 2
Breakthrough Therapy Status
Neridronic Acid for CRPS
The FDA has granted a breakthrough
therapy designation to neridronic acid
(Grnenthal/Abiogen Pharma), an inves-
tigational medication for the treatment
of patients with complex regional pain
syndrome (CRPS), a serious, disabling
orphan disease. CRPS is characterized
by severe, continuous, burning pain that
often occurs in an extremity after injury
or surgery.
Source: Grnenthal, December 20,
2016
Sublingual Cyclobenzaprine for PTSD
The FDA has granted breakthrough
therapy status to cyclobenzaprine sub-
lingual tablets (TNX-102 SL, Tonix
Pharmaceuticals) for the treatment of
patients with post-traumatic stress dis-
order. A phase 3 study is expected to
begin in the rst quarter of 2017.
Source: Tonix Pharmaceuticals,
December 19, 2016
Orphan Drug Designations
MGD006 for AML
The FDA has granted an orphan drug
designation to MGD006 (MacroGenics,
Inc.), a dual-afnity retargeting molecule
that recognizes both CD123 and CD3, for
the investigational treatment of patients
with acute myeloid leukemia (AML).
MGD006 is being evaluated in the United
States and Europe in a phase 1 dose-
escalation study designed to determine
the safety and tolerability of the molecule
in patients with relapsed/refractory AML
or myelodysplastic syndrome.
Source: MacroGenics, January 5, 2017
Emixustat for Stargardt Disease
Emixustat hydrochloride (Acucela Inc.)
has received orphan drug status for the
treatment of patients with Stargardt dis-
ease, the most common form of inherited
juvenile macular degeneration.
The visual cycle is the process by which
vitamin A is recycled in the eye; vitamin A
is crucial to the visual process. Emixustat
modulates the visual cycle by inhibiting
a critical enzyme of this pathway, retinal
pigment epithelium protein 65. Slowing
the visual cycle reduces the availabil-
ity of vitamin A derivatives (11-cis- and
all-trans-retinal) to form precursors of
A2E and related compounds. In animal
models of Stargardt disease and retinal
degeneration, emixustat was found to stop
and reverse the accumulation of A2E and
to preserve the integrity of the retina.
Source: Acucela, January 5, 2017
RG7916 for Spinal Muscular Atrophy
RG7916 (PTC Therapeutics) has
received an FDA orphan drug designa-
tion for the treatment of patients with
spinal muscular atrophy (SMA). SMA
is a rare genetic disorder that results in
neuromuscular disability beginning in
infancy and is the leading inherited cause
of mortality in infants and young children.
RG7916 is an oral small-molecule splic-
ing modier that directly targets the under-
lying molecular deciency of SMA by
modulating SMN2 splicing to increase the
expression of stable full-length SMN pro-
teins from the SMN2 gene. The compound
is under investigation in two clinical stud-
ies: SUNFISH, a trial in childhood-onset
(type 2/3) SMA patients, and FIREFISH, a
trial in infant-onset (type 1) patients.
Source: PTC Therapeutics, January 6,
2017
CX-4945 for Cholangiocarcinoma
The FDA has granted an orphan drug
designation to CX-4945 (Senhwa Bio-
sciences) for the treatment of patients
with cholangiocarcinoma. CX-4945 is a
small-molecule drug that inhibits protein
kinase CK2, which plays a key role in
the DNA damage repair mechanisms of
cancer cells. CX-4945 has demonstrated
favorable safety, pharmacokinetic, and
pharmacodynamic characteristics in the
treatment of patients with advanced chol-
angiocarcinoma, according to the devel-
oper. This cancer is difcult to detect in
its early stages, and the ve-year survival
rate is approximately 20%.
Source: Senhwa Biosciences, January
4, 2017
PIKA Rabies Vaccine
The FDA has granted an orphan drug
designation for a polyinosinicpolycyti-
dylic acid-based adjuvant (PIKA) rabies
vaccine (Yisheng Biopharma) that is in
phase 2 clinical development. The vaccine
uses a proprietary Toll-like receptor-3 acti-
vation technology.
Source: Yisheng Biopharma, January
4, 2017
ES-3000 for AML
ES-3000 (Escend Pharmaceuticals)
has received orphan drug status from
the FDA for the treatment of patients with
acute myeloid leukemia (AML). The FDA
previously granted ES-3000 an orphan
drug designation for the treatment of
patients with chronic myeloid leukemia.
ES-3000 is an orally bioavailable small
molecule that ablates leukemic stem cells
by reducing beta-catenin expression. The
Wnt/beta-catenin pathway is critical for
the survival of cancer stem cells. ES-3000
is also in development for the treatment of
patients with triple-negative breast cancer.
Source: Escend Pharmaceuticals,
December 28, 2016
A004 for Retinitis Pigmentosa
The FDA has granted orphan drug
status to A004 (MeiraGTx), an adeno-
associated virus-mediated gene therapy
product candidate containing the retinitis
pigmentosa GTPase regulator (RPGR)
gene for the treatment of patients with
X-linked retinitis pigmentosa (XLRP).
More than 70% of XLRP cases and up
to 20% of RP cases are caused by muta-
tions in the RPGR gene. Males with XLRP
caused by mutations in RPGR typically
have night blindness in their rst decade
of life, followed by the progressive reduc-
tion of their visual eld and the loss of
visual acuity. By the end of their fourth
decade, most patients are legally blind.
Source: MeiraGTx, December 20, 2016
Nintedanib for Mesothelioma
The FDA has granted an orphan drug
designation to nintedanib (Boehringer
Ingelheim) for the treatment of patients
with mesothelioma. Nintedanib is an oral
triple angiokinase inhibitor that simul-
taneously inhibits vascular endothelial
growth factor receptor, platelet-derived
growth factor receptor, and broblast
growth factor receptor signaling path-
ways. These three angiokinase recep-
tors, which are not targeted by available
therapies, play an important role in angio-
genesis, tumor growth, and metastases.
Source: Boehringer Ingelheim,
December 14, 2016
ABTL0812 for Pancreatic Cancer
ABTL0812 (Ability Pharmaceuticals)
has received orphan drug status from
the FDA for the treatment of patients
with pancreatic cancer. The investiga-
tional compound, now in phase 2 clini-
cal development, causes cell death by
autophagy through the overexpression
of TRIB3, an endogenous Akt regulator.
It is a rst-in-class, fully differentiated,
oral, targeted anticancer compound
inhibiting the PI3K/Akt/mTOR pathway
without being a direct kinase inhibitor.
Source: Ability Pharmaceuticals,
December 14, 2016
BHV-0223 for ALS
The FDA has granted orphan drug
status to BHV-0223 (Biohaven Pharma-
ceutical Holding Company), an orally dis-
solving tablet being developed for the
treatment of patients with amyotrophic
lateral sclerosis (ALS), also known as Lou
Gehrigs disease.
BHV-0223 is a sublingually absorbed
dissolving tablet formulation of rilu-
zole. It was designed to address some
of the shortcomings associated with
the solid oral dosage form of riluzole,
which ALS patients have difculty swal-
lowing. Because BHV-0223 is systemi-
cally absorbed through the oral mucosa
rather than through the gastrointestinal
system, it is expected to eliminate the
negative food effect associated with rilu-
zole, to bypass rst-pass metabolism, and
to deliver effective doses of the drug at
lower concentrations.
Source: Biohaven, December 9, 2016
Refusal to File Letter
Bupivacaine Implants for Pain
Innocoll has received a refusal to le
letter from the FDA for Xaracoll (bupi-
vacaine HCl collagen-matrix implants)
for the treatment of postsurgical pain.
After a preliminary review, the FDA
determined that the application, which
was submitted in October 2016, was not
sufciently complete to permit a sub-
stantive review. The FDA indicated,
among other things, that Xaracoll should
be characterized as a drug/device com-
bination, which would require Innocoll
to submit additional information. Xara-
coll is a surgically implantable and bio-
resorbable bupivacaine-collagen matrix
that uses a proprietary collagen-based
delivery technology.
Source: Innocoll, December 29, 2016
Complete Response Letter
Lutathera for Neuroendocrine Tumors
The FDA has issued a complete
response letter (CRL) regarding
the new drug application (NDA) for
Lutathera (lutetium Lu 177 dotatate,
Advanced Accelerator Applications), a
Lu 177labeled somatostatin analogue
peptide, for the treatment of adults with
Vol. 42 No. 2 February 2017 P&T
81
gastroenteropancreatic neuroendocrine
tumors. The CRL referred to issues with
the format, traceability, uniformity, and
completeness of the NETTER-1 and
Erasmus clinical datasets that were pre-
venting FDA reviewers from perform-
ing the required independent analysis
of these clinical studies. In addition, the
CRL requested analyses for gender, age,
and racial subgroups, as well as other
stratication factors and disease charac-
teristics. A safety update on clinical and
nonclinical studies was also requested.
Finally, the CRL noted that observations
made during inspections of manufactur-
ing facilities supporting the NDA must
be resolved before the NDA could be
approved.
Source: Advanced Accelerator
Applications, December 21, 2016
DRUG SAFETY ISSUES
Acid-Suppressant Drugs
Linked to GI Infections
In a population-based study conducted
in Scotland, the use of commonly pre-
scribed acid-suppressant medications
(ASMs), such as proton pump inhibi-
tors (PPIs), has been linked to an
increased risk of intestinal infections with
Clostridium difcile and Campylobacter
bacteria, which can cause serious ill-
ness. The study involved 188,323 patients
exposed to PPIs and H2 receptor antago-
nists (H2RAs) and 376,646 controls who
were not exposed to ASMs between 1999
and 2013.
Compared with individuals in the com-
munity who did not take acid-suppressant
drugs, those who did had 1.7-times and
3.7-times increased risks for C. difcile
and Campylobacter infections, respec-
tively. Among hospitalized patients, those
using acid-suppressant medications had
1.4-times and 4.5-times increased risks,
respectively. The adjusted hazard ratios
for culture-positive diarrhea for the PPI-
and H2RA-exposed cohort compared
82 P&T February 2017 Vol. 42 No. 2
with the unexposed cohort were 2.72 for
samples submitted from the community
and 1.28 for samples submitted from
hospitals.
Source: Wiley, January 5, 2017
Chantix Boxed Warning Dropped
The FDA has approved updates to the
labeling for varenicline (Chantix, Pzer),
including removal of the boxed warn-
ing regarding serious neuropsychiatric
events. The removal of the boxed warn-
ing was based on results from a pivotal
smoking-cessation trial in patients with
and without a history of psychiatric dis-
orders, and was consistent with recent
recommendations from the FDAs
Psychopharmacologic Drugs Advisory
Committee and its Drug Safety and Risk
Management Advisory Committee.
Additional labeling revisions based
on the EAGLES trial include updates to
the corresponding warning regarding
neuropsychiatric safety and the addition
of information on the superior efcacy of
varenicline compared with bupropion or
a transdermal nicotine patch.
Source: FDA, December 19, 2016
Anesthesia and Sedation in
Children and Pregnant Women
The FDA has warned that repeated
or lengthy use of general anesthetic and
sedation drugs during surgeries or pro-
cedures in children younger than 3 years
of age or in pregnant women during
their third trimester may affect the
development of childrens brains.
The agency has been investigating
the potential adverse effects of general
anesthetic and sedation drugs on chil-
drens brain development since the rst
animal study on this topic was published
in 1999. Health care providers are advised
to balance the benets of appropriate
anesthesia in young children and preg-
nant women against the potential risks,
especially for procedures that may last
longer than three hours or if multiple pro-
cedures are required in children younger
than 3 years of age.
Source: FDA, December 14, 2016
Pioglitazone and Bladder Cancer
As a result of an updated review, the
FDA has concluded that the use of the
type-2 diabetes medication pioglitazone
(Takedas Actos, Actoplus Met, Acto-
plus Met XR, Duetact, and Oseni) may
be linked to an increased risk of blad-
der cancer. The labels of pioglitazone-
containing medications already include
warnings about this risk, but the FDA has
approved new label updates to describe
additional study data.
Source: FDA, December 12, 2016
CLINICAL TRIAL NEWS
Contrave for Obesity
The phase 3, randomized, open-label
IGNITE trial was designed to evaluate the
use of Contrave (naltrexone and bupro-
pion extended-release tablets, Orexigen
Therapeutics) in combination with a com-
mercially available lifestyle-intervention
program compared with usual care in
a real-world weight-loss setting. The
results showed that treatment with Con-
trave, when used in a manner consis-
tent with prescribing information in the
United States, resulted in a signicant
reduction in body weight compared with
usual care. After 26 weeks of treatment,
participants in the Contrave group lost
signicantly more weight compared with
the usual-care group (9.5% versus 0.9%,
respectively; P < 0.0001).
Source: Orexigen Therapeutics,
January 6, 2017
Humira Biosimilar
The comparative, confirmatory
REFLECTIONS B538-02 study has met
its primary endpoint by demonstrating
the equivalent efcacy, as measured
by the American College of Rheuma-
tology 20% response rate at week 12,
of PF-06410293 (Pzer) and Humira
(adalimumab, AbbVie), each adminis-
tered with methotrexate, in patients with
moderate-to-severe rheumatoid arthritis.
PF-06410293, a monoclonal antibody, is
being developed as a potential biosimilar
to Humira, which is approved in the
United States for multiple indications,
including rheumatoid arthritis, juvenile
idiopathic arthritis, psoriatic arthritis,
ankylosing spondylitis, adult Crohns
disease, pediatric Crohns disease, ulcer-
ative colitis, plaque psoriasis, hidradenitis
suppurativa, and uveitis.
Source: Pzer, January 5, 2017
RHB-105 for H. Pylori Infection
RHB-105 (RedHill Biopharma) is an
investigational xed-dose oral combina-
tion therapy consisting of two antibiotics
and a proton pump inhibitor in a single
capsule. The product has a planned indi-
cation for the treatment of patients with
Helicobacter pylori infection. A phase 3
study of RHB-105 has met its primary
endpoint of superiority over the histori-
cal standard-of-care (SoC) eradication
rate of 70% (P < 0.001). The study results
demonstrated 89% efcacy in eradicating
H. pylori infection with RHB-105. Sub-
sequent open-label treatment with SoC
therapies of patients in the placebo arm
demonstrated a 63% eradication rate.
Source: RedHill Biopharma, January
4, 2017
Sollpura for Cystic Fibrosis
The SOLUTION trial of Sollpura
(Anthera Pharmaceuticals), a nonporcine
pancreatic enzyme replacement therapy
(PERT), in cystic brosis patients with
exocrine pancreatic insufciency (EPI)
narrowly missed its noninferiority margin
versus a PERT comparator (Pancreaze,
Janssen). Anthera expects to release data
from the extension phase of this study
during the rst quarter of 2017. The com-
pany also plans to initiate another study
of Sollupra in patients with EPI due to
cystic brosis.
Source: Anthera Pharmaceuticals,
December 27, 2016
Biosimilar Trastuzumab
For Breast, Gastric Cancers
Phase 3 results have conrmed the
efcacy, safety, and immunogenicity of
MYL-1401O (Mylan/Biocon), a proposed
biosimilar trastuzumab, in comparison
with that of branded trastuzumab (Her-
ceptin, Genentech). Herceptin is indi-
cated for the treatment of patients with
certain human epidermal growth factor
receptor 2 (HER2)-positive breast and
gastric cancers.
The HERITAGE trial was a double-
blind, randomized study designed to
compare MYL-1401O with Herceptin in
patients with centrally conrmed, mea-
surable HER2-positive metastatic breast
cancer who had not received chemo-
therapy or trastuzumab for metastatic
disease. The results showed an overall
response rate of 69.6% for MYL-1401O
compared with 64.0% for Herceptin at
week 24 (the trials primary endpoint).
Tumor progression, progression-free
survival, and overall survival were not
statistically different between the two
groups at week 48.
Source: Mylan, December 27, 2016
Vadastuximab for AML
Seattle Genetics has received notice
from the FDA that a clinical hold or partial
clinical hold has been placed on several
early-stage trials of vadastuximab talirine
in subjects with acute myeloid leukemia
(AML). The clinical holds were initiated
to evaluate the potential risk of hepato-
toxicity in patients who were treated with
vadastuximab and who received alloge-
neic stem cell transplant either before
or after treatment. Six patients were
identied with hepatotoxicity, including
several cases of veno-occlusive disease,
with four deaths.
Vadastuximab talirine is an investiga-
tional antibodydrug conjugate targeted
to the CD33 transmembrane receptor.
CD33 is expressed on most AML and
myelodysplastic syndrome blast cells.
Vadastuximab is designed to be stable
in the bloodstream and to release a cell-
killing pyrrolobenzodiazepine dimer
agent after internalization into CD33-
expressing cells.
Source: Seattle Genetics, December
27, 2016
Emicizumab for Hemophilia
The primary endpoint has been reached
in a pivotal phase 3 study evaluating pro-
phylactic treatment with emicizumab
(Chugai Pharmaceutical/Roche/Genen-
tech) in patients 12 years of age or older
with hemophilia A and inhibitors to fac-
tor VIII. The study showed a statistically
signicant reduction in the number of
bleeds over time in patients treated with
emicizumab prophylaxis compared with
those receiving no prophylactic treatment.
The study also met all secondary end-
points, including a statistically signicant
reduction in the number of bleeds over
time with emicizumab prophylaxis treat-
ment in patients who had received prior
bypassing-agent prophylaxis treatment.
Emicizumab is an investigational
bispecic monoclonal antibody designed
to bring together factors IXa and X
proteins required to activate the natu-
ral coagulation cascade and restore the
blood-clotting process. Emicizumab is
administered via a subcutaneous injection
of a ready-to-use solution once weekly.
Source: Roche, December 22, 2016
Sotagliozin for Type-1 Diabetes
A pivotal phase 3 trial of sotagliozin
(Lexicon Pharmaceuticals) has met
its primary endpoint, demonstrating a
statistically significant reduction in
Vol. 42 No. 2 February 2017 P&T
83
hemoglobin A1C (HbA1C) at 24 weeks
in patients with type-1 diabetes receiv-
ing optimized insulin therapy. Patients
treated with sotagliozin had mean HbA1C
reductions from baseline of 0.39% with a
200-mg once-daily dosage of sotagliozin
(P < 0.001) and 0.37% with a 400-mg once-
daily dosage of sotagliozin (P < 0.001)
compared with a reduction of 0.03% with
placebo after 24 weeks of treatment.
Sotagliozin is a rst-in-class, oral dual
inhibitor of two proteins responsible for
glucose regulationsodium-glucose
cotransporter types 1 and 2 (SGLT1 and
SGLT2). SGLT1 is the primary trans-
porter for absorption of glucose and
galactose in the gastrointestinal tract,
and SGLT2 is primarily responsible for
glucose reabsorption by the kidneys.
Source: Lexicon Pharmaceuticals,
December 21, 2016
Plazomicin for Infections
Resistant to Multiple Drugs
Plazomicin (Achaogen, Inc.), an anti-
biotic being developed to ght multidrug-
resistant bacterial infections, has met
the primary objective of noninferiority
compared with meropenem in a phase 3
registration trial in patients with compli-
cated urinary tract infections and acute
pyelonephritis.
In addition, in a phase 3 trial in patients
with serious infections due to carbapenem-
resistant Enterobacteriaceae (CRE), a
lower rate of mortality or serious disease-
related complications was observed for
plazomicin compared with colistin, one of
the few remaining antibiotics for the treat-
ment of infections due to CRE. Achaogen
plans to submit a new drug application
for plazomicin to the FDA in the second
half of 2017.
Source: Achaogen, December 12, 2016
Edurant/Tivicay for HIV
Two phase 3 studies designed to evalu-
ate the efcacy, safety, and tolerability
84 P&T February 2017 Vol. 42 No. 2
of switching virologically suppressed
patients from a three- or four-drug
antiretroviral regimen to the two-drug
regimen of rilpivirine (Edurant, Janssen)
and dolutegravir (Tivicay, ViiV Health-
care) have met the primary endpoint of
noninferiority at week 48.
In both studies, the subjects achieved
plasma human immunodeficiency
virus-1 (HIV-1) RNA levels of less than
50 copies/mL. Regulatory submissions
for the investigational two-drug regimen
of rilpivirine and dolutegravir as a single
tablet are expected in 2017.
Rilpivirine is a prescription HIV
medication that is used with other anti-
retroviral drugs to treat patients with
HIV-1 infection who have never received
HIV medications and who have a viral
load of no more than 100,000 copies/mL.
Dolutegravir is an HIV-1 integrase strand
transfer inhibitor indicated in combina-
tion with other antiretroviral agents for
the treatment of HIV-1 infection in adults
and pediatric patients weighing at least
30 kg.
Source: Janssen, December 19, 2016
Pegpleranibfor AMD
Two pivotal phase 3 studies evaluat-
ing the safety and efcacy of pegpleranib
(Novartis) in combination with ranibi-
zumab (Lucentis, Genentech) for the
treatment of patients with neovascular
age-related macular degeneration did
not meet the primary endpoint of supe-
riority for the pegpleranib/ranibizumab
combination therapy over ranibizumab
monotherapy.
At month 12, patients in the peg-
pleranib/ranibizumab groups showed
a 10.74-letter improvement in best cor-
rected visual acuity (BCVA) compared
with a 9.82-letter improvement with
ranibizumab alone in study OPH1002.
Similarly, the pegpleranib/ranibizumab
combination treatment groups showed
a 9.91-letter BCVA improvement com-
pared with a 9.82-letter improvement with
ranibizumab alone in study OPH1003.
Pegpleranib is a 32-mer pegylated
DNA aptamer that selectively binds to
platelet-derived growth factor (PDGF)-
BB and PDGF-AB homo- and hetero-
dimers, respectively, thereby disrupting
the interaction with their cognate tyrosine
kinase receptors.
Source: Novartis, December 12, 2016
Plecanatide for IBS
With Constipation
Positive results have been reported
from the rst of two pivotal phase 3
trials evaluating the efcacy and safety of
plecanatide (Synergy Pharmaceuticals),
an investigational once-daily, orally
administered compound, in adults with
irritable bowel syndrome with constipa-
tion (IBS-C). Both doses of plecanatide
(3 mg and 6 mg) met the studys primary
endpoint, showing statistical signifi-
cance in the percentage of patients who
were overall responders compared with
placebo during the 12-week treatment
period (21.5% in the 3-mg group and 24.0%
in the 6-mg group compared with 14.2%
in the placebo group; P = 0.009 for 3 mg
and P < 0.001 for 6 mg).
Plecanatide is a peptide made up of
16 amino acids. With the exception of a
single amino acid substitution, it is identi-
cal to uroguanylin, an endogenous human
gastrointestinal peptide that targets
receptors in the proximal small intestine.
Source: Synergy Pharmaceuticals,
December 9, 2016
Solanezumab for Alzheimers
The monoclonal antibody solanezumab
(Eli Lilly) failed to meet the primary end-
point in a pivotal phase 3 study involv-
ing patients with mild dementia due to
Alzheimers disease, and Lilly announced
that it will not pursue regulatory sub-
missions of the medication. Patients
treated with solanezumab did not expe-
rience a statistically signicant slowing in
cognitive decline compared with patients
given placebo. This nding represented
an 11% reduction in decline (P = 0.095),
as measured by the Alzheimers Disease
Assessment ScaleCognitive subscale.
Source: Eli Lilly, December 8, 2016
Cimzia for Plaque Psoriasis
UCB and Dermira, Inc., have
announced positive results from the
phase 3, placebo-controlled CIMPASI-1
trial, which evaluated the efcacy and
safety of certolizumab pegol (Cimzia) in
adults with moderate-to-severe chronic
plaque psoriasis.
A total of 234 patients were randomly
assigned to three dosing arms: 400 mg
every two weeks (n = 88); 400 mg at
weeks 0, 2, and 4 followed by 200 mg
every two weeks (n = 95); or placebo
every two weeks (n = 51). At week 16, the
response rate for patients who achieved
75% or greater disease improvement from
baseline, as measured by the Psoriasis
Area and Severity Index, was 75.8% for
patients receiving the 400-mg dose every
two weeks and 66.5% for patients receiv-
ing the 200-mg dose every two weeks,
compared with 6.5% for patients receiving
placebo. The response rate for patients
achieving at least a two-point improve-
ment to a nal score of clear or almost
clear skin on the Physicians Global
Assessment scale at week 16 was 57.9%
for the 400-mg dose-treated patients
and 47.0% for the 200-mg dose-treated
patients, compared with 4.2% for the
patients receiving placebo.
Source: UCB, December 8, 2016
Actimmune for Friedreichs Ataxia
A phase 3 trial evaluating Actimmune
(interferon gamma-1b, Horizon Pharma)
for the treatment of patients with Fried-
reichs ataxia (FA) failed to meet its
primary endpoint of a statistically signi-
cant change from baseline in the modied
FA Rating Scale at 26 weeks compared
with placebo. FA is a degenerative neuro-
muscular disorder that affects approxi-
mately 4,000 to 6,000 people in the United
States. There are no approved treatments
for the disease.
Actimmune is currently indicated to
reduce the frequency and severity of seri-
ous infections associated with chronic
granulomatous disease, a genetic dis-
order that affects the functioning of some
cells of the immune system. Actimmune
is also indicated to delay the time to dis-
ease progression in patients with severe,
malignant osteopetrosis, a genetic dis-
order that affects normal bone formation.
Source: Horizon Pharma, December
8, 2016
IDP-118 for Plaque Psoriasis
Positive results have been reported
from a phase 3, double-blind, random-
ized study that compared IDP-118 lotion
(halobetasol propionate and tazarotene,
Valeant Pharmaceuticals) with vehicle
in 215 patients with moderate-to-severe
plaque psoriasis.
After 12 weeks of treatment, IDP-118
was signicantly more effective than vehi-
cle, with a 45.3% success rate (P < 0.001).
This pivotal study was preceded by a
phase 2 trial in which IDP-118 was clinically
superior to halobetasol propionate and
tazarotene, with a success rate of 52.5%.
Source: Valeant, December 8, 2016
DEVICE APPROVALS
Aptima HIV-1 Assay
The FDA has approved the Aptima
HIV-1 Quant assay (Hologic, Inc.) for
monitoring the viral load in patients
infected with human immunodeciency
virus 1 (HIV-1). The nucleic acid ampli-
cation test is designed for the quantita-
tive detection of RNA from HIV in plasma
specimens. The assay is not approved
for HIV-1 diagnosis in the United States.
Source: Hologic, January 3, 2017
AeroForm Tissue Expander
For Breast Reconstruction
The FDA has allowed the marketing
of the AeroForm device (AirXpanders),
a system for soft-tissue expansion in
two-stage breast reconstruction after
mastectomy and in the treatment of
underdeveloped breasts and soft-tissue
deformities. The patient uses a dose
controller to independently inate the
expander.
The AeroForm device differs from
available saline-lled tissue expanders,
which are expanded by the surgeon, who
uses a needle to pierce the skin and inject
saline into the expander through a port or
injection area. The AeroForm expander
is lled with air; there is no need for a
needle, and the patient has control over
slowly expanding the device at home.
Source: AirXpanders, December 20,
2016
Continuous Glucose
Monitoring System
The FDA has expanded the approved
use of the Dexcom G5 mobile continuous
glucose monitoring system (Dexcom,
Inc.) to allow the replacement of nger-
stick blood glucose testing for treatment
decisions in diabetes patients 2 years
of age and older. This is the rst FDA-
approved continuous glucose monitoring
system that can be used to make diabetes
treatment decisions without conrma-
tion with a traditional nger-stick test.
The system was previously approved to
complement, not replace, nger-stick
testing for diabetes treatment decisions.
Source: Dexcom, December 20, 2016
OneTouch Vibe Plus Insulin Pump
The FDA has cleared the OneTouch
Vibe Plus insulin pump and continu-
ous glucose monitoring (CGM) system
for the treatment of diabetes patients
2 years of age and older. The OneTouch
Vibe Plus (Animas Corporation) is
continued on page 96
Vol. 42 No. 2 February 2017 P&T
85
 Provide your members with the option thats

FDA APPROVED FOR INTERMEDIATE

OR HIGH-RISK MYELOFIBROSIS
In COMFORT-I* and COMFORT-II, Jakafi (ruxolitinib) significantly reduced spleen volume
compared with patients receiving placebo or best available therapy, respectively 1-3

The primary end point was the proportion of patients achieving The primary end point was the proportion of patients achieving
a 35% reduction in spleen volume from baseline at week 24 as a 35% reduction in spleen volume from baseline at week 48 as
measured by CT or MRI1,2 measured by CT or MRI1,3

COMFORT-I Primary End Point: Spleen Volume COMFORT-II Primary End Point: Spleen Volume
Reduction at Week 241,2 Reduction at Week 481,3

Jakafi (n = 155) Jakafi (n = 146)

Placebo (n = 154) BAT (n = 73)
50
42% P < 0.0001
50
P < 0.0001
40 40
(n = 65)
Patients (%)
29%
Patients (%)

30 30
(n = 41)
20 20

10 10

0
0.7% 0 0%
(n = 1)
(n = 0)
35% Spleen Volume Reduction From Baseline 35% Spleen Volume Reduction From Baseline

BAT, best available therapy.

* COMFORT-I (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment-I) was a randomized, double-blind, placebo-controlled
phase 3 study with 309 patients with intermediate-2risk or high-risk myelofibrosis.1,2

COMFORT-II (COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment-II) was a randomized, open-label phase 3 study with 219
patients with intermediate-2risk or high-risk myelofibrosis.1,3

Best available therapy in COMFORT-II included hydroxyurea (46.6%) and glucocorticoids (16.4%), as well as no medication, anagrelide, epoetin
alfa, thalidomide, lenalidomide, mercaptopurine, thioguanine, danazol, peginterferon alfa-2a, interferon-, melphalan, acetylsalicylic acid,
cytarabine, and colchicine.4

Important Safety Information

Treatment with Jakafi can cause thrombocytopenia, anemia
and neutropenia, which are each dose-related effects.
Perform a pre-treatment complete blood count (CBC) and
monitor CBCs every 2 to 4 weeks until doses are stabilized,
and then as clinically indicated
Manage thrombocytopenia by reducing the dose or temporarily
interrupting Jakafi. Platelet transfusions may be necessary
Patients developing anemia may require blood transfusions
and/or dose modifications of Jakafi
Severe neutropenia (ANC <0.5 10 9/L) was generally reversible
by withholding Jakafi until recovery
Serious bacterial, mycobacterial, fungal and viral infections have
occurred. Delay starting Jakafi until active serious infections
have resolved. Observe patients receiving Jakafi for signs and
symptoms of infection and manage promptly
Jakafi is a registered trademark of Incyte Corporation.
2017, Incyte Corporation. All rights reserved. RUX-2054b 01/17
Tuberculosis (TB) infection has been reported. Observe
patients taking Jakafi for signs and symptoms of active TB and
manage promptly. Prior to initiating Jakafi, evaluate patients
for TB risk factors and test those at higher risk for latent
infection. Consult a physician with expertise in the treatment of
TB before starting Jakafi in patients with evidence of active or
latent TB. Continuation of Jakafi during treatment of active TB
should be based on the overall risk-benefit determination
Progressive multifocal leukoencephalopathy (PML) has
occurred with ruxolitinib treatment for myelofibrosis. If PML is
suspected, stop Jakafi and evaluate
Advise patients about early signs and symptoms of herpes
zoster and to seek early treatment
Increases in hepatitis B viral load with or without associated
elevations in alanine aminotransferase and aspartate
aminotransferase have been reported in patients with chronic
hepatitis B virus (HBV) infections. Monitor and treat patients
with chronic HBV infection according to clinical guidelines
 Table 1: Myelofibrosis: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind,
Placebo-controlled Study During Randomized Treatment
Jakafi Placebo
(N=155) (N=151)
BRIEF SUMMARY: For Full Prescribing Information, see package insert.
All Gradesa Grade 3 Grade 4 All Grades Grade 3 Grade 4
CONTRAINDICATIONS None.
Adverse Reactions (%) (%) (%) (%) (%) (%)
WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment with
Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Bruisingb 23 <1 0 15 0 0
Prescribing Information]. Manage thrombocytopenia by reducing the dose or temporarily interrupting Jakafi. Dizzinessc 18 <1 0 7 0 0
Platelet transfusions may be necessary [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in
Full Prescribing Information]. Patients developing anemia may require blood transfusions and/or dose Headache 15 0 0 5 0 0
modifications of Jakafi. Severe neutropenia (ANC less than 0.5 X 109/L) was generally reversible by withholding Urinary Tract Infectionsd 9 0 0 5 <1 <1
Jakafi until recovery [see Adverse Reactions (6.1) in Full Prescribing Information]. Perform a pre-treatment Weight Gaine 7 <1 0 1 <1 0
complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically
indicated. [see Dosage and Administration (2.1.1) and Adverse Reactions (6.1) in Full Prescribing Information]. Flatulence 5 0 0 <1 0 0
Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections have occurred. Delay starting Herpes Zosterf 2 0 0 <1 0 0
therapy with Jakafi until active serious infections have resolved. Observe patients receiving Jakafi for signs and a
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0
symptoms of infection and manage promptly. Tuberculosis Tuberculosis infection has been reported in patients b
includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site
receiving Jakafi. Observe patients receiving Jakafi for signs and symptoms of active tuberculosis and manage hematoma, increased tendency to bruise, petechiae, purpura
c
includes dizziness, postural dizziness, vertigo, balance disorder, Menieres Disease, labyrinthitis
promptly. Prior to initiating Jakafi, patients should be evaluated for tuberculosis risk factors, and those at higher d
includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria urine,
risk should be tested for latent infection. Risk factors include, but are not limited to, prior residence in or travel to bacteria urine identified, nitrite urine present
e
countries with a high prevalence of tuberculosis, close contact with a person with active tuberculosis, and a history includes weight increased, abnormal weight gain
f
of active or latent tuberculosis where an adequate course of treatment cannot be confirmed. For patients with includes herpes zoster and post-herpetic neuralgia
evidence of active or latent tuberculosis, consult a physician with expertise in the treatment of tuberculosis before Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median
starting Jakafi. The decision to continue Jakafi during treatment of active tuberculosis should be based on the time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (<1%)
overall risk-benefit determination. PML Progressive multifocal leukoencephalopathy (PML) has occurred with discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin
ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster Advise reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then
patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible if suspected gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern
[see Adverse Reactions (6.1) in Full Prescribing Information]. Hepatitis B Hepatitis B viral load (HBV-DNA titer) was observed in patients regardless of whether they had received transfusions during therapy. In the
increases, with or without associated elevations in alanine aminotransferase and aspartate aminotransferase, randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving
have been reported in patients with chronic HBV infections taking Jakafi. The effect of Jakafi on viral replication in placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the
patients with chronic HBV infection is unknown. Patients with chronic HBV infection should be treated and median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo treated
monitored according to clinical guidelines. Symptom Exacerbation Following Interruption or patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 or 4
Discontinuation of Treatment with Jakafi Following discontinuation of Jakafi, symptoms from thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was generally
myeloproliferative neoplasms may return to pretreatment levels over a period of approximately one week. Some reversible with dose reduction or dose interruption. The median time to recovery of platelet counts above 50 X
patients with myelofibrosis have experienced one or more of the following adverse events after discontinuing 109/L was 14 days. Platelet transfusions were administered to 5% of patients receiving Jakafi and to 4% of
Jakafi: fever, respiratory distress, hypotension, DIC, or multi-organ failure. If one or more of these occur after patients receiving control regimens. Discontinuation of treatment because of thrombocytopenia occurred in
discontinuation of, or while tapering the dose of Jakafi, evaluate for and treat any intercurrent illness and consider <1% of patients receiving Jakafi and <1% of patients receiving control regimens. Patients with a platelet count
restarting or increasing the dose of Jakafi. Instruct patients not to interrupt or discontinue Jakafi therapy without of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia
consulting their physician. When discontinuing or interrupting therapy with Jakafi for reasons other than compared to patients with a platelet count greater than 200 X 109/L (17% versus 7%). Neutropenia In the two
thrombocytopenia or neutropenia [see Dosage and Administration (2.5) in Full Prescribing Information], consider Phase 3 clinical studies, 1% of patients reduced or stopped Jakafi because of neutropenia. Table 2 provides the
tapering the dose of Jakafi gradually rather than discontinuing abruptly. Non-Melanoma Skin Cancer frequency and severity of clinical hematology abnormalities reported for patients receiving treatment with Jakafi
Non-melanoma skin cancers including basal cell, squamous cell, and Merkel cell carcinoma have occurred in or placebo in the placebo-controlled study.
patients treated with Jakafi. Perform periodic skin examinations. Lipid Elevations Treatment with Jakafi has
been associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) Table 2: Myelofibrosis: Worst Hematology Laboratory Abnormalities in the Placebo-Controlled Studya
cholesterol, and triglycerides. The effect of these lipid parameter elevations on cardiovascular morbidity and Jakafi Placebo
mortality has not been determined in patients treated with Jakafi. Assess lipid parameters approximately 8-12 (N=155) (N=151)
weeks following initiation of Jakafi therapy. Monitor and treat according to clinical guidelines for the management
of hyperlipidemia. Laboratory All Gradesb Grade 3 Grade 4 All Grades Grade 3 Grade 4
ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other Parameter (%) (%) (%) (%) (%) (%)
sections of the labeling: Thrombocytopenia, Anemia and Neutropenia [see Warnings and Precautions (5.1) in Thrombocytopenia 70 9 4 31 1 0
Full Prescribing Information] Risk of Infection [see Warnings and Precautions (5.2) in Full Prescribing Information] Anemia 96 34 11 87 16 3
Symptom Exacerbation Following Interruption or Discontinuation of Treatment with Jakafi [see Warnings and
Precautions (5.3) in Full Prescribing Information] Non-Melanoma Skin Cancer [see Warnings and Precautions Neutropenia 19 5 2 4 <1 1
(5.4) in Full Prescribing Information]. Because clinical trials are conducted under widely varying conditions, a
Presented values are worst Grade values regardless of baseline
b
adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience in Additional Data from the Placebo-controlled Study 25% of patients treated with Jakafi and 7% of
Myelofibrosis The safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine
of follow-up of 10.9 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase transaminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 2% for Jakafi with 1%
3 studies, patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 89% Grade 3 and no Grade 4 ALT elevations. 17% of patients treated with Jakafi and 6% of patients treated with
of patients treated for more than 6 months and 25% treated for more than 12 months. One hundred and eleven placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase (AST). The
(111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In patients incidence of Grade 2 AST elevations was <1% for Jakafi with no Grade 3 or 4 AST elevations. 17% of patients
starting treatment with 15 mg twice daily (pretreatment platelet counts of 100 to 200 X 109/L) and 20 mg twice treated with Jakafi and <1% of patients treated with placebo developed newly occurring or worsening Grade 1
daily (pretreatment platelet counts greater than 200 X 109/L), 65% and 25% of patients, respectively, required a elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was <1% for Jakafi with no Grade 3 or
dose reduction below the starting dose within the first 8 weeks of therapy. In a double-blind, randomized, placebo- 4 cholesterol elevations. Clinical Trial Experience in Polycythemia Vera In a randomized, open-label,
controlled study of Jakafi, among the 155 patients treated with Jakafi, the most frequent adverse drug reactions active-controlled study, 110 patients with polycythemia vera resistant to or intolerant of hydroxyurea received
were thrombocytopenia and anemia [see Table 2 ]. Thrombocytopenia, anemia and neutropenia are dose related Jakafi and 111 patients received best available therapy [see Clinical Studies (14.2) in Full Prescribing
effects. The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache [see Information]. The most frequent adverse drug reaction was anemia. Table 3 presents the most frequent
Table 1]. Discontinuation for adverse events, regardless of causality, was observed in 11% of patients treated with non-hematologic treatment emergent adverse events occurring up to Week 32. Discontinuation for adverse
Jakafi and 11% of patients treated with placebo. Table 1 presents the most common adverse reactions occurring events, regardless of causality, was observed in 4% of patients treated with Jakafi.
in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.
Table 3: Polycythemia Vera: Treatment Emergent Adverse Events Occurring in 6% of Patients on with the strong CYP3A4 inducer rifampin in healthy subjects. No dose adjustment is recommended; however,
Jakafi in the Open-Label, Active-controlled Study up to Week 32 of Randomized Treatment monitor patients frequently and adjust the Jakafi dose based on safety and efficacy [see Pharmacokinetics
Jakafi Best Available Therapy (12.3) in Full Prescribing Information].
(N=110) (N=111) USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Risk Summary There are
no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment
Adverse Events All Gradesa (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) with ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.
Headache 16 <1 19 <1 Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Abdominal Painb 15 <1 15 <1 Animal Data Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis,
at doses of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of
Diarrhea 15 0 7 <1 teratogenicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and
Dizzinessc 15 0 13 0 maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times the
Fatigue 15 0 15 3 clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights of
approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of
Pruritus 14 <1 23 4 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In a
Dyspnead 13 3 4 0 pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implantation
Muscle Spasms 12 <1 5 0 through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for fertility
indices or for maternal or embryofetal survival, growth and development parameters at the highest dose
Nasopharyngitis 9 0 8 0 evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Nursing
Constipation 8 0 3 0 Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were
excreted in the milk of lactating rats with a concentration that was 13-fold the maternal plasma. Because many
Cough 8 0 5 0
drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants
Edemae 8 0 7 0 from Jakafi, a decision should be made to discontinue nursing or to discontinue the drug, taking into account
Arthralgia 7 0 6 <1 the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Jakafi in pediatric
patients have not been established. Geriatric Use Of the total number of patients with myelofibrosis in clinical
Asthenia 7 0 11 2
studies with Jakafi, 52% were 65years and older, while 15% were 75 years and older. No overall differences in
Epistaxis 6 0 3 0 safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal
Herpes Zosterf 6 <1 0 0 Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in
healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], moderate
Nausea 6 0 4 0
[CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) additional
a
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of
b
includes abdominal pain, abdominal pain lower, and abdominal pain upper
c
includes dizziness and vertigo
ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal
d
includes dyspnea and dyspnea exertional function. However, plasma AUC values of ruxolitinib metabolites increased with increasing severity of renal
e
includes edema and peripheral edema impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The
f
includes herpes zoster and post-herpetic neuralgia change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in
Other clinically important treatment emergent adverse events observed in less than 6% of patients metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal of some active metabolites by
treated with Jakafi were: Weight gain, hypertension, and urinary tract infections. Clinically relevant dialysis cannot be ruled out. When administering Jakafi to patients with myelofibrosis and moderate
laboratory abnormalities are shown in Table 4. (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count between 50 X
Table 4: Polycythemia Vera: Selected Laboratory Abnormalities in the Open-Label, Active-controlled 109/L and 150 X 109/L, a dose reduction is recommended. A dose reduction is also recommended for patients
Study up to Week 32 of Randomized Treatmenta with polycythemia vera and moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min). In
all patients with end stage renal disease on dialysis, a dose reduction is recommended [see Dosage and
Jakafi Best Available Therapy
Administration (2.4) in Full Prescribing Information]. Hepatic Impairment The safety and pharmacokinetics
(N=110) (N=111)
of single dose Jakafi (25 mg) were evaluated in a study in healthy subjects (N=8) and in subjects with mild
Laboratory All Gradesb Grade 3 Grade 4 All Grades Grade 3 Grade 4 [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or severe hepatic impairment [Child-Pugh C (N=8)]. The
Parameter (%) (%) (%) (%) (%) (%) mean AUC for ruxolitinib was increased by 87%, 28% and 65%, respectively, in patients with mild, moderate
and severe hepatic impairment compared to patients with normal hepatic function. The terminal elimination
Hematology
half-life was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus
Anemia 72 <1 <1 58 0 0 2.8 hours). The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the
Thrombocytopenia 27 5 <1 24 3 <1 corresponding increase in ruxolitinib exposure except in the severe (Child-Pugh C) hepatic impairment cohort
where the pharmacodynamic activity was more prolonged in some subjects than expected based on plasma
Neutropenia 3 0 <1 10 <1 0
concentrations of ruxolitinib. When administering Jakafi to patients with myelofibrosis and any degree of
Chemistry hepatic impairment and with a platelet count between 50 X 109/L and 150 X 109/L, a dose reduction is
Hypercholesterolemia 35 0 0 8 0 0 recommended. A dose reduction is also recommended for patients with polycythemia vera and hepatic
impairment [see Dosage and Administration (2.4) in Full Prescribing Information].
Elevated ALT 25 <1 0 16 0 0
OVERDOSAGE There is no known antidote for overdoses with Jakafi. Single doses up to 200 mg have been
Elevated AST 23 0 0 23 <1 0 given with acceptable acute tolerability. Higher than recommended repeat doses are associated with increased
Hypertriglyceridemia 15 0 0 13 0 0 myelosuppression including leukopenia, anemia and thrombocytopenia. Appropriate supportive treatment
a
Presented values are worst Grade values regardless of baseline
should be given. Hemodialysis is not expected to enhance the elimination of ruxolitinib.
b
National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0
DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib
is metabolized by CYP3A4 and to a lesser extent by CYP2C9. CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib
Jakafi is a registered trademark of Incyte. All rights reserved.
increased 33% and 91%, respectively following concomitant administration with the strong CYP3A4 inhibitor U.S. Patent Nos. 7598257; 8415362; 8722693; 8822481; 8829013; 9079912
ketoconazole in healthy subjects. Concomitant administration with mild or moderate CYP3A4 inhibitors did not 2011-2016 Incyte Corporation. All rights reserved.
result in an exposure change requiring intervention [see Pharmacokinetics (12.3) in Full Prescribing Revised: March 2016 RUX-1778
Information]. When administering Jakafi with strong CYP3A4 inhibitors, consider dose reduction [see Dosage
and Administration (2.3) in Full Prescribing Information]. Fluconazole: The AUC of ruxolitinib is predicted to
increase by approximately 100% to 300% following concomitant administration with the combined CYP3A4
and CYP2C9 inhibitor fluconazole at doses of 100 mg to 400 mg once daily, respectively [see Pharmacokinetics
(12.3) in Full Prescribing Information]. Avoid the concomitant use of Jakafi with fluconazole doses of greater
than 200 mg daily [see Dosage and Administration (2.3) in Full Prescribing Information]. CYP3A4 inducers:
The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, following concomitant administration
 Pharmaceutical Approval Update
Michele B. Kaufman, PharmD, BCGP, RPh

Prasterone (Intrarosa) Vaginal Insert discharge (14.2%) and abnormal Pap smear (2.1%). Among
Manufacturer: Endoceutics, Quebec, Canada the patients with abnormal Pap smears, there was one case
Date of Approval: November 16, 2016 of low-grade squamous intraepithelial lesion and 10 cases of
Indication: Prasterone is indicated for the treatment of atypical cells of undetermined signicance.
moderate-to-severe dyspareunia due to menopause. Sources: Endoceutics, Intrarosa prescribing
Drug Class: Intravaginal steroid information, FDA
Uniqueness of Drug: This is the rst agent
approved by the Food and Drug Administration Crisaborole (Eucrisa) Ointment, 2%
(FDA) to treat women experiencing moderate-to- Manufacturer: Anacor Pharmaceuticals,
severe pain during sexual intercourse (dyspareunia), Palo Alto, California
a symptom of vulvar and vaginal atrophy (VVA), due Date of Approval: December 14, 2016
to menopause. During menopause, vaginal tissue Indication: Crisaborole ointment is indicated
estrogen levels decrease, which may lead to VVA for the topical treatment of mild-to-moderate atopic
that can cause symptoms such as pain during sexual Michele B. Kaufman, dermatitis (AD) in patients 2 years of age and older.
intercourse. In addition, Intrarosa is the rst FDA- PharmD, BCGP, RPh Drug Class: Phosphodiesterase 4 (PDE-4)
approved product containing the active ingredient inhibitor
prasterone, which is also known as dehydroepiandrosterone Uniqueness of Drug: Crisaborole ointment is the rst
(DHEA). Other forms of DHEA are used in dietary supplements and only nonsteroidal topical monotherapy that inhibits the
that are not approved by the FDA. PDE-4 enzyme in the skin. Overactive PDE-4 has been shown
Warnings and Precautions: to contribute to the signs and symptoms of AD, also known as
Current or past history of breast cancer. Estrogen is eczema. AD is a chronic condition impacting nearly 18 million
a metabolite of prasterone. Use of exogenous estrogen is children and adults in the United States. Of all people living
contraindicated in women with a known or suspected history with AD, approximately 90% have a mild-to-moderate form.
of breast cancer. Intrarosa has not been studied in women with Crisaborole is the rst new prescription product to treat mild-
a history of breast cancer. to-moderate AD in more than 10 years.
Use in pregnant women and lactating women. Use of Warnings and Precautions:
Intrarosa is limited to postmenopausal women. Animal repro- Hypersensitivity reactions. Contact urticaria and hyper-
duction studies have not been conducted with prasterone, and sensitivity reactions have occurred in crisaborole-treated
there are no data on use of this agent in pregnant women. In patients. Hypersensitivity should be suspected in the event of
addition, there is no information on the presence of prasterone severe pruritus, swelling, and erythema at the application site
in human milk, the effects on the breastfed infant, or effects or at a distant site. If signs and symptoms of hypersensitivity
on milk production. occur, discontinue crisaborole immediately and initiate
Contraindications. Intrarosa should not be used in any appropriate therapy.
postmenopausal woman with undiagnosed abnormal genital Use in pregnant women. There are no crisaborole data
bleeding. The cause of any persistent or recurring genital available in pregnant women to inform of drug-associated
bleeding should be evaluated to determine the cause prior to risks for major birth defects and miscarriage. In animal
being considered for treatment with Intrarosa. reproduction studies, there were no adverse developmental
Dosage and Administration: Intrarosa is available as a effects observed with oral crisaborole in pregnant rabbits
6.5-mg vaginal insert. The dose is one insert, once daily at and rats during organogenesis at doses up to three and
bedtime, using the provided applicator. ve times, respectively, of the maximum recommended
Commentary: The efficacy of once-daily, intra- human dose.
vaginal Intrarosa was established in two 12-week placebo- Use in lactating women. There is no information available
controlled clinical trials of 406 healthy postmenopausal women on the presence of crisaborole in human milk, the effects of
(4080 years of age), who identied moderate-to-severe pain the drug on the breastfed infant, or the effects of the drug on
during sexual intercourse as their most bothersome symptom milk production after topical application to women who are
of VVA. Women were randomly assigned to receive Intrarosa or breastfeeding. Crisaborole ointment is systemically absorbed;
a placebo vaginal insert. Intrarosa, when compared to placebo, therefore, risks and benets should be weighed before
was shown to reduce the severity of pain experienced during recommending this agent to a breastfeeding woman.
sexual intercourse. The safety of Intrarosa was established in Adverse reactions. The most common adverse reaction
four 12-week placebo-controlled trials and one 52-week open- to crisaborole ointment in clinical trials was application-site
label trial. The most common adverse reactions were vaginal pain, which occurred in 4% of patients (n = 45) compared with
1% (n = 6) of placebo-treated patients following twice-daily
Michele B. Kaufman, PharmD, BCGP, RPh, is a freelance medical administration over four weeks of treatment.
writer living in New York City and a Pharmacist in the NewYork Dosage and Administration: A thin layer of crisaborole
Presbyterian Lower Manhattan Hospital Pharmacy Department. ointment should be applied twice daily to affected areas.

90 P&T February 2017 Vol. 42 No. 2

 Pharmaceutical Approval Update
Commentary: The safety and efcacy of crisaborole were
established in two placebo-controlled trials with a total of
1,522 participants ranging in age from 2 to 79 years with mild-
to-moderate atopic dermatitis. Patients had a 5% to 95% treatable
body surface area. Overall, participants receiving crisaborole
ointment achieved greater response, with clear or almost clear
skin after 28 days of treatment.
Sources: Anacor Pharmaceuticals, Eucrisa prescribing
information
Tenofovir Alafenamide (Vemlidy) Tablets
Manufacturer: Gilead Sciences, Inc., Foster City, California
Date of Approval: November 10, 2016
Indication: Tenofovir alafenamide (TAF) tablets are indi-
cated as a once-daily treatment for adults with chronic hepa-
titis B virus (HBV) infection with compensated liver disease.
Drug Class: HBV nucleoside reverse transcriptase inhibitor
Uniqueness of Drug: TAF is a novel, targeted prodrug
of tenofovir that has demonstrated antiviral efcacy similar
to and at a dose less than one-tenth that of the 300-mg teno-
fovir disoproxil fumarate (TDF) tablet (Viread, Gilead). TAF
has greater plasma stability and can more efciently deliver
tenofovir to hepatocytes; therefore, it can be given at a lower
dose, resulting in less circulating tenofovir. TAF, therefore,
has improved renal and bone laboratory safety parameters
compared with TDF.
Warnings and Precautions:
Boxed warning: lactic acidosis/severe hepatomegaly
with steatosis. Lactic acidosis/severe hepatomegaly with
steatosis, including fatal cases, have been reported with the use
of nucleoside analogues, including TAF, in combination with
other antiretrovirals. Most cases have been in women. Obesity
and prolonged nucleoside exposure may be risk factors. TAF
should be used with caution in any patient with known risk
factors for liver disease; however, cases have also been reported
in patients with no known risk factors. TAF treatment should
be withheld in any patient who develops clinical or laboratory
ndings suggestive of lactic acidosis or pronounced hepato-
toxicity (which may include hepatomegaly and steatosis even
in the absence of marked transaminase elevations).
Boxed warning: post-treatment severe acute exacerba-
tion of HBV. Discontinuation of anti-HBV therapy may lead
to severe acute HBV exacerbations. Hepatic function should
be closely monitored in patients who discontinue TAF. If
appropriate, restarting of anti-HBV therapy may be warranted.
HBV and HIV-1 coinfection. TAF monotherapy is not
recommended for treating human immunodeciency virus
type-1 (HIV-1) infection because resistance may develop.
New onset or worsening renal impairment. Renal impair-
ment, including acute renal failure and Fanconi syndrome
(renal tubular injury with severe hypophosphatemia), has been
reported with the use of tenofovir prodrugs in both animal
toxicology studies and human trials. In TAF clinical trials,
no cases of Fanconi syndrome or proximal renal tubulopathy
were reported. Patients taking tenofovir prodrugs who have
impaired renal function and those taking nephrotoxic agents,
including nonsteroidal anti-inammatory drugs (NSAIDs), are
at increased risk of developing renal-related adverse effects.
Assessment of serum creatinine, serum phosphorus, estimated
creatinine clearance, urine glucose, and urine protein is recom-
mended before initiating TAF therapy and during therapy as
clinically appropriate. TAF should be discontinued in patients
who develop clinically signicant renal function decreases or
evidence of Fanconi syndrome.
Drug interactions. TAF is a substrate of P-glycoprotein
(P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP
activity may lead to changes in TAF absorption. Drugs that
induce P-gp activity are expected to decrease the absorption of
TAF, resulting in decreased plasma TAF concentrations, which
may lead to loss of therapeutic effect. Coadministration of TAF
with other drugs that inhibit P-gp and BCRP may increase
TAF absorption and increase the TAF plasma concentration.
Because TAF is primarily excreted by the kidneys by a
combination of glomerular ltration and active tubular secre-
tion, coadministration with drugs that reduce renal function or
compete for active tubular secretion may increase concentra-
tions of tenofovir and other renally eliminated drugs; this may
increase the risk of adverse reactions. Some examples of these
drugs include, but are not limited to, acyclovir, ganciclovir,
valacyclovir, valganciclovir, aminoglycosides, and high-dose
or multiple NSAIDs.
Other established or potentially clinically signicant drug
interactions are listed in the full prescribing information.
No signicant drug interactions have been observed based on
TAF drug interaction studies with ethinyl estradiol, itraconazole,
ketoconazole, ledipasvir/sofosbuvir, midazolam, norgestimate,
sertraline, sofosbuvir, and sofosbuvir/velpatasvir.
Dosage and Administration: The recommended TAF
dose is 25 mg (one tablet) taken orally once daily with food. No
dosage adjustment is required in patients with mild, moderate,
or severe renal impairment or with mild hepatic impairment.
TAF is not recommended in patients with end-stage renal
disease (estimated creatinine clearance less than 15 mL per
minute) or with decompensated (ChildPugh B or C) hepatic
impairment.
Commentary: The safety and efcacy of TAF is supported by
48-week data from two randomized phase 3 studies (Studies 108
and 110) in 1,298 treatment-nave and treatment-experienced
adult patients with chronic HBV infection. Study 108 random-
ized and treated 425 hepatitis B e antigen (HBeAg)-negative
patients with either TAF or TDF. Study 110 randomized and
treated 873 HBeAg-positive patients with either TAF or TDF.
Both studies met their primary endpoint of noninferiority to
TDF based on the percentage of patients with chronic hepa-
titis B with plasma HBV DNA levels less than 29 IU/mL at
48 weeks of therapy. In an integrated analysis of both studies,
TAF-treated patients showed improvements in certain bone
and renal laboratory parameters compared with TDF-treated
patients. TAF-treated patients also had numerically higher
rates of normalization of blood serum alanine aminotransferase
levels (83% versus 75% [Study 108] and 72% versus 67% [Study
110]). Both analogues were generally well tolerated with a
1% adverse event discontinuation rate. The most common
adverse events reported were abdominal pain, back pain, cough,
fatigue, headache, and nausea occurring in similar rates in both
treatment groups.
Sources: Gilead, Vemlidy prescribing information, Food
and Drug Administration Q
Vol. 42 No. 2 February 2017 P&T
91
DRUG FORECAST
Brivaracetam (Briviact)
A Novel Adjunctive Therapy for Partial-Onset Seizures
Farbod Khaleghi, PharmD Candidate; and Eric C. Nemec II, PharmD, BCPS
INTRODUCTION
Epilepsy is the fourth most common
neurological disorder and affects more
than 65 million individuals worldwide.1
This condition is marked by the presence
of epileptic seizures, which result from an
abnormal synchronous ring of excitatory
neurons in the brain.1,2 When neurons re
synchronously, a wave of depolarization
known as a paroxysmal depolarizing shift
occurs.2 During this period, the neurons
experience a lowered resistance to ring,
leading to multiple action potentials that
generate abnormally increased electrical
activity within the brain.
There are various types of epilepsy
syndromes that are dened based on a
combination of symptoms. While general-
ized seizures begin in both hemispheres
of the brain, partial-onset seizures (POS)
(also called focal or localized seizures)
and other forms of epilepsy originate in
only one hemisphere. Patients presenting
with new-onset seizures must be carefully
evaluated to determine if the seizures are
secondary to non-neurological causes;
differential diagnoses may include hypo-
glycemia, alcohol withdrawal, or electro-
lyte abnormalities. Diagnosis of epilepsy
involves ruling out these other etiologies
via laboratory testing, brain imaging, and
an electroencephalogram. Patients with
epilepsy may have developed the con-
dition secondary to genetic factors or
other pathologies, such as brain trauma,
malignancy, stroke, or neurological
infection.1,2 While a majority of patients
Mr. Khaleghi is a PharmD candidate at Western
New England University College of Pharmacy
in Springeld, Massachusetts. Dr. Nemec is
Director of Research and Assessment and
Clinical Associate Professor of Physician
Assistant Studies at Sacred Heart University
in Faireld, Connecticut. Drug Forecast is a
regular column coordinated by Alan Caspi,
PhD, PharmD, MBA, President of Caspi and
Associates in New York, New York.
Disclosure: The authors report no nancial or
commercial relationships in regard to this article.
92 P&T February 2017 Vol. 42 No. 2
with epilepsy are able to maintain sei-
zure control with one to two antiepileptic
drugs (AEDs), many individuals require
adjunctive therapy to achieve long-term
remission.
Brivaracetam (Briviact, UCB, Inc.), a
propyl analogue of levetiracetam, an anti-
convulsant and racetam derivative, was
granted Food and Drug Administration
(FDA) approval as an add-on therapy in
February 2016. It is indicated as adjunc-
tive therapy for treating POS in adults
and adolescents 16 years of age or older.3
MECHANISM OF ACTION
Brivaracetam is a third-generation
antiepileptic racetam derivative and a
4-n-propyl analogue of levetiracetam.13
While the exact mechanism of action
of brivaracetam is unknown, its anti-
convulsant effects are believed to be due
to its highly selective afnity for synaptic
vesicle protein 2A (SV2A) in the brain.
The SV2A glycoprotein is a protein-
coding gene implicated in synaptic signal
transduction.4 It is believed to play a role
in the regulation of neurotransmission
by stimulating vesicle fusion and main-
taining a reserve of secretory vesicles.4
Studies in SV2A-decient animals have
demonstrated an increased propensity
for seizures.5 Brivaracetams actions as an
SV2A ligand lend it broad-spectrum activ-
ity against POS. Its chemical structure is
shown in Figure 1.
Figure 1 Chemical Structure
Of Brivaracetam3
PHARMACOKINETICS
Brivaracetam exhibits linear and
time-independent pharmacokinetics at
its approved doses. It is freely soluble
in water, ethanol, methanol, and glacial
acetic acid.3 The drug experiences near-
complete absorption after oral adminis-
tration and is weakly bound to plasma
proteins.3 Brivaracetams volume of dis-
tribution is 0.5 L/kg, and it is rapidly and
evenly distributed in most tissues. In addi-
tion, the amide moiety of the drug mol-
ecule undergoes hydrolysis via hepatic
and extrahepatic amidase to a carboxylic
acid metabolite.3 This reaction is medi-
ated mainly by cytochrome P450 2C19
(CYP2C19). Genetic polymorphisms
in CYP2C19 may cause production of
the metabolite to be decreased. Poor
metabolizers or patients taking con-
current CYP2C19 inhibitors may require
dose reduction. Finally, brivaracetam is
excreted primarily in the urine within
72 hours of intake.3
CLINICAL TRIALS
The efcacy of brivaracetam as an
adjunctive therapy for POS was estab-
lished in several randomized controlled
trials. Phase 3 trial data follow. (See
Table 1 for a summary.)
Ryvlin et al.6
A phase 3, double-blind, randomized,
placebo-controlled trial conducted across
88 centers throughout Europe and India
evaluated brivaracetam versus placebo in
399 adults with POS. The objective of the
study was to evaluate the efcacy, safety,
and tolerability of brivaracetam versus
placebo in patients with uncontrolled POS
despite adequate therapy with one or two
concomitant AEDs.
Eligible patients were randomized
to receive brivaracetam 20 mg per day
(BRV20), 50 mg per day (BRV50), 100 mg
per day (BRV100), or placebo, admin-
istered twice daily in equal doses. The
primary endpoint was percent reduction
in baseline-adjusted POS frequency per
week over the 12-week treatment period
 DRUG FORECAST

Table 1 A Summary of Phase 3 Trials of Brivaracetam as an Adjunctive Therapy for Partial-Onset Seizures in Adults
Study Design Population Group Number Male Age in Years Duration of Median Reduction
(ITT) Gender (mean [SD]) Epilepsy in Baseline-
(n [%]) in Years Adjusted POS
(mean [SD]) Frequency per
Week (%)
Ryvlin et al. Prospective, multi- Patients with Placebo 100 54 (54.0) 36.4 (13.0) 20.4 (12.3) 17.0
(2014)6 center, double- uncontrolled focal 20 mg 99 61 (61.6) 35.7 (12.5) 22.1 (13.6) 30.0 (P = 0.019)
(NCT00490035) blind, randomized, seizures despite
placebo- treatment with 50 mg 99 54 (54.5) 38.9 (13.6) 22.3 (13.0) 26.8 (P = 0.092)
controlled 12 AEDs 100 mg 100 58 (58.0) 38.0 (13.1) 22.1 (12.8) 32.5 (P = 0.004)
Biton et al. Prospective, multi- Patients with Placebo 98 43 (43.9) 37.5 (12.6) 24.3 (12.2) 17.8
(2014)7 center, random- well-characterized
(NCT00464269) ized, double-blind, partial epilepsy 5 mg 97 49 (50.5) 38.9 (11.6) 22.2 (12.1) 20.0
placebo-controlled, not fully controlled 20 mg 100 52 (52.0) 37.3 (13.3) 22.9 (14.0) 22.5
parallel-group, despite treatment
xed-dose with 12 AEDs 50 mg 101 51 (50.5) 38.9 (12.3) 26.2 (12.0) 30.5 (P = 0.003)
Klein et al. Prospective, multi- Patients with Placebo 259 133 (50.9) 39.8 (12.5) 22.7 (13.3) 17.6
(2014)8 center, double- uncontrolled POS
(NCT00490035) blind, randomized, despite ongoing 100 mg 252 102 (40.3) 39.1 (13.4) 22.2 (13.3) 37.2 (P < 0.001)
placebo- treatment with
controlled 12 AEDs 200 mg 249 133 (53.2) 39.8 (12.8) 23.4 (14.6) 35.6 (P < 0.001)
Kwan et al. Prospective, multi- Patients with focal
(2014)9 center, random- or generalized Placebo 121 69 (57.0) 36.5 (11.5) 18.9
(NCT00504881) ized, double-blind, epilepsy
placebo-controlled, uncontrolled on
BRV 359 181 (50.4) 35.6 (11.5) 26.9 (P = 0.070)
exible dose 13 AEDs
AEDs = antiepileptic drugs; BRV = brivaracetam; ITT = intention to treat; POS = partial-onset seizure; SD = standard deviation.

versus placebo. Secondary endpoints
included median percent reduction from
baseline in POS frequency per week, 50%
or greater responder rate, and seizure
freedom from all seizure types.
Ultimately, the study did not meet
its primary efcacy endpoint. Percent
reduction in baseline-adjusted POS fre-
quency per week over placebo was 6.8%
for BRV20 (P = 0.239), 6.5% for BRV50
(P = 0.261), and 11.7% for BRV100
(P = 0.019). However, median percent
reduction from baseline in POS frequency
per week was 30.0% for BRV20 (P = 0.019),
26.8% for BRV50 (P = 0.092), and 32.5% for
BRV100 (P = 0.004), compared with 17%
for placebo. Adverse events are listed in
Table 2. The study concluded that while
the primary efcacy analysis based on
the BRV50 dose was not statistically sig-
nicant, BRV100 signicantly reduced
POS frequency per week versus placebo.
Biton et al.7
A phase 3, prospective, multicenter,
randomized, double-blind, placebo-
controlled, parallel-group, xed-dose
trial conducted across 85 centers in
Australia, Brazil, Canada, Mexico, and
the U.S. evaluated brivaracetam versus
placebo in 400 patients. The purpose of
the study was to evaluate the efcacy,
safety, and tolerability of brivaracetam
compared with placebo in patients with
uncontrolled POS.
Eligible patients were randomized
to receive BRV5, BRV20, BRV50, or
placebo, administered twice daily in equal
doses. The primary endpoint was per-
cent reduction over placebo in baseline-
adjusted POS frequency per week over
the 12-week treatment period. Secondary
endpoints included median percent reduc-
tion from baseline in POS frequency per
week and 50% or greater responder rate.
Percent reduction in POS frequency
per 28 days over placebo reached sta-
tistical signicance for BRV50 (22.0%;
P = 0.004), but not for the other dose
groups (BRV5 or BRV20). In addition,
statistical signicance was achieved for
the 50% or greater responder rate in the
BRV50 group compared with placebo
(32.7% versus 16.7%; P = 0.008). BRV50
also displayed benets with percent
reduction in POS frequency from base-
line compared with placebo (30.5% versus
17.8%; P = 0.003). The study concluded
that adjunctive therapy with BRV50 offers
signicant reductions in the frequency of
POS when compared with placebo.
Klein et al.8
A randomized, double-blind, placebo-
controlled, multicenter trial conducted
across 147 sites in 27 countries through-
out North America, Europe, Latin
America, and Asia evaluated brivar-
acetam versus placebo in 768 patients
with uncontrolled POS despite treatment
with one or two AEDs. Patients receiv-
ing concomitant levetiracetam were
excluded.
Eligible patients were randomized to
receive BRV100, BRV200, or placebo,
administered twice daily in equal doses.
The coprimary efcacy endpoints were
percent reduction over placebo in 28-day
adjusted POS frequency and 50% or greater
responder rate based on percent reduction
in POS frequency from baseline.

Vol. 42 No. 2 February 2017 P&T 93

DRUG FORECAST
The study met both of its primary ef-
cacy endpoints. Percent reduction in POS
frequency per 28 days over placebo was
22.8% for BRV100 (P < 0.001) and 23.3%
for BRV200 (P < 0.001). Similarly, the 50%
or greater responder rate was 21.6% for
placebo, 38.9% for BRV100 (P < 0.001),
and 37.8% for BRV200 (P < 0.001).
Treatment-related adverse events
occurred in 155 of 261 (59.4%) placebo
patients versus 340 of 503 (67.6%)
brivaracetam patients. (Table 2) Dis-
continuation rates due to treatment-
related adverse effects were 3.8% for
placebo, 8.3% for BRV100, and 6.8%
for BRV200. The study concluded that
adjunctive therapy with BRV100 and
BRV200, without the concomitant use of
levetiracetam, was benecial in reduc-
ing POS frequency in patients with focal
seizures, without resulting in signicant
safety or tolerability issues.
Kwan et al.9
A phase 3, double-blind, randomized,
placebo-controlled, exible-dose trial
conducted across 74 sites in 15 coun-
tries throughout Europe and Asia evalu-
ated varying doses of brivaracetam
versus placebo in 480 patients with
uncontrolled epilepsy (431 with POS, 49
with generalized epilepsy).
Eligible patients were randomized to
receive placebo or brivaracetam, admin-
istered twice daily in equal doses. The
brivaracetam was initiated at BRV20 and
increased, as needed, to BRV150 during
an eight-week period. This dose-nding
period was followed by an eight-week
fixed-dose maintenance period. The
primary efcacy endpoint was percent
reduction in baseline-adjusted POS
frequency per week.
From October 2007 through December
2008, 90.0% of BRV-treated patients and
91.7% of placebo-treated patients com-
pleted the study. Baseline characteris-
tics were largely similar between the two
treatment groups. The study met its pri-
mary efcacy endpoint. In patients with
POS, percent reduction in POS frequency
from baseline was 26.9% for brivaracetam
versus 18.9% for placebo (P = 0.070). The
study concluded that adjunctive therapy
with brivaracetam given at individualized
doses ranging from 20150 mg per day
was well tolerated and effective at reduc-
ing seizure frequency in patients with
uncontrolled epilepsy.
94 P&T February 2017 Vol. 42 No. 2
Summary of Meta-Analyses
Three meta-analyses reviewing
the efcacy and safety of brivarace-
tam as an adjunctive therapy for POS
were identied. The rst included six
randomized, placebo-controlled, single-
or double-blind add-on trials involving
2,399 patients (1,715 receiving brivar-
acetam and 684 receiving placebo). The
following endpoints were assessed: 50%
or greater reduction in seizure frequency,
seizure freedom, incidence of treatment-
related adverse events, and treatment
withdrawal. In regard to all of the primary
endpoints, an x2 test indicated no signi-
cant statistical heterogeneity between
the trials. It was determined that 45% of
levetiracetam-nave patients responded
to brivaracetam and 19% to placebo, sug-
gesting a 25% real response rate that was
not attributable to placebo. Brivaracetam
was found to be more effective than pla-
cebo in reducing seizure frequency by
50% or more when added to concomitant
AEDs in patients with refractory partial
epilepsy. While there was insufcient
data to perform a doseresponse regres-
sion analysis, the results of the trials
suggest that a dose-dependent effect
saturated when the dose of brivarace-
tam reached 50 mg per day. The authors
concluded that brivaracetam was effec-
tive as an add-on treatment in adults with
refractory focal epilepsy and may offer
additional benets in those patients who
are levetiracetam-nave.1
The second meta-analysis included
ve randomized, double-blind, placebo-
controlled, parallel-group trials that
assessed the efcacy and safety of bri-
varacetam compared with placebo as
adjunctive therapy for patients with
POS. Patients in the trials must have
received at least one concomitant AED
at a stable and optimal dosage prior to
study commencement. Brivaracetam at
doses of 20, 50, 100, and 150 mg per day
was associated with signicantly higher
50% responder rates. Brivaracetam 5 mg
per day was not associated with any sig-
nicant difference in 50% responder rate
when compared with placebo. In addi-
tion, treatment-related adverse events
varied depending on the dose. Brivar-
acetam dosed at 150 mg per day was
more associated with somnolence than
any other dose. Similarly, fatigue and
irritability were associated with brivar-
acetam 50 mg per day. In conclusion, it
was determined that the use of brivarace-
tam at doses greater than 5 mg per day
resulted in statistically signicant reduc-
tions in seizure frequency with respect to
the 50% responder rate. Brivaracetam was
mostly well tolerated, with the exception
of some irritability and somnolence asso-
ciated with the 50-mg and 150-mg per day
doses, respectively.10
The third meta-analysis included
ve randomized, placebo-controlled,
single- or double-blind add-on trials
that investigated the efficacy and
safety of brivaracetam at varying
doses. The following endpoints were
assessed: 50% or greater reduction
in seizure frequency and seizure-
free rates. Overall, the 50% responder
rates of patients receiving brivarace-
tam 20, 50, or 100 mg per day were sig-
nicantly higher than those receiving
placebo (20 mg: risk ratio [RR] = 1.63,
P = 0.003; 50 mg: RR = 2.00, P < 0.00001;
100 mg: RR = 1.80, P = 0.01). In addition,
patients in all brivaracetam groups expe-
rienced higher seizure-free rates when
compared with placebo regardless of
dosage (RR = 4.11, P = 0.01). Patients
receiving brivaracetam of any dosage
experienced signicantly higher rates
of adverse effects compared with those
receiving placebo, specically somno-
lence (P = 0.02) and fatigue (P = 0.009).
The authors concluded that brivaracetam
demonstrated efcacy as an adjunctive
treatment for refractory POS, as indicated
by its statistically signicant increases in
the 50% responder rate (P < 0.00001) and
seizure-free rate (P = 0.01).11
WARNINGS AND PRECAUTIONS
AEDs may increase the risk of
suicidal behaviors or thoughts in patients
taking these medications for any indica-
tion. Patients taking brivaracetam should
be monitored for depression, suicidal
ideations, or any unusual changes in
mood and behavior.3
Brivaracetam may also cause dose-
dependent increases in somnolence and
adverse effects such as fatigue, malaise,
sedation, and lethargy. In the phase 3
controlled, adjunctive epilepsy trials,
these adverse effects were seen in 25%
of patients randomized to receive at least
50 mg per day of brivaracetam compared
with 14% of patients receiving placebo.3
Treatment with brivaracetam is associ-
ated with dizziness and disturbances in

Table 2 Safety Data for Brivaracetam
(100 mg per day)
Adverse Event Rate (%)
(Incidence 5%) Ryvlin et al.6 Klein et al.8
Somnolence 8.0
Dizziness 5.0
Fatigue 8.0
Headache 9.0
Urinary tract infection N/R
Nasopharyngitis 1.0
Vertigo 2.0
Nausea 1.0
Irritability 5.1
N/R = not reported.
gait and coordination, such as vertigo,
ataxia, and nystagmus. In the phase 3
controlled adjunctive epilepsy trials, these
adverse reactions were reported in 16% of
patients randomized to receive at least
50 mg per day of brivaracetam compared
with 10% of patients receiving placebo.
The risk of gait disturbances is greatest
early in treatment, but may occur at any
time throughout therapy.3
Brivaracetam is also associated with
psychiatric adverse events, including
nonpsychotic symptoms, such as irritabil-
ity, anxiety, aggression, anger, agitation,
and depression, and psychotic symptoms,
such as paranoia and acute psychosis. In
the phase 3 controlled, adjunctive epilepsy
trials, these adverse reactions were
reported in 13% of patients randomized
to receive at least 50 mg per day of bri-
varacetam compared with 8% of patients
receiving placebo.3
Brivaracetam is also associated with
hypersensitivity reactions, namely
bronchospasm and angioedema. The
medication should be discontinued in
patients who develop hypersensitivity
reactions after being treated with
brivaracetam.3
DRUGDRUG INTERACTIONS
Due to the potential for CYP2C19
induction, coadministration with rifampin
decreases the plasma concentrations of
brivaracetam. The dose may need to be
doubled in patients receiving concomitant
treatment with rifampin.3
Coadministration with carbamazepine
may increase exposure to its active metab-
olite, carbamazepine-epoxide.
While existing data did not reveal
any safety concerns in patients
receiving concomitant treatment
with carbamazepine, the dose of
carbamazepine may need to be
19.4 reduced if tolerability issues arise
10.3 during therapy.3
Because brivaracetam may
7.5
increase the plasma concentra-
6.7 tions of phenytoin, phenytoin
5.1 levels should be monitored
when brivaracetam is added
N/R
to or removed from ongoing
N/R phenytoin therapy.3
N/R When coadministered
with levetiracetam, brivarace-
N/R tam provided no additional
therapeutic benet.3
SPECIAL POPULATIONS
Pregnancy and Lactation
Brivaracetam is in pregnancy
category C, and there are currently
no well-controlled studies in pregnant
women. However, in animal studies, there
was evidence of developmental toxicity
at plasma exposures greater than clini-
cal exposures. Therefore, brivaracetam
should only be used in pregnant patients
if the potential benet outweighs the risk
to the fetus. In addition, pregnant patients
taking brivaracetam are advised to enroll
in the North American Antiepileptic Drug
Pregnancy Registry at 1-888-233-2334 or
www.aedpregnancyregistry.org. No data
are available on the excretion of brivar-
acetam in human milk. However, in rat
studies, it was found that brivaracetam is
excreted in milk.3
Pediatric and Geriatric Use
The safety and efcacy of brivarace-
tam has not been established in patients
younger than 16 years of age. However, in
juvenile rats and dogs, potential adverse
effects on postnatal growth and develop-
ment were observed. In addition, in the
double-blinded, placebo-controlled epi-
lepsy trials, there were too few patients
ages 65 years or older to assess the medi-
cations efcacy. However, dose selection
for elderly patients should begin at the
lower end of the dosing range and should
be made with careful consideration of the
patients hepatic function, renal function,
and other drug therapy.3
DRUG FORECAST
Renal and Hepatic Impairment
Patients with impaired renal function
do not require dose adjustments of brivar-
acetam. However, the medication is not
recommended in patients with end-stage
renal disease receiving dialysis because
there are no data in this patient popula-
tion. For patients with any stage of hepatic
impairment, the recommended starting
dose of brivaracetam is 25 mg twice daily
and the recommended maximum dose is
75 mg twice daily.3
DOSAGE AND ADMINISTRATION
The recommended starting dose for
brivaracetam is 50 mg twice daily (100 mg
total daily dose).3 Gradual dose escala-
tion is not necessary when initiating
treatment. The dosage may be adjusted
down to 50 mg daily or up to 200 mg daily
depending on patient tolerability and
therapeutic response.2 Brivaracetam is
available as an oral tablet (10 mg, 25 mg,
50 mg, 75 mg, and 100 mg), oral solution
(10 mg/mL), and intravenous (IV) injec-
tion (50 mg/mL). If oral administration of
brivaracetam is not feasible, the injectable
form may be administered at the same
dosage and frequency as the tablets and
oral solution. However, it is important to
note that the clinical study experience
with brivaracetam injection is limited to
four consecutive days of therapy.3
The oral tablets and solution may be
taken with or without food. Brivarace-
tam tablets should be swallowed whole
with liquid and not chewed or otherwise
crushed. The oral solution should be mea-
sured out and delivered with a calibrated
measuring device in order to accurately
deliver the prescribed dose. The oral solu-
tion does not need to be diluted and may
be administered using a nasogastric or
gastrostomy tube. Any unused brivar-
acetam oral solution should be discarded
after ve months of opening the bottle.3
Brivaracetam injection is for IV use
and is single-dose only. The injection
does not need to be diluted, though it
may be mixed with the following diluents:
0.9% sodium chloride injection USP, lac-
tated Ringers injection, or 5% dextrose
injection USP. The injection should be
administered over two to 15 minutes. If
diluted, the solution may be stored in
PVC bags, but must not be stored for
more than four hours at room tempera-
ture. Generally, the medication may be
stored at 25C (77F), with excursions
Vol. 42 No. 2 February 2017 P&T
95
DRUG FORECAST
permitted between 15C to 30C (59F
to 86F). The injection and oral solution
formulations should not be frozen.3
COST
Brivaracetam is supplied in three
formulations: 10-mg, 25-mg, 50-mg,
75-mg, and 100-mg tablets; 10-mg/mL
oral solution; and 10-mg/mL injection
for IV administration.3 The 10-mg tab-
lets are available for dose titration. The
average wholesale price (AWP) for a
60-tablet package of all dosages of the
tablet formulation or for the 300-mL bottle
of oral solution is $1,092.12 The AWP for a
package of 10 single-dose 5-mL vials for
IV administration is $468.12
P&T COMMITTEE
CONSIDERATIONS
Brivaracetam is an FDA-approved
medication indicated as adjunctive ther-
apy in patients with POS. Clinical studies
have evaluated the safety and efcacy of
brivaracetam in comparison with treat-
ment with placebo and found that bri-
varacetam (dosed 50 mg per day, 100 mg
per day, or 200 mg per day) demonstrates
signicant reductions in POS frequency
across all doses (P < 0.01 for all arms).
Brivaracetam is available in tablet, oral
solution, and injection formulations with
a price that is comparable to other FDA-
approved therapies for adjunctive treat-
ment of POS. The oral formulations are
available with at pricing; therefore, all
strengths would likely need to be added
to a drug formulary.
Despite promising data from clinical
studies, there is a lack of evidence sug-
gesting that brivaracetam offers any ben-
et over other AEDs, such as levetirace-
tam. While the available data suggests
brivaracetam may provide some benet
over placebo, this is not sufcient cause
for it to be included on hospital formu-
laries. Brivaracetam may have a role as
an adjunctive therapy for patients whose
epilepsy remains uncontrolled despite
taking one to two concomitant AEDs.
CONCLUSION
Brivaracetam is a racetam derivative
and SV2A ligand approved as adjunctive
therapy for the treatment of POS in adults
and adolescents 16 years of age and older.
This medication has shown promise in
patients with epilepsy whose seizures
persist despite adequate treatment.
96 P&T February 2017 Vol. 42 No. 2
continued from page 85
Brivaracetam was well tolerated through-
out all three phase 3 trials, which led to its the only insulin pump integrated with
FDA approval. The drug offers improved Dexcom G5 (Dexcom, Inc.) mobile CGM
seizure control with minimal safety risks technology, combining insulin dosing
for patients with epilepsy. technology from Animas with the CGM
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cacy and safety of brivaracetam at dif- manufacturer.
ferent doses for partial-onset epilepsy:
a meta-analysis of placebo-controlled Source: Exact Imaging, December 9,
studies. Expert Opin Pharmacother 2016 Q
2015;16(12):17551767.
11. Ma J, Huang S, You C, et al. Adjunctive
brivaracetam for patients with refrac-
tory partial seizures: A meta-analysis of
randomized placebo-controlled trials.
Epilepsy Res 2015;114:5965.
12. Red Book Online. Ann Arbor, Michi-
gan: Truven Health Analytics. Accessed
December 19, 2016. Q
 FDA Flags Inconsistent Hospital Reporting
Of Medical Device Problems
Hazy Reporting Rules Beget Confusion
Stephen Barlas
oncerns about medical devices going awry in hospitals
C are pushing the Food and Drug Administration (FDA)
to create a new adverse effects reporting system, which,
as it is developed over the next ve years, will produce seismic
changes both directly and indirectly in the way hospitals collect
and report incident information. Passive hard-copy
reports, dinosaurs in this electronic day and age,
will be out. The establishment of the new National
Evaluation System for Health Technology (NEST)
will usher in an era of active electronic reports
that include clinical data (the current hot term is
real-world evidence or RWE) about patients hurt by
medical devices. New software will appear. Although
reporting to the NEST will be voluntary, hospitals,
medical device manufacturers, disease registries, Stephen Barlas
insurance companies, and others will be forced to
understand new industry software standards, such as the sud-
denly popular Fast Healthcare Interoperability Resources;
purchase new inventory and claims software; and upgrade device
tracking to identify unique device identication (UDI) barcodes.
Signicant capital expenditures will be involved.
What portion of our health care dollars should we be spend-
ing on reporting in this time when health care dollars are
shrinking? asks Janis Orlowski, MD, MACP, Chief Health
Care Ofcer for the American Association of Medical Colleges
in Washington, D.C. We have to be very cognizant of that.
The FDAs recent push for medical device regulation has
something to do with an investigation of 17 hospitals conducted
in December 2015. It conrmed what the FDA probably already
knew: the medical device reports that hospitals are supposed
to submit to the FDA and, in some instances, to device manu-
facturers are very often not submitted.1 The negative impact
on patient safety can be signicant.
The FDAs concern gave birth to a December 2016 workshop
called The Role of Hospitals in Modernizing Evidence Generation
for Device Evaluation: Harnessing the Digital Revolution for
Surveillance. At the meeting, Jeffrey Natterman, Risk Manager
and Associate Senior Counsel for the Johns Hopkins Hospital,
said, One of the problems at hospitals is that no one knows
they are supposed to do it. The it was a reference to reporting
adverse effects from medical devices. The FDA is committed
to undertaking an education program with hospitals, but the
details have not been announced.
Over the past year, the FDA has focused on improving report-
ing from medical device manufacturers, too, mostly through the
Mr. Barlas is a freelance writer in Washington, D.C., who covers
issues inside the Beltway. Send ideas for topics and your comments
to sbarlas@verizon.net.
issuance of guidance documents, many of which have included
controversial segments. For example, in December the FDA
issued a nal guidance called Public Notication of Emerging
Postmarket Medical Device Signals.2 Various industry ofcials,
such as Diane Wurzburger, Executive of Regulatory Affairs
for GE Healthcare, had asked the FDA to include
language committing the FDA to validate with the
manufacturer any signal the agency receives. The
FDA declined to do so.
The Current System ... and Its Limitations
Under federal rules, hospitals have 10 days to
report serious device-related injuries to the devices
manufacturer and to notify both the manufacturer and
the FDA about any deaths that may have resulted.
Manufacturers are required to le reports with the
FDA within 30 days of learning about an injury or death that
may have been caused by a device. Manufacturers must also
report to the FDA when they become aware that their device
has malfunctioned and would be likely to cause or contribute
to a death or serious injury if the malfunction were to reoccur.
The above reports are sent in on a 3500A form. Although a
user facility is not required to report a device malfunction, it
can voluntarily inform the FDA of product problems through
MedWatch, the FDAs safety information and adverse event
reporting program.
Hospitals cannot be blamed fully for failures to report. The
reporting requirement states that reporting is necessary if a
device may have caused death or serious illness or injury
or a malfunction. The qualier may throws confusion into
the denition. Isaac Chang, PhD, Director of the Division of
Postmarket Surveillance at the FDAs Center for Devices and
Radiological Health (CDRH), says that a hospital does not have
to provide causality before reporting. Almost every word
of the reporting requirement can be parsed. Serious illness
or injury means a life-threatening situation or permanent
impairment, or damage to a body function or structure. Even
temporary impairment dictates a report when there was quick
medical or surgical intervention to prevent it from becoming
permanent. And even if a life-threatening condition is a tem-
porary threat, it must be reported. The malfunction portion
of the requirement is equally ambiguous.
Controversial Guidance Documents
The FDA tried to clarify some of these conundrums when
it published nal guidance called Medical Device Reporting for
Manufacturers in November.3 Again, this guidance only covers
manufacturers, not hospitals, though health care facilities have
similar rules. It denes what actually triggers a companys
Vol. 42 No. 2 February 2017 P&T
97
 FDA Flags Inconsistent Hospital Reporting of Medical Device Problems
responsibility to report the injuries and malfunctions men-
tioned in the previous paragraph. The precipitating event is
when a manufacturer receives or otherwise becomes aware
of information from any source that reasonably suggests that
one of its marketed devices caused injury or malfunctioned.
The becomes aware of and reasonably suggests portions with the hospital community to nd that right path, especially
of the requirement are open to interpretation.
One concern has to do with the use of trend analysis to
determine whether a reportable event has occurred in the past.
That comes up in the guidances explication of when a company
becomes aware of information, which includes trend analysis.
It is unclear from the nal guidance whether trend analysis is
required or is something that, if done voluntarily, must be an
element in a decision as to whether the company becomes
aware that a reportable event under medical device reporting
(MDR) necessitates remedial action to prevent an unreasonable
risk of substantial harm to public health. Jeffrey Secunda, MS,
MBA, Vice President of Technology and Regulatory Affairs for
the Advanced Medical Technology Association in Washington,
D.C., the device manufacturers trade group, states, It is not
clear when an event that was previously evaluated as not
reportable would become reportable based on a trend.
Hospital Underreporting
Over the past year, however, the high visibility issue has
been the FDAs concern about hospital underreporting of medi-
cal device problems. Throughout their workday, hospital staff
members use a variety of medical devices: imaging machines,
electrocardiographs, and in vitro tests to make diagnoses; infu-
sion pumps, ventilators, and robotics to provide treatment; and
an array of implants to replace diseased joints and organs. The
agency held a meeting at its suburban Maryland location on
December 5 and outlined some of its concerns about hospital
reporting, its ongoing initiatives to encourage reporting, and its
understanding of the barriers that either prevent or discourage
hospitals from reporting instances in which a device may have
caused death, serious illness, or injury or a malfunction.
The agency has long guessed that reporting is sketchy at
best. That assumption was born out in early 2016 when the
FDA announced the results of 17 hospital inspections it initiated
in December 2015.1 The hospitals were chosen because there
were reports of events at these facilities related to the spread
of uterine cancer from the use of morcellators or the spread of
infections associated with contaminated duodenoscopes. While
these events appeared to be the kind that would have fallen
under current medical device reporting requirements, we did not
see corresponding adverse event reports in our adverse event
MAUDE [Manufacturer and User Facility Device Experience]
database, states Jeffrey Shuren, MD, JD, Director of the FDAs
CDRH. Some of the reporting lapses were found at Massachusetts
General Hospital in Boston, at NewYorkPresbyterian Hospital,
and at two hospitals in Los Angelesthe Ronald Reagan UCLA
Medical Center and the CedarsSinai Medical Center. Among
the 17 hospitals reviewed, the FDA said six didnt properly report
both patient deaths and injuries linked to medical devices within
10 days, as required. Five other hospitals didnt report serious
injuries in a timely manner, according to the agency.
We believe that these hospitals are not unique in that there
is limited to no reporting to the FDA or to the manufacturers
98 P&T February 2017 Vol. 42 No. 2
at some hospitals, Dr. Shuren wrote in an agency blog report.
Hospital staff often were not aware of, nor trained to comply
with, all of the FDAs medical device reporting requirements.
We feel certain there is a better way to work with hospitals to
get the real-world information we need, and we should work
in light of developments in the creation and evaluation of
electronic health information.1
While those and other hospitals can make a case for the
turgidity of reporting regulations, it is also true that hospitals
that fail to report have very little to worry about in terms of
FDA remedial action. In the case of the 17 hospitals subject to
the FDA inspections starting in December 2015, the agency
issued a Form FDA 483 to 15 of them, which noted observa-
tions that the FDA investigators made during the inspections.
Observations listed on a Form FDA 483 do not represent a
nal agency determination regarding a facilitys compliance.
The violations noted during the inspections varied by facility but
included observations that written MDR procedures had not
been developed, maintained, and implemented. For some
hospitals with signicant violations of the MDR regulation, FDA
received a response that we determined was not adequate to
address those violations, and we engaged with these facilities
to facilitate an effective path to voluntary compliance, states
Deborah Kotz, an FDA spokeswoman. These hospitals indi-
cated their willingness to work with us and address the viola-
tions, and at this time, we do not believe any additional action
with regard to these hospitals is necessary. The FDA plans to
partner with hospitals to educate them on the agencys MDR
requirements to improve their reporting of device-related
adverse events.
Long-Standing Problems
The FDA recognized about ve years ago, before the inves-
tigation of the 17 hospitals reconrmed it, that a better sys-
tem for reporting was needed. In 2012, the agency issued a
report, Strengthening Our National System for Medical Device
Postmarket Surveillance, that described the limitations of cur-
rent authorities and approaches to medical device post-market
surveillance and proposed a strategy for a national medical
device post-market surveillance system.4
There are issues, I am not going to lie, states Hopkins
Natterman, referring to the barriers hospitals face when com-
plying with the reporting requirement. Part of the problem is
lack of buy-in from hospital leadership. Concern about hos-
pital liability also dampens reporting. It has happened that
we send a report to the manufacturer, and then it goes into a
black hole, Natterman continues. Then we get sued, and we
end up struggling with the manufacturer to get information.
Even if every hospital in the country reported adverse events
correctly, the FDA would still have a MAUDE database lled
with passive information. Such passive surveillance has impor-
tant limitations because it relies on people to identify that harm
occurred or risk is present, recognize that the harm or risk
is associated with the use of a particular device, and take the
time to report it. In the past few years, the FDA has initiated
efforts to make it easier for some hospitals to report and for
the agency to obtain adverse effect information beyond what
a hospital reports on its 3500A.
 FDA Flags Inconsistent Hospital Reporting of Medical Device Problems
The Medical Product Safety Network (MedSun) was created
in 2002. Composed of 300 hospitals, it allows them to submit
data electronically (not necessary in MAUDE) and gives the
FDA the ability to go into a hospital and tweeze out additional
information. But participation in MedSun is limited, in part
because the FDA requires 10 reports to be led every year.
Hopkins Natterman says that of the six hospitals in the Johns
Hopkins Health System, only hisJohns Hopkins Hospital
les MedSun reports.
MedSun is an improvement over MAUDE because it collects
more than just passive information. But the Holy Grail is the
collection of more robust data. Obtaining clinical informa-
tion from hospitals, insurance companies, electronic health
records (EHRs), medical registries, and other sources would
be an even bigger boon. The Sentinel system does that. It was
authorized by Congress in 2008, but has taken more than half
a decade to progress beyond a pilot stage. It allows the FDA
to weed through medical claims data submitted by insurers in
an attempt to nd early-warning signs that a device is causing
problems. The Sentinel system apparently has access to claims
for nearly 200 million Americans.5
The medical device surveillance program within Sentinel is
called BloodScan. It looks for problems with biologic products,
such as vaccines, allergenic products, blood, blood components,
and blood derivatives, tissues, and cellular and gene therapies.
It has a lot of power, given those 200 million individuals, when
it comes to looking for rare events for the purpose of analysis.
However, 10% of the records in the Sentinel database are from
EHRs, and the rest are from claims data. That has a lot of
limitations for the kind of work we want to do, admits Steven
Anderson, PhD, MPP, Director of the Ofce of Biostatistics and
Epidemiology in the FDAs Center for Biologics Evaluation and
Research. Of the 24 data partners in the program, a major one
is Hospital Corporation of America, which has 160 hospitals
and 20 million patient encounters a year. Dr. Anderson notes,
however, that there are signicant shortcomings to BloodScan,
including medical chart validation, which can take from
six to eight months. That is, if the transfusion is even noted in
the chart; 50% or more are not noted, he says.
The ultimate bonanza is a system that leverages RWEdata
developed through routine clinical practice. These data would
be captured in electronic health information (such as device
registries, EHRs, and payer claims forms) that incorporated
UDIs to quickly identify poorly performing devices; accurately
characterize and disseminate information about real-world
device performance, including the clinical benets and risks
of marketed devices; and efciently generate data to support
pre-market clearance or approval of new devices and new uses
of currently marketed devices.
That evolution is moving forward with the creation of the
NEST. The FDA issued a $3 million grant in September to the
Medical Device Innovation Consortium (MDIC) to establish
the coordinating center, which would organize and run the
NEST. It is envisioned as a virtual network of data partners,
connected through reusable, standardized data use agreements,
that permits access to data from multiple sources to optimize
data standardization, expedite project-specic research agree-
ments, and reduce the cost of evidence development through
economies of scale.
Early critical data partners include the National Patient-
Centered Clinical Research Network, Sentinel, coordinated
registry networks, payers, large health care systems, claims
data systems, the device industry, the National Center for
Health Statistics, and patients, to name a few examples. Dawn
Bardot, PhD, Vice President of Technology Innovation for
MDIC, did not reply to a request for information about the
NESTs progress.
The concept of the NEST is well and good. However, the
problem with collecting RWE on medical devices is that the
quality of clinical information is inconsistent. In July, the FDA
issued draft guidance on what it would like to see from the
various sectors that could contribute medical device RWE.6
The responses indicate the long road the FDA has ahead of it
as it tries to wrestle various sectors into a unied approach to
submission of RWE. The 510(k) Coalition, composed of device
manufacturers, feels the draft guidance relies too heavily on
registries. The nal guidance needs to be clear that RWE is not
limited to situations where the data is derived from a registry,
states Ralph Hall, a partner at Leavitt Partners, a Washington
policy shop headlined by former Health and Human Services
(HHS) Secretary Mike Leavitt.
The Coalition also believes that the draft guidance is not
clear enough on the usage of different types of RWE and real-
world data (RWD). Most of the examples in the draft guidance
seem to focus on clinical-type data, and do not consider data
from sources such as engineering analysis and bench testing,
Hall explains. Such information is often highly valuable in the
device context. Hall declined to elaborate.
RWD could be used in regulatory decision-making. But what
about actions short of that, such as recalls or notications to
physicians and consumers about devices on the market that
have shown recent troublesome effects? It is that instance
the agency attempted to clarify when it issued its nal guid-
ance document in December: Public Notication of Emerging
Postmarket Medical Device Signals.2 The objective was to
dene the emerging signals that raise an issue about a
device on the market that the agency has determined has the
potential to impact patient management decisions and/or the
known riskbenet prole of the device. An emerging signal
can arrive at the FDA from a variety of sources including, but
not limited to, MDRs, MedSun reports, data from mandated
post-market studies, clinical trials or data published in the
scientic literature, epidemiologic research including evalu-
ation of administrative databases, health care claims data or
registries, and inquiries or investigations from global, federal,
or state health agencies.
Mark B. Leahey, President and Chief Executive Ofcer of
the Medical Device Manufacturers Association in Washington,
D.C., worries that the FDAs guidance may have unintended
consequences related to unvalidated information being relied
upon by patients, providers, and the public to make certain
clinical decisions that may not be in a patients best interest.
But in the nal guidance, the FDA nowhere states the need
for any emerging signal to be validated before the agency
issues a communication of concern. Rather, it cites a standard
that the available evidence is of sufcient strength. It does
note, however, that the device manufacturer will be consulted
during the process of signal renement, unless time does not
continued on page 115
Vol. 42 No. 2 February 2017 P&T
99
 New Pharmacotherapies in
Chronic Lymphocytic Leukemia
Jacqueline L. Olin, MS, PharmD, BCPS, CDE, FASHP, FCCP;
Katherine Canupp, BS, PharmD Candidate; and Morgan B. Smith, PharmD, BCOP
INTRODUCTION
Chronic lymphocytic leukemia (CLL) is the most common
adult leukemia in the Western world. The American Cancer
Society predicted approximately 18,000 new cases in 2016,
with nearly 5,000 estimated deaths.1 CLL is characterized as
a B-cell malignancy, marked by a progressive accumulation
of incompetent clonal B lymphocytes with a CLL phenotype.
The main diagnostic criterion of CLL is the presence of at
least 5 x 109 B-cell lymphocytes per liter with a CLL pheno-
type in peripheral blood.2 In comparison to normal peripheral
blood B cells, CLL cells are CD5-positive.3 In addition, they
express B-cell surface antigens CD19, CD20, and CD23. The
extent of expression of these surface markers is part of the
process involved in distinguishing CLL from other hematologic
malignancies.
The exact cause of CLL is unknown, and there are few known
risk factors. However, it is more common in men, in people
with a family history of the disease, and in people of European
genetic ancestry.3 It is also more common in the elderly, with
an average age of 72 years at diagnosis, although up to 30%
of cases occur in individuals younger than 55 years of age.3
Some studies have linked CLL to exposure to chemicals such
as Agent Orange.3 Farming and long-term exposure to some
pesticides may potentially increase risk.3
Many individuals with CLL are asymptomatic at diagno-
sis, and the disease may be detected upon routine labora-
tory examination. Others may present with constitutional
symptoms including fever, weight loss, fatigue, night sweats,
and weakness, while a physical examination may demon-
strate lymphadenopathy, splenomegaly, and hepatomegaly.3
Depending on prognostic factors and comorbidities, 82.6% of
CLL patients are expected to survive at least ve years, based
on data from the National Institutes of Healths Surveillance,
Epidemiology, and End Results or SEER program.4 Advances in
molecular and cytogenetic analyses have allowed more precise
risk-stratication models that have dened current treatment
algorithms composed of novel targeted agents. Novel treatment
options beyond conventional chemotherapy include monoclonal
antibodies and targeted small-molecule inhibitors impacting
B-cell signaling. Allogeneic stem cell transplant offers a cura-
tive option but is reserved for select individuals: Few qualify
given its toxicities. This article describes clinical outcomes and
therapeutic application of newly approved pharmacotherapies
and highlights emerging investigational therapeutic options.
Dr. Olin is a Professor of Pharmacy at Wingate University School
of Pharmacy in Wingate, North Carolina. Katherine Canupp is a
Doctor of Pharmacy Candidate, Class of 2019, at the same institution.
Dr. Smith is a Clinical SpecialistHematology/Oncology at Novant
Health Presbyterian Medical Center in Charlotte, North Carolina.
106 P&T February 2017 Vol. 42 No. 2
PROGNOSTIC FACTORS AND
TREATMENT STRATIFICATION
The initial diagnosis of CLL is based on the presence of at
least 5 x 109 B lymphocytes per liter of peripheral blood with
a CLL phenotype and by ruling out other lymphoproliferative
disorders.2,5 Lymphadenopathy and/or splenomegaly with less
than 5 x 109 B lymphocytes per liter of peripheral blood is the
denition of small lymphocytic lymphoma (SLL), which some
experts consider to be a different manifestation of the same
disease.2,5 Once a diagnosis of CLL is established, the Rai and
Binet staging systems are used worldwide in the assessment
of prognosis.2,5 They are based on physical examination nd-
ings and on hemoglobin and platelet concentrations. Both
systems dene lower-risk disease as the presence of lympho-
cytosis in the absence of enlarged lymph nodes, splenomegaly,
hepatomegaly, anemia, or thrombocytopenia. Individuals with
intermediate- and higher-risk CLL have multiple palpable
enlarged areas and cytopenias. Median survival times are
approximately 12.5 years, seven years, and one to two years for
low-, intermediate-, and high-risk CLL, respectively.5 The Rai
and Binet clinical staging systems do not identify which low-risk
patients will progress rapidly. Additional molecular markers
are used in risk stratication and treatment determination.
Continued progress in understanding the pathology of CLL
has led to the discovery of a large number of novel prognostic
markers.68 Establishing a prognostic score for patients with
CLL continues to be an area of research, and there are more
than 20 such markers available.8,9 Immunoglobulin heavy-
chain variable (IGHV) mutational status is a strong indepen-
dent predictor of survival outcomes in CLL, with unmutated
(2% or fewer cells mutated) or VH3-21 mutated IGHV indicating
a poor prognosis and shorter treatment-free period and overall
survival (OS), regardless of stage.5,10 Treatment selection is
determined by the presence of certain chromosomal abnormali-
ties. In particular, a deletion of chromosomes 11 (del[11q])
and 17 (del[17p]) and/or mutation of the TP53 gene have been
associated with worse prognosis.6,9 Therefore, evaluation for
the presence of these three specic cytogenetic abnormalities,
among others, has been incorporated into treatment guidelines,
particularly before each anticipated treatment to account for
mutations occurring over the course of the disease.5,9 Treatment
options are stratied by cytogenetic abnormality (Table 1).
TREATMENT PRINCIPLES
With the exception of allogeneic hematopoietic stem cell
transplantation (HSCT), CLL is not generally considered
curable. However, long-term disease-free survival has been
demonstrated in some subsets of patients.11 Goals of chemo-
Disclosures: The authors report no commercial or nancial interests
in regard to this article.
 New Pharmacotherapies in Chronic Lymphocytic Leukemia
Table 1 Selected First-Line Treatment
Options for Chronic Lymphocytic Leukemia5,9
CLL Without del(17p) and/or TP53 Mutation
Physically Fit Patients Elderly or Frail Patients or
Those With Signicant
Comorbidities
Fludarabine + Obinutuzumab + chlorambucila
cyclophosphamide + rituximab Ibrutiniba
Pentostatin + Ofatumumab + chlorambucil
cyclophosphamide + rituximab Rituximab + chlorambucil
Fludarabine + rituximab Bendamustine rituximabb
Bendamustine rituximab
CLL With del(17p) and/or TP53 Mutation
Ibrutinib
Idelalisib rituximabc
High-dose methylprednisolone + rituximab
Allogeneic stem cell transplant
CLL = chronic lymphocytic leukemia; del(17p) = chromosome 17 deletion;
NCCN = National Comprehensive Cancer Network.
a
Category 1 recommendation as per NCCN guidelines
b
Not guideline-recommended for patients categorized as frail
c
Not endorsed by NCCN
therapy include inducing remission and prolonging life while
minimizing treatment-related adverse effects. No survival
advantage was demonstrated when comparing immediate
with deferred initiation of treatment in older trials of alkylat-
ing agents.12 Therefore, chemotherapy is not offered in earlier
stages where presentation is often asymptomatic; patients are
managed with periodic follow-up until the development of signs
and symptoms, including progressive lymphadenopathies,
splenomegaly, or cytopenias.2,5,9 The current availability of
more targeted therapies and molecular markers points to
the need for continued research into the impact of earlier
treatment options.
Historically, chlorambucil (Leukeran, Aspen Global) was the
standard therapy for initial treatment, and it is still an option
today, now most often given in combination with an anti-CD20
monoclonal antibody.5 A phase 3 trial comparing udarabine
to chlorambucil in patients with a median age of 70 years
showed improved complete response (CR) with udarabine,
but no difference in OS.13 Thus, chlorambucil monotherapy
remains a rst-line option for older patients with comorbidi-
ties.5,9 Introduction of the biologic agent rituximab, an anti-
CD20 monoclonal antibody, revolutionized the management
of B-cell malignancies, including CLL, with the combination of
udarabine, cyclophosphamide, and rituximab (FCR) becom-
ing the recognized gold standard in patients able to tolerate
intensive therapy.14,15
In the CLL8 trial, untreated physically t patients were
randomized to receive six courses of FCR or udarabine and
cyclophosphamide (FC). Progression-free survival (PFS)
was higher in the FCR group after three years (65% versus
45%; hazard ratio [HR], 0.56; 95% condence interval [CI],
0.460.69]).16 With 5.9 years of follow-up, median OS was
86 months for the FC group and not yet reached for the FCR
group (P = 0.001.)16 However, patients with del(17p) did not
benet as much from FCR, and older patients with comorbidi-
ties, including reduced renal function, may not tolerate FCR as
well as other options.16 Data from a phase 2 FCR study showed
that patients with a mutated IGHV gene achieved sustained
remission after a median 12.8 years of follow-up, which was
the rst success of this type demonstrated in CLL.11 The com-
bination of bendamustine with rituximab (BR) was compared
with FCR in untreated physically t patients and did not meet
the prespecied criteria for noninferiority.14 Because BR was
associated with fewer infectious complications, it remains
a consideration for older patients at risk for infections.5,9,17
Front-line chemotherapy options for CLL are stratied based
on del(17p)/TP53 mutations and the patients tness level or
ability to handle intensive chemotherapy (Table 1).5,9
A potentially curative modality is allogeneic HSCT, which
remains an option for patients with del(17p)/TP53 abnor-
malities and/or patients who have not responded to or have
relapsed with rst-line therapy. While many CLL patients are
not candidates for HSCT due to age and comorbidities, the
use of nonmyeloablative reduced-intensity conditioning (RIC)
regimens has expanded accessibility. A summary of prospective
studies using RIC HSCT in CLL patients with median follow-
up of up to six years demonstrated approximately 40% median
PFS and 50% to 60% median OS, with the most signicant
complication of chronic graft-versus-host disease (cGVHD)
in almost 50% of patients.18 The novel B-cell-receptor signal-
ing inhibitors ibrutinib (Imbruvica, Pharmacyclics, Inc.) and
idelalisib (Zydelig, Gilead Sciences, Inc.) have prolonged PFS
in higher-risk patients in whom transplant was previously the
only option; these therapies are discussed below. An overview
of the newly available pharmacotherapies for CLL rst-line
therapy, including place in therapy, pharmacotherapeutic
considerations, and cost implications, can be found in Table 2.
BIOLOGIC THERAPIES
Anti-CD20 Antibody Therapies
Because the addition of rituximab to udarabine and cyclo-
phosphamide demonstrated improved activity and was well
tolerated, FCR became a rst-line therapy. Further research
into the biological activity of the CD20 receptor led to the
development of ofatumumab (Arzerra, Novartis) and obinutu-
zumab (Gazyva, Genentech), which have distinct CD20-binding
characteristics. Ofatumumab, a fully human monoclonal CD20
antibody, and rituximab have been classied as type-1 anti-CD20
antibodies because they lead to binding with C1q, which acti-
vates complement-dependent cytotoxicity (CDC).25,26 However,
ofatumumab binds at distinct, discontinuous regions of CD20,
which differentiates it from rituximab.26,27 Obinutuzumab,
a type-2 anti-CD20 antibody, binds to CD20 with less inten-
sity, resulting in lower CDC but more lysosomal cell death
(antibody-dependent cellular cytotoxicity).25,26 Continued
studies of ofatumumab and obinutuzumab will help further
dene the clinical impact of their molecular differences.
Obinutuzumab
Obinutuzumab was approved by the Food and Drug
Administration (FDA) in combination with chlorambucil for
CLL in treatment-nave individuals based on the results of
Vol. 42 No. 2 February 2017 P&T
107
 New Pharmacotherapies in Chronic Lymphocytic Leukemia

Table 2 New Pharmacotherapies in Chronic Lymphocytic Leukemia

Medication Drug Class Indication Adverse Effects* Additional Comments Cost24
(Brand, Recommended Dose
Manufacturer)
Biological Therapies: CD20 Antagonists
Obinutuzumab Humanized Untreated CLL in Infusion reactions Screen for HBV prior to initiation Strength:
(Gazyva, IgG1 combination with Neutropenia and monitor during treatment 25 mg/1 mL
Genentech)19 monoclonal chlorambucil: Thrombocytopenia and for several months after Package size:
antibody Cycle 1 (28 days) Anemia discontinuation. 40 mL
Day 1 100 mg IV Pyrexia Use cautiously or discontinue if
AWP per mL =
Day 2 900 mg IV Cough HBV reactivation occurs during
$167.93
Day 8 1,000 mg IV Nausea treatment.
Day 15 1,000 mg IV Diarrhea Patients with pre-existing cardio-
Cycles 26 pulmonary conditions are at
Day 1 1,000 mg IV every increased risk for severe infusion
28 days reactions.
Premedicate with acetamin- Live virus vaccines are not
ophen, corticosteroid, and recommended during treatment.
antihistamine 3060minutes There is potential for progressive
prior to infusion. multifocal leukoencephalopathy.
Ofatumumab Fully human Untreated CLL or relapsed Infusion reactions Strength:
(Arzerra, IgG1-kappa CLL in combination with Neutropenia 20 mg/1 mL
Novartis)20 monoclonal udarabine and cyclo- Package size:
antibody phosphamide: 50 mL
Cycle 1 (28 days)
AWP per mL =
Day 1 300 mg IV
$124.91
Day 8 1,000 mg IV
Cycles 212
Day 1 1,000 mg IV in every
subsequent 28-day cycle
(maximum 12 cycles for
treatment nave or 6 cycles
for relapsed disease)
Extended treatment in
patients who responded to
at least two lines of therapy:
Cycle 1: Same as above.
Then 1,000 mg 7 weeks later
and every 8 weeks up to a
maximum of 2 years.
For all indications, pre-
medicate with acetamino-
phen, corticosteroid, and
antihistamine 30120minutes
prior to infusion
table continues

the CLL11 trial.19,28 Given the age and comorbidities present
in the majority of individuals with CLL, the CLL11 trial evalu-
ated participants with coexisting conditions. Treatment-nave
patients with comorbidities (N = 781), as indicated by either a
cumulative illness rating scale score greater than 6 or moder-
ate renal impairment, were randomized to one of three arms:
chlorambucil alone, obinutuzumab plus chlorambucil, or ritux-
imab plus chlorambucil. Patients median age was 73 years,
and 82% had at least three comorbidities. Median PFS was
signicantly improved in both combination arms (26.7 months,
16.3 months, and 11.1 months in the obinutuzumab plus
chlorambucil, rituximab plus chlorambucil, and chlorambucil
groups, respectively; HR for progression or death, 0.18; 95%
CI, 0.130.24; P < 0.001 for obinutuzumab plus chlorambucil
compared with chlorambucil). Direct comparison of obinutu-
zumab plus chlorambucil with rituximab plus chlorambucil
demonstrated prolonged PFS (HR, 0.39; 95% CI, 0.310.49;
P < 0.001.) The PFS benet with obinutuzumab did not extend
to those patients with del(17p).28 Grade 3 or 4 infusion reactions
occurred in 20% of participants during the rst obinutuzumab

108 P&T February 2017 Vol. 42 No. 2

 New Pharmacotherapies in Chronic Lymphocytic Leukemia

Table 2 New Pharmacotherapies in Chronic Lymphocytic Leukemia (continued)

Medication Drug Class Indication Adverse Effects* Additional Comments Cost24
(Brand, Recommended Dose
Manufacturer)
Small-Molecule Therapies
Ibrutinib Brutons Untreated or relapsed/ Neutropenia Avoid use with moderate or Strength:
(Imbruvica, tyrosine refractory CLL: Thrombocytopenia strong CYP3A inducers and inhibi- 140 mg
Pharmacyclics)21 kinase 420 mg orally once daily Diarrhea tors (including grapefruit prod- Package size:
inhibitor until disease progression or Anemia ucts, Seville oranges, starfruit). 90 or 120
unacceptable toxicity Musculoskeletal Avoid use in patients with moder- capsules
pain ate or severe hepatic impairment.
AWP per
Rash Monitor CBC monthly during
capsule =
Nausea treatment, including differential.
$136.57
Bruising Fetal risk has been demonstrated.
Fatigue Patients 65 years old have
Hemorrhage increased risk for serious adverse
Pyrexia effects.

Idelalisib PI3K-delta Relapsed/refractory CLL, in Diarrhea Avoid CYP3A inducersand Strengths:

(Zydelig, inhibitor combination with rituximab: Pyrexia substrates. 100 mg or
Gilead)22 150 mg orally twice daily Fatigue Serious allergic reactions, 150 mg
until disease progression or Nausea including anaphylaxis, have been Package size:
unacceptable toxicity Cough reported. 60 tablets
Pneumonia May cause fetal harm when
AWP per tablet =
Abdominal pain administered during pregnancy.
$191.14
Chills
Rash
Neutropenia
Hypertriglyceridemia
Hyperglycemia
ALT/AST elevations
Venetoclax BCL-2 Relapsed/refractory CLL, Neutropenia Avoid live attenuated vaccines Strengths:
(Venclexta, inhibitor with 17p chromosome Diarrhea prior to, during, and after therapy 10 mg, 50 mg,
AbbVie)23 deletion: Nausea until B-cell recovery occurs. 100 mg
Titrate from 20 mg orally Anemia Avoid use with moderate or Package sizes:
once daily to 400 mg orally Upper respiratory strong CYP3A inducers and inhibi- 2 or 14 tablets
once daily over ve weeks. tract infection tors (including grapefruit prod- (10 mg), 1 or 7
Premedicate with IV uids, Thrombocytopenia ucts, Seville oranges, starfruit) tablets (50 mg),
xanthine oxidase inhibitor, Fatigue and P-glycoprotein inhibitors. 1 or 120 tablets
or urate oxidase inhibitor as May cause fetal harm when (100 mg)
clinically indicated administered during pregnancy.
AWP per tablet =
$9.56 (10 mg),
$47.80 (50 mg),
$95.60 (100 mg)
* Common adverse effects seen in 10% or more patients with ofatumumab or obinutuzumab; common adverse effects seen in 20% or more patients with other
agents.
ALT = alanine aminotransferase; AST = aspartate aminotransferase; AWP = average wholesale price; BCL-2 = B-cell lymphoma-2 protein;
CBC = complete blood count; CLL = chronic lymphocytic leukemia; CYP = cytochrome P450; HBV = hepatitis B virus; IgG1 = immunoglobulin G1;
IV = intravenously; PI3K = phosphatidylinositol-3 kinase.

infusion and were more severe with obinutuzumab, but not
during subsequent infusions.25
Obinutuzumab demonstrated activity in heavily pretreated
patients in a phase 1/2 study, but it is not approved by the
FDA for this indication.29 Patients administered obinutu-
zumab should receive acetaminophen, a corticosteroid, and
an antihistamine 30120 minutes prior to infusion and should
be closely monitored during the infusion for blood
pressure changes, flushing, pyrexia, chills, and other
infusion reactions.19

Vol. 42 No. 2 February 2017 P&T 109

 New Pharmacotherapies in Chronic Lymphocytic Leukemia
Ofatumumab
Ofatumumab plus chlorambucil was evaluated in the
COMPLEMENT-1 trial, a phase 3 study in treatment-nave CLL
patients deemed to be ineligible for udarabine based on age
or comorbidities.20,30 Participants were randomized to receive
ofatumumab with chlorambucil (n = 221) or chlorambucil alone
(n = 226) with continued treatment until best response or a
maximum of 12 cycles, with the primary endpoint of median
PFS. Participants median age was 69 years, and 72% had at least
two comorbidities, which included cardiovascular, metabolic,
respiratory, renal, or other conditions. After 28.9 months of
follow-up, PFS was improved in the combination therapy arm
with median PFS of 22.4 months versus 13.1 months (HR, 0.57;
95% CI, 0.450.72; P < 0.001). In patients with del(17p), PFS
was unchanged with the addition of ofatumumab (HR, 0.46;
95% CI, 0.181.19). Patients receiving combination therapy were
more likely to experience neutropenia, but rates of infection
were similar between groups. Grade 3 and 4 infusion reactions
were experienced in 10% of patients. As with obinutuzumab,
patients receiving ofatumumab should receive premedication
and should be closely monitored for infusion reactions. The
ndings of this trial led to FDA approval of ofatumumab with
chlorambucil in untreated patients ineligible for udarabine.20,30
Ofatumumab is also FDA-approved with udarabine and
cyclophosphamide for relapsed disease, as extended treatment
in patients who responded to at least two lines of therapy, and
for patients failing udarabine or alemtuzumab.20 Its activity
in the setting of relapsed disease was demonstrated in the
COMPLEMENT-2 study with improved PFS of ofatumumab
with FC compared with FC alone (HR, 0.67; 95% CI, 0.510.88;
P = 0.0032).31 The PROLONG investigators evaluated ofatu-
mumab as a maintenance therapy in 238 patients for up to
two years compared with observation, and improved PFS was
observed with therapy (HR, 0.50; 95% CI, 0.380.66; P < 0.001).32
Activity of ofatumumab has been observed in patients failing
udarabine or alemtuzumab.20,33
Small-Molecule Therapies
Ibrutinib
Ibrutinib is a small-molecule therapy and Brutons tyrosine
kinase (BTK) inhibitor approved for several hematologic
malignancies.21 BTK has a well-characterized role in the B-cell
receptor signaling pathway that leads to proliferation and cell
survival.34,35 Specically, it promotes homing and adhesion
of CLL cells to the microenvironment, an activity that is
chemokine-mediated.36,37 Ibrutinib forms covalent bonds with
a cysteine residue in the active site of the BTK.21 This leads
to an inhibition of enzymatic activity of the BTK and thus
inhibits malignant B-cell proliferation and survival, resulting
in cell death.21
Ibrutinib was compared with chlorambucil in an international,
open-label, randomized phase 3 trial of 269 previously untreated
patients with CLL at least 65 years of age.37 Up to half of the
participants had creatinine clearance of less than 60 mL/min
at baseline, and a third had a cumulative illness rating score
greater than 6. Treatment with ibrutinib resulted in longer
rates of PFS and OS. The relative risk of progression or death
was 84% lower with ibrutinib (HR, 0.16; 95% CI, 0.090.28;
P = 0.001).37 Adverse effects with ibrutinib included grade 34
110 P&T February 2017 Vol. 42 No. 2
major hemorrhages in ve patients. Grade 23 atrial bril-
lation occurred in six patients with drug discontinuation in
two patients, and grade 3 hypertension occurred in six patients,
none requiring dose modication. In a follow-up analysis of this
trial and other studies of ibrutinib in previously treated patients,
median PFS and OS still hadnt been reached, with more than
89% PFS at two years.38 Outcomes were favorable with ibru-
tinib in previously treated patients as well.39 Patients taking
ibrutinib should be educated about and monitored for signs
and symptoms of bleeding, infection, and atrial brillation.21
Idelalisib
Idelalisib is another small molecule that affects B-cell
signaling pathways. Phosphatidylinositol-3 kinases (PI3Ks) in
lymphocytes and other cells regulate processes such as prolif-
eration and migration and have been shown to be expressed
in isolated B-CLL cells.40,41 Inhibition of the PI3K-delta isoform
pathway leads to enhanced apoptosis.41 Idelalisib is an inhibi-
tor of PI3K-delta that affects signaling through B-cell receptor
pathways by inducing apoptosis.22 It is approved in combina-
tion with rituximab for treatment of relapsed or refractory
CLL based on ndings of the Study 116 trial.22,42 The combi-
nation of idelalisib and rituximab was compared with ritux-
imab alone in CLL patients who had progressed on previous
regimens with a median of at least three drugs; PFS was the
primary endpoint. Patients (N = 220) had a median age of
71 years with median estimated creatinine clearance of
6267 mL per minute. Median PFS was 5.5 months in the
rituximab-only arm and had not yet been reached with combi-
nation therapy when the study was halted at the prespecied
stopping point for efcacy (P = 0.001). OS at one year was
improved with combination therapy (92% versus 80%; HR, 0.28;
P = 0.02). Of note, the PFS benet of idelalisib was extended to
those patients with del(17p).42 Given the activity of idelalisib
and the limited options for patients with del(17p), idelalisib was
approved in Europe for treatment-nave patients with del(17p)
and is recommended by the German CLL study group as an
option for rst-line therapy in this subgroup.9
Of concern with idelalisib are fatal or severe hepatotoxicity,
severe diarrhea or colitis, and serious or fatal infections, which
occurred in 18%, 14%, and 21% of patients in monotherapy trials
and 11%, 19%, and 36% of patients in combination trials, respec-
tively.22 In a phase 2 study of idelalisib as rst-line therapy,
54% experienced grade 3 or higher transaminitis.43 A safety
analysis was conducted with patients receiving idelalisib for
multiple indications. Of 1,073 evaluated patients, 51% experi-
enced transaminitis of any grade with median onset of 39 days.
Rechallenge of some participants with at least grade 3 transam-
initis resulted in no further recurrence.44 Patient counseling
for idelalisib should include monitoring and awareness to alert
the provider about severe skin reactions, diarrhea, or new or
worsening coughing or shortness of breath.22
Venetoclax
While improved CLL outcomes have been demonstrated
with ibrutinib and idelalisib, there is still the potential for
relapse and resistance, particularly in patients with del(17p).
The B-cell lymphoma-2 (BCL-2) family of proteins regulates
cellular apoptosis and oncogenic functions. Selective inhibi-
 New Pharmacotherapies in Chronic Lymphocytic Leukemia
tion of BCL-2 has resulted in tumor lysis within 24 hours.45
Venetoclax (Venclexta, AbbVie/Genentech) is thought to bind
BCL-2 and restore apoptosis.23 This small-molecule therapy is
approved specically for patients with del(17p) CLL who have
received at least one prior therapy.23
Venetoclax was studied in a phase 1 dose-escalation study
(1501,200 mg per day) of 116 participants with relapsed or
refractory CLL or SLL.23,38 Patients median age was 66 years,
they had received from one to 11 previous therapies, and 30%
had the del(17p) mutation. The overall response rate (ORR)
across all doses was 79%, with a 71% response rate among those
with del(17p). Clinically signicant tumor lysis syndrome (TLS)
occurred in three patients, with one requiring dialysis and one
sudden death after a dose increase. In the study expansion
with revised dose-escalation adjustments and administration
of TLS prophylactic medications in higher-risk participants,
no clinically signicant TLS occurred. Other adverse effects
included diarrhea (52%), upper respiratory infection (48%),
and grade 34 neutropenia (41%).46 At 24 months, the subset
of participants maintained on the 400-mg daily dose had esti-
mated PFS of 62% (95% CI, 4575). Grade 3 or higher adverse
events occurred in 86%, with neutropenia as the most common.
Most were treated with granulocyte-colony stimulating factor,
and all responded.47
A phase 2 study of 107 participants with relapsed or refractory
CLL demonstrated 79.4% ORR (95% CI, 70.586.6) at one year.
Some participants had failed ibrutinib or idelalisib, which
provides further support for venetoclax in higher-risk popula-
tions.48 Several studies are under way evaluating venetoclax
in previously untreated CLL, including various combinations
with ibrutinib, obinutuzumab, and rituximab (NCT02758665,
NCT02756897, and NCT02950051).4951
Patients receiving venetoclax should be instructed to drink at
least six glasses of water daily, should be educated about symp-
toms of TLS, and should receive appropriate TLS prophylaxis as
indicated. Inpatient dose initiation and escalation is recommended
for high-risk patients, such as those with any lymph nodes 10 cm
or larger or with an absolute lymphocyte count of 25 x 109 per
liter or greater and any lymph nodes 5 cm or larger.23
HSCT
Prior to the availability of the small-molecule therapies,
allogeneic HSCT was the only treatment option for relapsed/
refractory high-risk patients, such as those with del(17p). Use
of RIC regimens has expanded accessibility and produced
curative potential, but cGVHD has been a limitation. While
small-molecule therapies provide alternatives for managing
high-risk patients, their long-term efcacy remains unknown.
HSCT may still be a viable option for some patients. A suggested
sequencing of modalities is the use of the novel agents until,
ideally, an achievement of a maximum response (or even if no
response) and then HSCT, especially in younger patients with
a well-matched donor available.52
EMERGING THERAPIES
Acalabrutinib (ACP-196)
BTK inhibition has become an important advance in the treat-
ment of CLL because this target has been shown to be highly
active in the malignancy.3436 However, ibrutinib is associated
with high levels of toxicity, drug resistance due to incomplete
BTK receptor blockade, and Richters transformation (evolution
of CLL into large-cell lymphoma).53,54 Acalabrutinib (ACP-196,
Acerta Pharma) is a second-generation irreversible inhibitor
of BTK that offers several pharmacological improvements
compared with its rst-generation counterpart. This agent
represents a more selectively targeted BTK inhibitor that does
not bind to alternative kinases, such as epidermal growth factor
receptor, TEC family, and insulin receptor kinase, thereby
providing improved tolerability. In addition, acalabrutinib
has more rapid oral absorption (peak plasma values occur
between 0.6 and 1.1 hours versus one and two hours) and a
shorter half-life (one hour versus four to 13 hours) compared
with ibrutinib, allowing for twice-daily dosing. This method
of administration has been shown to provide better plasma
exposure (continuous, greater-than-95% blockade of BTK) than
ibrutinib. As a result, rates of drug resistance and Richters
transformation may be effectively reduced.55
Acalabrutinib was initially shown to be safe and effective in
an uncontrolled, multicenter, phase 1/2 trial of 60 relapsed/
refractory CLL patients in which the ORR with 100-mg twice-
daily dosing was 95% (partial response [PR], 85%; PR with
lymphocytosis, 10%) with a median follow-up period of
14.3 months. Stable disease (SD) occurred in 5% of patients.
ORR in patients with del(17p) was 100%. No cases of Richters
transformation were reported, and only a single case of disease
progression occurred. Patients had a median of three prior
therapies, and a majority had poor prognostic features. Most
toxicities were grade 12, with the most common being
headache (43%), diarrhea (39%), increased weight (26%),
pyrexia (23%), and upper respiratory infection (23%). Therapy
discontinuation due to toxicity occurred in three patients
(5%).55 Preliminary ndings in an ongoing phase 1/2 study
(NCT02029443) of acalabrutinib in 74 patients with treatment-
nave CLL reected similar results (ORR, 96%; PR, 86%; PR plus
lymphocytosis, 10%; SD, 4%). The median time to response
was two months, with a rapid reduction in lymphadenopathy.
Treatment was highly tolerable, with 97% of patients continu-
ing on the study drug.56 A phase 3 trial is under way based on
these results (NCT02475681).57
Lenalidomide
Lenalidomide (Revlimid, Celgene), an FDA-approved
immunomodulatory agent for multiple myeloma, mantle cell
lymphoma, and myelodysplastic syndrome,58 is being explored
as a treatment option for CLL. Although well known for its
antiangiogenic, antineoplastic mechanisms, lenalidomide is
classied as an immunomodulatory agent due to its ability to
enhance the immune system. It counters T-cell dysfunction
known to exist in patients with CLL and also inhibits the sup-
pressive effects that malignant CLL clones have on the immune
system.5961 Among the mechanisms of cancer-induced immune-
system suppression discovered to date, checkpoint inhibition
has been identied as a potential target in CLL. Malignancies
of many types, including CLL, use the programmed death
receptor-1 (PD-1) pathway to diminish the growth and activ-
ity of T cells that would normally be malignant cell lysis.59,62,63
Lenalidomide blocks the inhibitory interaction that occurs
between the programmed death receptor ligand-1 (PD-L1)
Vol. 42 No. 2 February 2017 P&T
111
 New Pharmacotherapies in Chronic Lymphocytic Leukemia
found on malignant cells and the PD-1 found on CD4+ and CD8+
T cells, thereby increasing T-cell cytotoxicity and enhancing
immune system function.60
Existing data suggest a potential role for lenalidomide in the
management of CLL. Trials to date have demonstrated an ORR
of 56% and 58% when lenalidomide is given as monotherapy at
1025 mg orally daily on days 121 of a 28-day schedule in both
the untreated and relapsed/refractory settings.64,65 Toxicities
unusual to lenalidomide but found in studies with CLL patients
include TLS and a unique tumor are. This are has been allogeneic stem cell transplantation.72
positively correlated with response rates in clinical trials and
is characterized by symptoms associated with immune-system
activation, specically increased B-cell antigen presentation.
These symptoms include acute lymphadenopathy with inam-
mation in the overlying skin, fever, and rash.66 Titrating CLL
patients from lower doses (510 mg daily) by 5 mg every
28 days to 25 mg daily may provide noninferior response rates
and reduce the incidence of the are reaction.66
Although combinations of lenalidomide with traditional
chemotherapy agents were found to be prohibitively toxic,
lenalidomide has been combined with anti-CD20 monoclonal
antibodies to provide synergy and added efcacy without
excessive toxicities.67,68 Addition of rituximab to lenalidomide
is associated with ORR approaching 83% in the rst-line setting
and 61% in the relapsed/refractory setting, with or without the
presence of poor prognostic features.69,70 Lenalidomide has
been included in the National Comprehensive Cancer Network
guidelines as a treatment option both alone and in combination
with rituximab in the relapsed/refractory setting, regardless
of mutation status.4 However, it is still not recommended in
the rst-line setting, nor has the FDA granted approval for
lenalidomide use in CLL. The combination of lenalidomide and
the second-generation anti-CD20 monoclonal ofatumumab may
provide even better results, with phase 2 data suggesting an
ORR of 71% with 24% CR in the relapsed/refractory setting.71
Further studies with anti-CD20 monoclonal antibodies are in
development and should help elucidate the role of lenalido-
mide in CLL.
CAR T-Cell Therapy
Antineoplastic treatment strategies that harness the immune
system have become the mainstay of cancer research today.
In particular, therapies meant to amplify T cells in the adaptive
immune system have been shown to provide durable treatment
outcomes in a wide range of malignancies. Chimeric antigen
receptor (CAR) technology involves the genetic reprogram-
ming of a patients own T cells to recognize and target specic
surface antigens, thereby increasing their specicity toward
particular malignant clones. This emerging therapeutic option
has been studied thus far in the management of B-cell malignan-
cies including non-Hodgkins lymphoma, acute lymphoblastic
leukemia, and CLL. However, a major limitation exists with
regard to CAR technology use in CLL given the well-known
dysfunctional or exhausted state of T cells in patients with
this malignancy.59 For CAR T-cell development, T-cell lympho-
cytes are collected through leukapheresis, transduced with
a chimeric T-cell receptor/immunoglobulin transgene, and
expanded using CD3 and CD28 T-cellactivating antibodies.72
Once the desired CAR T dose is attained, quality control and
112 P&T February 2017 Vol. 42 No. 2
assurance assays are conducted on the product prior to release
for clinical use. After approximately 1014 days, these cells
are ready to be transfused back into the patient following a
round of preparatory lymphosuppressive chemotherapy. Once
infused, they work to destroy malignant cells expressing the
antigen targeted by the CAR, with the lymphosuppression
being needed to make room for these targeted cells to mul-
tiply. This autologous T-cell procedure can provide targeted
antitumor activity without the morbidities associated with
Data from 29 patients who received CAR T cells targeted to
the CD19 (B lymphocyte) receptor for CLL have been published
in the literature through small clinical trials.7376 The results
have shown promise for second-generation CD19 CAR T cells
in the relapsed/refractory setting, with both durable complete
remissions and ORRs ranging from 38% to 86%. However,
much variability exists between them in both the use and type
of conditioning regimen and the dose of CD19 CAR T cells
infused. Patients received conditioning regimens composed
of cyclophosphamide with or without pentostatin/udarabine
and CD19 CAR T-cell doses of 0.4 to 3 x 107 cells/kg.7376
Optimization of these parameters is needed to establish the
clinical benet that this therapeutic option may provide.
The largest and most recently documented study to be com-
pleted is a phase 1 trial that demonstrated a 57% ORR among
14 patients with relapsed/refractory CLL.76 Lymphodepleting
preparatory regimens consisted of cyclophosphamide plus
either udarabine (n = 3), pentostatin (n = 5), or bendamus-
tine (n = 6). Doses of CD19 CAR T cells infused ranged from
0.14 x 108 to 11 x 108 (median, 1.6 x 108). Four patients achieved
a CR and four achieved a PR. The CD19 CAR T cells persisted
for four years in the rst two patients who achieved CR. No
patients who achieved a CR had progressed or shown evidence
of minimal residual disease, suggesting this treatment may
be a possible cure for CLL. All patients achieving a response
experienced cytokine release syndrome, which was correlat-
ing both with T-cell expansion in vivo and clinical response.
CD19 CAR T-cell infusions were well tolerated, with only mild
infusion-related, low-grade fevers and chills noted. Two patients
developed TLS.76
Other Agents
Outside of the emerging therapies previously discussed,
many other pharmacotherapeutic mechanisms are being
researched for the management of CLL. Phase 2 studies are
under way for novel antibodies targeting the B-cell lineage-
specic CD37 (NCT02538614) and CD19 (NCT01466153,
NCT02005289) surface antigens.7779 In addition, checkpoint
inhibitors, specically those that target PD-1 and PD-L1, are
being researched as part of combination regimens in both the
untreated and relapsed/refractory settings. However, given
the dysfunctional T-cell state found in CLL, the malignancy is
relatively resistant to PD-1 inhibition alone, and development of
the agents as monotherapy is unlikely to occur.59,62,63 Preclinical
data suggest PD-1 inhibitors act in a synergistic manner with
BTK inhibitors,80 and a phase 2 study of combination therapy
with nivolumab (Opdivo, Bristol-Myers Squibb) and ibrutinib
is ongoing in patients with relapsed/refractory or high-risk
untreated CLL (NCT02420912).81
 New Pharmacotherapies in Chronic Lymphocytic Leukemia
ECONOMIC CONSIDERATIONS
Given that CLL is the most common leukemia in the United
States and primarily affects older individuals, most treatment
costs are borne by Medicare. Average wholesale prices per
unit of the newer treatments appear in Table 2. The economic
burden for CLL has to be considered in the context that patients
may require multiple lines of therapy and possibly HSCT. The
cost of ibrutinib at standard dose could be expected to be
higher than $100,000 per year, which can exceed the cost of
some HSCT scenarios.52 A systematic review of the literature
identifying costs in CLL reported annual direct costs per person
of $43,913 in the United States, with 26.2% to 79% potentially
attributable to drug therapy.82 In comparison, the median
100-day total cost for an allogeneic SCT was estimated at
$203,026.83 However, if patients receive multiple lines of drug
therapy, the potential estimated costs are in the millions of
dollars.84 While intravenous therapies are covered by Medicare
Part B, the newer oral agents will be covered by Medicare
Part D, which will shift more cost burden to patients.84 The
shift of cost responsibility to the patient may impact adherence,
which may in turn, affect the degree of response to therapy.84
CONCLUSION
New therapeutic advances have changed the treatment land-
scape for patients with CLL. New biological therapies, including
ofatumumab and obinutuzumab, and small-molecule inhibitors,
including ibrutinib, idelalisib, and venetoclax, provide innova-
tive mechanisms in both the rst-line and relapsed/refractory
treatment settings. Some of these therapies have demonstrated
activity against highly resistant, harder-to-treat CLL and offer
alternatives or additions to HSCT. Key emerging therapies,
including strategies that target the immune system, have
shown some great potential. The cost of treatment, especially
when multiple lines may be needed, will greatly inuence
management and must be considered in treatment decisions,
both from an individual patient and a societal perspective.
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FDA Flags Reporting of Device Problems
continued from page 99
permit because of the risk of patient harm or because it is not
feasible, e.g., CDRH cannot reach all manufacturers.
The FDA can issue all the guidance documents in the world,
and they can all be clear as a bell, but device reporting will still
be sketchy because there is no penalty for failing to submit a
report. Moreover, even if all reports that should be submitted
were submitted, the data, especially from hospitals, would
still be lacking. The EHR software developed by companies
such as Cerner and Epic and certied by the HHS Ofce of
the National Coordinator for Health Information Technology
does not allow for the hospital to code for the UDI. I see that
as a missed opportunity, states Chantal Worzala, MPA, Vice
President for Health Information and Policy Operations at the
American Hospital Association in Chicago, Illinois.
That shortcoming may be xed in the next few years. But
the ability to track devices via UDIs will be costly for hospitals
to implement, and it is hard to see the FDA forcing them to
spend the money.
REFERENCES
1. Shuren J. FDA is working with hospitals to modernize data
collection about medical devices. FDA Voice blog. October 24, 2016.
Available at: http://blogs.fda.gov/fdavoice/index.php/2016/10/
fda-is-working-with-hospitals-to-modernize-data-collection-about-
medical-devices. Accessed December 29, 2016.
2. Food and Drug Administration. Public notication of emerging
postmarket medical device signals (emerging signals): guidance
for industry and Food and Drug Administration staff. December
14, 2016. Available at: www.fda.gov/downloads/medicaldevices/
deviceregulationandguidance/guidancedocuments/ucm479248.
pdf. Accessed December 29, 2016.
3. Food and Drug Administration. Medical device reporting for
manufacturers: guidance for industry and Food and Drug
Administration staff. November 8, 2016. Available at: www.fda.
gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/docu-
ments/document/ucm359566.pdf. Accessed December 29, 2016.
4. Food and Drug Administration. Strengthening our national system
for medical device postmarket surveillance. September 2012.
Available at: www.fda.gov/downloads/AboutFDA/Center-
sOfces/CDRH/CDRHReports/UCM301924.pdf. Accessed
December 29, 2016.
5. Sentinel Coordinating Center. Background. Available at:
www.sentinelinitiative.org/background. Accessed December
29, 2016.
6. Food and Drug Administration. Use of real-world evidence to
support regulatory decision-making for medical devices: draft
guidance for industry and Food and Drug Administration staff.
September 16, 2016. Available at: www.fda.gov/ucm/groups/
fdagov-public/@fdagov-meddev-gen/documents/document/
ucm513027.pdf. Accessed January 3, 2017. Q
Vol. 42 No. 2 February 2017 P&T
115
 NOW FDA APPROVED!

PREFILLED
SYRINGE
0.5 mg
LUCENTIS 0.5 mg has been studied in 6 clinical
trials* and is now available in a prelled syringe.1-7
Single-use syringe designed for the treatment
of a single eye.

INDICATION
LUCENTIS (ranibizumab injection) 0.5 mg is
indicated for the treatment of patients with:
Neovascular (wet) age-related macular
degeneration (wAMD)
Macular edema following retinal vein
occlusion (RVO)
IMPORTANT SAFETY INFORMATION
LUCENTIS is contraindicated in patients
with ocular or periocular infections or
hypersensitivity to ranibizumab or
any of the excipients in LUCENTIS.
WARNINGS AND PRECAUTIONS
Intravitreal injections, including those
with LUCENTIS, have been associated
with endophthalmitis, retinal detachment,
and iatrogenic traumatic cataract. Proper
aseptic injection technique should always
be utilized when administering LUCENTIS.
Patients should be monitored during the
week following the injection to permit early
treatment, should an infection occur.
Increases in intraocular pressure (IOP) have
been noted both pre-injection and post-
injection (at 60 minutes) with LUCENTIS. IOP
and perfusion of the optic nerve head should
be monitored and managed appropriately.
Although there was a low rate of arterial
thromboembolic events (ATEs) observed
in the LUCENTIS clinical trials, there is a
potential risk of ATEs following intravitreal
use of VEGF inhibitors. ATEs are dened
as nonfatal stroke, nonfatal myocardial
infarction, or vascular death (including
deaths of unknown cause).
Fatal events occurred more frequently in
patients with DME and DR at baseline treated
monthly with LUCENTIS compared with
control. Although the rate of fatal events
was low and included causes of death
typical of patients with advanced diabetic
complications, a potential relationship
between these events and intravitreal use
of VEGF inhibitors cannot be excluded.
ADVERSE EVENTS
Serious adverse events related to the
injection procedure that occurred in
<0.1% of intravitreal injections included
endophthalmitis, rhegmatogenous retinal
detachment, and iatrogenic traumatic
cataract.
In the LUCENTIS Phase III clinical trials, the
most common ocular side effects included
conjunctival hemorrhage, eye pain, vitreous
oaters, and increased intraocular pressure.
The most common non-ocular side effects
included nasopharyngitis, headache,
inuenza, sinusitis, cough, and nausea.
Please see Brief Summary of LUCENTIS full
prescribing information on adjacent page.
*The following randomized, double-masked
pivotal trials were conducted for the 2 LUCENTIS
indications: wAMD: MARINAPhase III, multicenter,
2-year, sham injectioncontrolled study; primary
end point at 1 year. ANCHORPhase III, multicenter,
2-year, active treatmentcontrolled study; primary
end point at 1 year. PIERPhase IIIb, 2-year, sham
injectioncontrolled study; primary end point at
1 year. HARBORPhase III, multicenter, 2-year,
active treatmentcontrolled dose-response study;
primary end point at 1 year. RVO: BRAVOPhase III,
multicenter, 1-year, sham injectioncontrolled study;
primary end point at 6 months. CRUISEPhase III,
multicenter, 1-year, sham injectioncontrolled study;
primary end point at 6 months.1-7
References: 1. Rosenfeld PJ, et al; MARINA Study
Group. N Engl J Med. 2006;355:1419-1431. 2. Brown
DM, et al; ANCHOR Study Group. Ophthalmology.
2009;116:57-65. 3. Regillo CD, et al; PIER Study Group.
Am J Ophthalmol. 2008;145:239-248. 4. Busbee
BG, et al; HARBOR Study Group. Ophthalmology.
2013;120:1046-1056. 5. Campochiaro PA, et al;
BRAVO Investigators. Ophthalmology. 2010;117:1102-
1112. 6. Brown DM, et al; CRUISE Investigators.
Ophthalmology. 2010;117:1124-1133. 7. LUCENTIS
[package insert]. South San Francisco, CA:
Genentech, Inc; January 2017.
2017 Genentech, Inc. South San Francisco, CA
LUC/120616/0149 1/17

Brief summaryplease see the LUCENTIS package
insert for full prescribing information.
1 INDICATIONS AND USAGE
LUCENTIS is indicated for the treatment of patients with:
1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD)
1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
1.3 Diabetic Macular Edema (DME)
1.4 Diabetic Retinopathy (Non Proliferative Diabetic Retinopathy (NPDR),
Proliferative Diabetic Retinopathy (PDR)) in patients with Diabetic Macular
Edema (DME)
1.5 Myopic Choroidal Neovascularization (mCNV)
6.2 Clinical Studies Experience
Because clinical trials are conducted under widely varying conditions, adverse
reaction rates observed in one clinical trial of a drug cannot be directly
compared with rates in the clinical trials of the same or another drug and may
not reflect the rates observed in practice.
The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with
neovascular AMD in Studies AMD-1, AMD-2, and AMD-3; in 259 patients
with macular edema following RVO. The data also reflect exposure to 0.3 mg
LUCENTIS in 250 patients with DME and DR at baseline [see Clinical Studies (14
in the full prescribing information)].
Safety data observed in Study AMD-4 and in 224 patients with mCNV were
consistent with these results. On average, the rates and types of adverse
reactions in patients were not significantly affected by dosing regimen.
Ocular Reactions
Table 1 shows frequently reported ocular adverse reactions in LUCENTIS-
treated patients compared with the control group.
Table 1 Ocular Reactions in the DME and DR, AMD, and RVO Studies
DME and DR AMD AMD
2-year 2-year 1-year
6.3 Immunogenicity
As with all therapeutic proteins, there is the potential for an immune response
in patients treated with LUCENTIS. The immunogenicity data reflect the
percentage of patients whose test results were considered positive for
antibodies to LUCENTIS in immunoassays and are highly dependent on the
sensitivity and specificity of the assays.
The pre-treatment incidence of immunoreactivity to LUCENTIS was 0%-5%
across treatment groups. After monthly dosing with LUCENTIS for 6 to 24
months, antibodies to LUCENTIS were detected in approximately 1%-9% of
patients.
The clinical significance of immunoreactivity to LUCENTIS is unclear at this time.
Among neovascular AMD patients with the highest levels of immunoreactivity,
some were noted to have iritis or vitritis. Intraocular inflammation was not
observed in patients with DME and DR at baseline, or RVO patients with the
highest levels of immunoreactivity.
6.4 Postmarketing Experience
The following adverse reaction has been identified during post-approval use
of LUCENTIS. Because this reaction was reported voluntarily from a population
RVO of uncertain size, it is not always possible to reliably estimate the frequency or
6-month establish a causal relationship to drug exposure.
Ocular: Tear of retinal pigment epithelium among patients with

LUCENTIS

LUCENTIS

LUCENTIS

LUCENTIS
neovascular AMD

0.3 mg

0.5 mg

0.5 mg

0.5 mg
Control

Control

Control

Control
4 CONTRAINDICATIONS
7 DRUG INTERACTIONS
4.1 Ocular or Periocular Infections Drug interaction studies have not been conducted with LUCENTIS.
LUCENTIS is contraindicated in patients with ocular or periocular infections.
Adverse Reaction n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 LUCENTIS intravitreal injection has been used adjunctively with verteporfin
4.2 Hypersensitivity photodynamic therapy (PDT). Twelve (12) of 105 (11%) patients with
LUCENTIS is contraindicated in patients with known hypersensitivity to Conjunctival
hemorrhage 47% 32% 74% 60% 64% 50% 48% 37% neovascular AMD developed serious intraocular inflammation; in 10 of the 12
ranibizumab or any of the excipients in LUCENTIS. Hypersensitivity reactions patients, this occurred when LUCENTIS was administered 7 days ( 2 days)
may manifest as severe intraocular inflammation. Eye pain 17% 13% 35% 30% 26% 20% 17% 12% after verteporfin PDT.
5 WARNINGS AND PRECAUTIONS Vitreous floaters 10% 4% 27% 8% 19% 5% 7% 2% 8 USE IN SPECIFIC POPULATIONS
5.1 Endophthalmitis and Retinal Detachments Intraocular 8.1 Pregnancy
Intravitreal injections, including those with LUCENTIS, have been associated pressure increased 18% 7% 24% 7% 17% 5% 7% 2% Risk Summary
with endophthalmitis and retinal detachments. Proper aseptic injection Vitreous There are no adequate and well-controlled studies of LUCENTIS administration
technique should always be used when administering LUCENTIS. In addition, detachment 11% 15% 21% 19% 15% 15% 4% 2% in pregnant women.
patients should be monitored following the injection to permit early treatment
should an infection occur [see Dosage and Administration (2., 2.) in the full Intraocular Administration of ranibizumab to pregnant monkeys throughout the period
prescribing information and Patient Counseling Information (17)]. inflammation 4% 3% 18% 8% 13% 7% 1% 3% of organogenesis resulted in a low incidence of skeletal abnormalities at
Cataract 28% 32% 17% 14% 11% 9% 2% 2% intravitreal doses 13-times the predicted human exposure (based on maximal
5.2 Increases in Intraocular Pressure serum trough levels [Cmax]) after a single eye treatment at the recommended
Increases in intraocular pressure have been noted both pre-injection and post- Foreign body clinical dose. No skeletal abnormalities were observed at serum trough levels
injection (at 60 minutes) while being treated with LUCENTIS. Monitor intraocular sensation in eyes 10% 5% 16% 14% 13% 10% 7% 5% equivalent to the predicted human exposure after a single eye treatment at the
pressure prior to and following intravitreal injection with LUCENTIS and manage Eye irritation 8% 5% 15% 15% 13% 12% 7% 6% recommended clinical dose [see Animal Data].
appropriately [see Dosage and Administration (2. in the full prescribing
information)]. Lacrimation Animal reproduction studies are not always predictive of human response,
increased 5% 4% 14% 12% 8% 8% 2% 3% and it is not known whether ranibizumab can cause fetal harm when
5.3 Thromboembolic Events administered to a pregnant woman. Based on the anti-VEGF mechanism of
Although there was a low rate of arterial thromboembolic events (ATEs) Blepharitis 3% 2% 12% 8% 8% 5% 0% 1%
action for ranibizumab [see Clinical Pharmacology (12.1 in the full prescribing
observed in the LUCENTIS clinical trials, there is a potential risk of ATEs Dry eye 5% 3% 12% 7% 7% 7% 3% 3% information)], treatment with LUCENTIS may pose a risk to human embryofetal
following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, Visual disturbance development.
nonfatal myocardial infarction, or vascular death (including deaths of unknown or vision blurred 8% 4% 18% 15% 13% 10% 5% 3%
cause). LUCENTIS should be given to a pregnant woman only if clearly needed.
Eye pruritus 4% 4% 12% 11% 9% 7% 1% 2% Data
Neovascular (Wet) Age-Related Macular Degeneration
The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, Ocular hyperemia 9% 9% 11% 8% 7% 4% 5% 3% Animal Data
AMD-3) during the first year was 1.9% (17 of 874) in the combined group of Retinal disorder 2% 2% 10% 7% 8% 4% 2% 1% An embryo-fetal developmental toxicity study was performed on pregnant
patients treated with 0.3 mg or 0.5 mg LUCENTIS compared with 1.1% (5 of cynomolgus monkeys. Pregnant animals received intravitreal injections of
Maculopathy 5% 7% 9% 9% 6% 6% 11% 7% ranibizumab every 14 days starting on Day 20 of gestation, until Day 62 at
441) in patients from the control arms [see Clinical Studies (14.1 in the full
prescribing information)]. In the second year of Studies AMD-1 and AMD-2, the
Retinal doses of 0, 0.125, and 1 mg/eye. Skeletal abnormalities including incomplete
ATE rate was 2.6% (19 of 721) in the combined group of LUCENTIS-treated degeneration 1% 0% 8% 6% 5% 3% 1% 0% and/or irregular ossification of bones in the skull, vertebral column, and
patients compared with 2.9% (10 of 344) in patients from the control arms. Ocular discomfort 2% 1% 7% 4% 5% 2% 2% 2% hindlimbs and shortened supernumerary ribs were seen at a low incidence
In Study AMD-4, the ATE rates observed in the 0.5 mg arms during the first in fetuses from animals treated with 1 mg/eye of ranibizumab. The 1 mg/eye
Conjunctival dose resulted in trough serum ranibizumab levels up to 13 times higher
and second year were similar to rates observed in Studies AMD-1, AMD-2, and hyperemia 1% 2% 7% 6% 5% 4% 0% 0%
AMD-3. than predicted Cmax levels with single eye treatment in humans. No skeletal
Posterior capsule abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which
In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of opacification 4% 3% 7% 4% 2% 2% 0% 1% resulted in trough exposures equivalent to single eye treatment in humans.
LUCENTIS used adjunctively with verteporfin photodynamic therapy), the stroke No effect on the weight or structure of the placenta, maternal toxicity, or
rate (including both ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in Injection site
hemorrhage 1% 0% 5% 2% 3% 1% 0% 0% embryotoxicity was observed.
patients treated with 0.5 mg LUCENTIS compared to 1.1% (5 of 435) in patients
in the control arms (odds ratio 2.2 (95% confidence interval (0.8-7.1))). 8.2 Lactation
Non-Ocular Reactions Risk Summary
Macular Edema Following Retinal Vein Occlusion Non-ocular adverse reactions with an incidence of 5% in patients receiving There are no data available on the presence of ranibizumab in human milk, the
The ATE rate in the two controlled RVO studies during the first 6 months was LUCENTIS for DR, DME, AMD, and/or RVO and which occurred at a 1% higher effects of ranibizumab on the breastfed infant or the effects of ranibizumab on
0.8% in both the LUCENTIS and control arms of the studies (4 of 525 in the frequency in patients treated with LUCENTIS compared to control are shown milk production/excretion.
combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS and 2 in Table 2. Though less common, wound healing complications were also
of 260 in the control arms) [see Clinical Studies (14.2 in the full prescribing Because many drugs are excreted in human milk, and because the potential for
observed in some studies. absorption and harm to infant growth and development exists, caution should
information)]. The stroke rate was 0.2% (1 of 525) in the combined group of
LUCENTIS-treated patients compared to 0.4% (1 of 260) in the control arms. Table 2 Non-Ocular Reactions in the DME and DR, AMD, and RVO Studies be exercised when LUCENTIS is administered to a nursing woman.
Diabetic Macular Edema and Diabetic Retinopathy The developmental and health benefits of breastfeeding should be considered
DME and DR AMD AMD RVO
Safety data are derived from studies D-1 and D-2. All enrolled patients had along with the mothers clinical need for LUCENTIS and any potential adverse
2-year 2-year 1-year 6-month
DME and DR at baseline [see Clinical Studies (14.3, 14.4 in the full prescribing effects on the breastfed child from ranibizumab.
LUCENTIS

LUCENTIS

LUCENTIS

LUCENTIS

information)]. 8.3 Females and Males of Reproductive Potential

0.3 mg

0.5 mg

0.5 mg

0.5 mg
Control

Control

Control

Control

In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3 in the Infertility
full prescribing information)], the ATE rate at 2 years was 7.2% (18 of 250) with No studies on the effects of ranibizumab on fertility have been conducted. and it
0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg LUCENTIS, and 5.2% (13 of is not known whether ranibizumab can affect reproduction capacity. Based on
Adverse Reaction n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 the anti-VEGF mechanism of action for ranibizumab, treatment with LUCENTIS
250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg

LUCENTIS, 1.2% (3 of 250) with 0.3 mg LUCENTIS, and 1.6% (4 of 250) with Nasopharyngitis 12% 6% 16% 13% 8% 9% 5% 4% may pose a risk to reproductive capacity.
control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg LUCENTIS Anemia 11% 10% 8% 7% 4% 3% 1% 1% 8.4 Pediatric Use
and 10.8% (27 of 250) with 0.3 mg LUCENTIS; the stroke rate was 4.8% (12 Nausea 10% 9% 9% 6% 5% 5% 1% 2% The safety and effectiveness of LUCENTIS in pediatric patients have not been
of 249) with 0.5 mg LUCENTIS and 2.0% (5 of 250) with 0.3 mg LUCENTIS. established.
Cough 9% 4% 9% 8% 5% 4% 1% 2%
5.4 Fatal Events in Patients with DME and DR at baseline 8.5 Geriatric Use
Diabetic Macular Edema and Diabetic Retinopathy Constipation 8% 4% 5% 7% 3% 4% 0% 1% In the clinical studies, approximately 76% (2449 of 3227) of patients randomized
Safety data are derived from studies D-1 and D-2. All enrolled patients had Seasonal allergy 8% 4% 4% 4% 2% 2% 0% 2% to treatment with LUCENTIS were 65 years of age and approximately 51%
DME and DR at baseline [see Clinical Studies (14.3, 14.4 in the full prescribing Hypercholesterolemia 7% 5% 5% 5% 3% 2% 1% 1% (1644 of 3227) were 75 years of age [see Clinical Studies (14 in the full
information)]. prescribing information)]. No notable differences in efficacy or safety were seen
Influenza 7% 3% 7% 5% 3% 2% 3% 2% with increasing age in these studies. Age did not have a significant effect on
A pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3 in the full
prescribing information)], showed that fatalities in the first 2 years occurred in Renal failure 7% 6% 1% 1% 0% 0% 0% 0% systemic exposure.
4.4% (11 of 250) of patients treated with 0.5 mg LUCENTIS, in 2.8% (7 of 250) Upper respiratory 10 OVERDOSAGE
of patients treated with 0.3 mg LUCENTIS, and in 1.2% (3 of 250) of control tract infection 7% 7% 9% 8% 5% 5% 2% 2% More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been
patients. Over 3 years, fatalities occurred in 6.4% (16 of 249) of patients treated Gastroesophageal administered to patients. No additional unexpected adverse reactions were
with 0.5 mg LUCENTIS and in 4.4% (11 of 250) of patients treated with 0.3 reflux disease 6% 4% 4% 6% 3% 4% 1% 0% seen.
mg LUCENTIS. Although the rate of fatal events was low and included causes 17 PATIENT COUNSELING INFORMATION
of death typical of patients with advanced diabetic complications, a potential Headache 6% 8% 12% 9% 6% 5% 3% 3%
Advise patients that in the days following LUCENTIS administration, patients are
relationship between these events and intravitreal use of VEGF inhibitors cannot Edema peripheral 6% 4% 3% 5% 2% 3% 0% 1% at risk of developing endophthalmitis. If the eye becomes red, sensitive to light,
be excluded. Renal failure chronic 6% 2% 0% 1% 0% 0% 0% 0% painful, or develops a change in vision, advise the patient to seek immediate
6 ADVERSE REACTIONS Neuropathy care from an ophthalmologist [see Warnings and Precautions (5.1)].
The following adverse reactions are discussed in greater detail in other sections peripheral 5% 3% 1% 1% 1% 0% 0% 0%
of the label:
Endophthalmitis and Retinal Detachments [see Warnings and Precautions Sinusitis 5% 8% 8% 7% 5% 5% 3% 2%
(5.1)] Bronchitis 4% 4% 11% 9% 6% 5% 0% 2%
Increases in Intraocular Pressure [see Warnings and Precautions (5.2)] Atrial fibrillation 3% 3% 5% 4% 2% 2% 1% 0%
Thromboembolic Events [see Warnings and Precautions (5.3)] LUCENTIS
Fatal Events in patients with DME and DR at baseline [see Warnings and Arthralgia 3% 3% 11% 9% 5% 5% 2% 1% [ranibizumab injection]
Precautions (5.4)] Chronic obstructive Manufactured by: Initial US Approval: June 2006
6.1 Injection Procedure pulmonary disease 1% 1% 6% 3% 3% 1% 0% 0% Genentech, Inc. Revision Date: LUC/021815/0050(2) 2017
Serious adverse reactions related to the injection procedure have occurred Wound healing A Member of the Roche Group LUCENTIS is a registered
in < 0.1% of intravitreal injections, including endophthalmitis [see Warnings complications 1% 0% 1% 1% 1% 0% 0% 0% 1 DNA Way trademark of Genentech, Inc.
and Precautions (5.1)], rhegmatogenous retinal detachment, and iatrogenic South San Francisco, CA 2017 Genentech, Inc.
traumatic cataract. 94080-4990
 Experts Provide a Glimpse of the New
Post-SPRINT Era of Hypertension
Susan L. Worley
New guidelines for the management and treatment of hyper-
tension, one of the leading causes of death and disability
throughout the world,1 are scheduled to be released in 2017
by several internationally recognized organizations. In the
U.S., these guidelines, jointly prepared for the rst time by
the American College of Cardiology and the American Heart
Association (AHA), will serve as an update to the hypertension
management guidelines prepared by the Eighth Joint National
Committee (JNC 8) and published in 2014.2
Findings from several recent clinical trials
and analysesmost notably from the Systolic
Blood Pressure Intervention Trial (SPRINT)3
are expected to form the basis of these new
guidelines, which should feature new hyper-
tension treatment targets and new approaches
to the treatment of the elderly, among other
recommendations.
For the rst time in decades, the primary
focus in the eld has moved from pharma-
ceuticals to the meticulous analysis and inter-
pretation of cumulative research data and the
translation of key ndings to best clinical prac-
Raymond R. Townsend, MD
tices and directions for public health policy.4
While antihypertensive drug therapy has evolved to such a
degree that a range of relatively inexpensive and well-tolerated
medications (Table 1)3 can be used alone or in combination
to provide satisfactory control of hypertension in a majority of
individuals requiring treatment,5 questions surrounding the
intricacies of hypertension management remain. The herculean
task of sifting through available data for clinical pearlsinclud-
ing optimal ways to achieve more intensive treatment goals,
the best methods for monitoring and assessing hypertensive
patients, and the magic keys to ensuring adherence to treat-
mentswill occupy researchers long after the release of new
guidelines. Yet just one year after the publication of SPRINT
ndings, leading experts have already begun to distill informa-
tion from that landmark trial that is meaningful for clinicians
and their patients.
In Search of Treatment Targets
Sufcient evidence to suggest that a reduction in elevated
blood pressure can lead to a reduction in the incidence of
heart disease, including congestive heart failure and coronary
artery disease, as well as stroke and chronic kidney disease
(CKD), across a range of patient populations has been available
for nearly two decades. However, experts have long had dif-
culty reaching a consensus with regard to appropriate blood
pressure targets during treatment. This uncertainty can be
attributed in part to concerns about risks associated with blood
pressurelowering in some individuals and in part to a lack of
clear evidence to support intensive treatment. Inconclusive or
Susan Worley is a freelance medical writer who resides in Pennsylvania. of 50 years, those with diabetes, and those who had previously
118 P&T February 2017 Vol. 42 No. 2
unexpected clinical trials results have added to the uncertainty.
For instance, the landmark Action to Control Cardiovascular
Risk (ACCORD) trial, published in 2010, found that intensive
blood pressurelowering (to less than 120 mm Hg versus
less than 140 mm Hg) did not reduce overall cardiovascular
events among patients with type-2 diabetes, although there
was a reduction in strokes in the intensively treated group.6
Still, to those outside the eld who have long been accus-
tomed to the standard denition of hypertension
(readings of 140/90 mm Hg and higher), it
may seem puzzling that a target systolic blood
pressure (SBP) of less than 150 mm Hg, rather
than below 140 mm Hg, was recommended
by JNC 8 for people 60 years of age and older
in guidelines published less than three years
ago.2 Perhaps more puzzling is that this target
represented an increase in SBP compared with
the treatment goal of 130 mm Hg that appears
in 2003 guidelines7 for individuals with CKD
or diabetes. But Raymond R. Townsend, MD,
Director of the Hypertension Program and
Professor of Medicine at the Perelman School
of Medicine at the University of Pennsylvania,
who served as a member of the JNC 8 panel, says the recom-
mended SBP target of less than 150 mm Hg for people older
than 60 years can be explained by the panels unyielding
commitment to evidence-based medicine.
When our panel convened in 2008, our directives were to
establish guidelines based not on our professional opinions, but
rather on evidence from clinical trials, explains Dr. Townsend,
who in 2016 was named Physician of the Year by the AHA.
After extensive research, we found that there simply was no
solid evidence to support a systolic blood pressure target of
below 140.
The panel was able to conrm only that positive outcomes
in a range of clinical trials were consistently reported for
older patients whose SBP was lowered to a target of below
150 mm Hg. Panel members were not able to consider nd-
ings from SPRINT, which was launched in 2010, two years
after the panel convened.
To more clearly determine the potential benet of inten-
sive treatment, SPRINT randomly assigned 9,361 individuals
(50 years of age or older) with an SBP of 130 mm Hg or higher
and an increased risk of cardiovascular disease to intensive
treatment (SBP target of less than 120 mm Hg) or standard
treatment (SBP target of less than 140 mm Hg).3 In 2015,
the trial was stopped early after participants in the intensive
group were found to have a 25% lower risk of major cardio-
vascular events and a 27% lower relative risk of death from
any cause compared with those in the standard treatment
group. In addition, although noteworthy patient populations
were excluded from the trial (including those under the age
 Experts Provide a Glimpse of the New Post-SPRINT Era of Hypertension

Table 1 Selected Hypertension Medications*3

Class Drug Available Strengths Dose Range Per Day Daily Frequency
Diuretics Chlorthalidone 25mg 12.525 mg 1
Furosemide 20mg, 40mg, 80mg 2080 mg 2
Spironolactone 25mg 2550 mg 1
Triamterene/ 75/50mg 37.5/25 mg75/50 mg 1
hydrochlorothiazide
Amiloride 5mg 510 mg 12
Angiotensin-converting Lisinopril 5mg, 10mg, 20mg, 40mg 540 mg 1
enzyme inhibitor
Angiotensin-receptor Losartan 25mg, 50mg, 100mg 25100 mg 12
blockers Azilsartan 40mg, 80mg 4080 mg 1
Azilsartan/chlorthalidone 40/12.5mg, 40/25mg 40/12.540/25 mg 1
Calcium-channel blockers Diltiazem 120mg, 180 mg, 240 mg, 300 mg 120540 mg 1
Amlodipine 2.5mg, 5mg, 10mg 2.510 mg 1
Beta blockers Metoprolol tartrate 25mg, 50mg, 100mg 50200 mg 12
Atenolol 25mg, 50mg, 100mg 25100 mg 1
Atenolol/chlorthalidone 50/25mg 50/25 mg 1
Vasodilators Hydralazine 25mg, 50mg, 100mg 50200 mg 2
Minoxidil 2.5mg, 10mg 2.580 mg 12
Alpha2 agonist Guanfacine 1mg, 2mg 0.52 mg 1
Alpha blocker Doxazosin 1mg, 2mg, 4mg, 8mg 116 mg 1
Potassium supplements Potassium chloride tablets 20 mEq 2080 mEq 12
Potassium chloride oral solution 20 mEq/15 mL 2080 mEq 12
(10%)
* This list of medicationsthe primary formulary for the SPRINT trialincludes all major classes of antihypertensive agents. Other medications are available for this
disease.

had a stroke), consistent benets were seen across six different
subgroups when participants were treated to a lower target
SBP. Consequently, most experts agree that SPRINT will be
practice-changing, although it may take time to extract and
rene its most important clinical implications.
The Impact of SPRINT on Clinical Practice
At rst glance it appears that the results of SPRINT have
direct implications for people 50 years of age and older with
an SBP of at least 130 mm Hg while taking up to three anti-
hypertensive medications (patients with an SBP higher than
160 mm Hg while taking three or more medications were not
included in the trial). However, the process of generalizing
ndings from a selective patient population in a large trial and
applying them to patients commonly seen in clinical practice8
is challenging for a number of reasons, Dr. Townsend notes.
One of several important factors to consider is that patients
enrolled in a clinical trial tend to be more motivated than
patients that we typically see in clinical practice, Dr. Townsend
says. The patients enrolled in SPRINT tended to take their
medicines and tended to show up for their visits. They regu-
larly provided their urine samples, and so forth. In clinical
practice, about a quarter of the time patients dont really take
their medicines, or take them inconsistently, or they are less
careful about reporting their habits.
The relatively ample time and resources available to inves-
tigators and patients in a large trial likewise do not reect the
circumstances under which patients are typically monitored
during ofce visits and therefore can generate results that are
out of reach in clinical practice.
Patients enrolled in SPRINT often would spend an hour or
more per visit receiving attention and care, and asking ques-
tions, Dr. Townsend says. They also received free medication,
periodically would undergo free EKGs [electrocardiograms],
and always were carefully attended to by a group of nurses and
coordinators. In contrast, when a patient visits a busy ofce for
a standard blood pressure check, the patient is usually lucky
to spend 15 minutes with the doctor.
Perhaps most important, patients in a standard clinical
practice are unlikely to experience the results achieved in the
intensive treatment arm of SPRINT unless they actually meet
the trials inclusion and exclusion criteria.
Patients whose systolic blood pressure can be lowered to
less than 120 mm Hg with three or fewer medications are not
the kind of patients we typically see at a hypertension center.
Primary care physicians might encounter these patients, but

Vol. 42 No. 2 February 2017 P&T 119

 Experts Provide a Glimpse of the New Post-SPRINT Era of Hypertension
I am more likely to have patients referred to me when their
blood pressure cannot be adequately controlled on four or more
medications. Very recently a patient was referred to me with
a blood pressure of 180/110 while taking seven medications.
That patient, of course, would not have qualied for SPRINT,
Dr. Townsend says.
The method by which blood pressure was measured in
the trial also may have led to results that would be difcult
to duplicate in clinical practice. To eliminate confounding
circumstances associated with ofce-based blood pressure
measurementparticularly elevated readings that can occur
in the presence of an observer (known as white coat hyper-
tension)9an automated approach called automated ofce
blood pressure (AOBP)10,11 was used in SPRINT.
SPRINT investigators were able to obtain much more
accurate blood pressure readings, which on average were
likely 7 to 10 mm Hg lower than they would have been had
those readings been obtained in an ofce with a standard
sphygmomanometer, Dr. Townsend says. That limits the
generalizability of the trials ndings as things stand right
nowthat is, until we have a cultural paradigm shift in terms
of how we measure blood pressure in U.S. clinical practices.
Meanwhile, Dr. Townsend and other hypertension experts
anticipate that 2017 guidelines will account for the difference
between the automated readings obtained in SPRINT and
standard readings, most likely by recommending an SBP
treatment target of below 130 mm Hg. If more patients can be
encouraged to obtain semiautomated readings at home, which
may lead to more accurate and consistent readings than those
traditionally obtained with a sphygmomanometer,12 future
guidelines may eventually recommend SBP targets closer to
120 mm Hg. However, patients currently face an important
barrier to regular home monitoring.
Home blood pressure monitors, as valuable as they are,
are currently not covered by many health insurance policies,
Dr. Townsend says. Yet insurance will cover the cost of a
glucose monitor for patients who need oneeven though when
it comes to outcomes, there are far more data supporting the
value of lowering blood pressure compared with the value of
lowering blood sugar.
Ideally, home blood pressure monitoring should be used
to conrm high readings obtained during in-ofce screening
and to track a patients response to treatment. It also may be
used to conrm the presence of a white coat effect, when home
readings are lower, although whether minor differences due
to this effect can be considered an important risk factor for
sustained hypertension and related target organ damage is
still a matter of debate.9
However, Dr. Townsend says, when a patient has a reading
of 160/110 in the ofce and readings of 110/70 at home, that
patients likelihood of developing real hypertension, both at
home and in the ofce, will be greaterin part because of his
or her tendency to signicantly overshoot normal regulatory
mechanisms while in a medical environment. That tendency
will eventually lead to an accumulation of microfractures and
other types of damage to blood vessels that will increase the
probability of eventual target organ damage.
Like many hypertension experts in the U.S., Dr. Townsend
does not rank the development of new antihypertensive
120 P&T February 2017 Vol. 42 No. 2
medications among the most important unmet needs in his eld.
Instead, he would prefer to see the development of a foolproof
method for ensuring that patients take their medications.
We know that the drugs we are currently using work. They
provide benet to the people who take them. So its essential
that we develop new methods or strategies, perhaps using
mobile technologies, for encouraging adherence. Finding ways
to foster greater persistencethat is, strategies for ensuring
that people continue to take their medications after they already
have responded to treatmentalso is critical.
Shaping Public Policy
Findings from SPRINT already have begun to inuence
not only clinical practice but also research and health care
policy throughout the U.S. and around the world.4 Not long
before the trials ndings were published, the World Health
Organization (WHO) formally recognized hypertension as the
rst noncommunicable disease to rank among primary global
causes of major illness and premature mortality.13 At roughly
the same time, the World Hypertension League (WHL) for-
mally designated the U.S. Journal of Clinical Hypertension as
the primary forum for its policy statements and position papers
regarding the management of hypertensiona partnership
that should help coordinate global efforts to optimize the care
of hypertensive individuals and accelerate the standardization
of information reporting.
In a eld that attaches such importance to even minor
changes in millimeters of mercury, the standardization of
blood pressure measurement is particularly importantan
issue that was underscored by ndings from SPRINT. Yet
for many decades, says Michael A. Weber, MD, Professor of
Medicine at SUNY Downstate College of Medicine in New
York and Editor-in-Chief of the Journal of Clinical Hypertension,
there were few if any discussions about the best method for
measuring blood pressure.
Until about 10 years ago, Dr. Weber says, everyone knew,
or thought they knew, that using the standard sphygmoma-
nometer with a mercury column and listening with a stetho-
scope to the sounds over the brachial artery in the upper arm
represented the gold standard of blood pressure measure-
ment. Now that method has come under question for several
important reasons.
The high degree of inter- and intraobserver variability in read-
ings that rely so strongly on human performance, particularly
hearing, is a primary concern shared by experts in the eld,
says Dr. Weber, who also serves on the executive committee for
the International Society of Hypertension (ISH) and the board
of directors for the Center for Medicine in the Public Interest.
The potential for inaccuracies caused by simple carelessness
or bias also have been a concern. A growing uneasiness with
this standard method of measurement has inspired experts to
take a closer look at relatively inexpensive automated devices,
which have been available in drug stores and department
stores for more than a decade. Testing in recent years has
shown that compared with traditional measurement by
sphygmomanometer these devices are more reliable and
consistent.14
A few years ago, Dr. Weber says, my ofce switched to
using only automated devices, which we have found to be more
 Experts Provide a Glimpse of the New Post-SPRINT Era of Hypertension
accurate and free from bias. Another benet of this method
is that our patients can use the same devices at home that we
are using in the ofce.
The process of validating semiautomated and automated
methods of measuring blood pressure involves a comparison
of readings from these devices with direct measurements of
arterial pressure obtained from patients undergoing cardiac
catheterization. The latter procedure, which measures blood
pressure in the aorta (central blood pressure) rather than in
the arm, represents what many experts believe is the true gold
standard of blood pressure measurement. However, because
the invasive use of a catheter is not practical for regular use,
noninvasive methods for obtaining central blood pressure are
under investigation. Pulse-wave velocity, a noninvasive measure
of arterial stiffness that has been shown to be predictive of
coronary disease and its severity,15 is being used increasingly in
clinical trials and may eventually nd a place in clinical practice. in at least 80% of all individuals who require treatment, with
Ambulatory blood pressure measurement (ABPM) by non-
invasive methodsa technique that Dr. Weber and his col-
leagues, among others, helped pioneer in the late 1970shas
long been used for home monitoring and still is recommended
by the U.S. Preventive Services Task Force as a
routine method for conrming the diagnosis of
hypertension.16 ABPM also remains an important
method of identifying individuals at greater risk
for adverse outcomes due to a lack of normal
drop in blood pressure during the night. In
normal healthy people, blood pressures should
fall at night by at least 10%, says Dr. Weber, but
approximately 20% to 30% of people do not have
that fall in values and may even have values that
are higher at night. Although there is broad
agreement that such nighttime patterns are
strongly predictive of stroke and cardiovascular
events, the best approach to preventing events
Michael A. Weber, MD
in this population has yet to be determined.
A growing trend toward nighttime dosing of blood pressure
medications, however, may provide at least a partial solution.
We worry most about the early morning hours after people
wake up, Dr. Weber says. Those rst few hours are the most
dangerous times of the day, when a disproportionate number
of strokes and heart attacks occur. To offer patients greater
protection during those hours, I prefer to prescribe blood pres-
sure medications at night, and a few major clinical trials have
reported very strong results and good protection for patients
with nighttime dosing of medications. When this approach is
used regularly with all patients, it may be less important to
identify patients who dont have the appropriate fall in blood
pressure at night.
Nighttime dosing, adds Dr. Weber, also may help to limit the
faintness and dizziness that some patients experience during
the rst few hours after taking their medications.
Salt and Treatment-Resistant Hypertension
Important current research that will continue to inuence public
health policy in the coming years includes studies focused on salt
intake and on approaches to treatment-resistant hypertension.
A consensus among public health scholars that a reduction
in salt intake would lead to a population-wide reduction in blood
pressure and in turn a reduction in cardiovascular events has
led the WHO to recommend a 30% reduction in dietary salt
by 2025. However, leading international entities, including the
WHO, the WHL, and the ISH, have expressed concern over
conicting and controversial ndings regarding salt intake
and have uniformly urged greater rigor in salt studies.4 Future
studies will be expected to demonstrate, among other things,
more accurate methods for quantifying salt intake in individuals,
better statistical methodology, improved techniques for 24-hour
urine collection, and better assessment of clinical endpoints.
Effective approaches to treatment-resistant hypertension are
among the greatest unmet needs in the eld, although both
the prevalence and cause of this phenomenon have been dif-
cult to discern. With the use of just three classes of currently
available antihypertensive medications, most leading hyper-
tension experts agree that it is possible to control hypertension
relatively few side effects.
Right now most of us work primarily with three types of
drugsthose that block the renin-angiotensin system, which
include the ACE [angiotensin-converting enzyme] inhibitors
and ARBs [angiotensin-receptor blockers]; the
calcium-channel blockers; and the thiazide-
like diuretics. Those are the big three, the holy
trinity of hypertension medications, and using
these it is possible to develop effective, well-
tolerated regimens for most patients. When
we do encounter individuals with so-called
treatment-resistant hypertension, most of the
time it turns out that these patients are not taking
their medications reliably, Dr. Weber says.
For some patients who are truly resistant to
these three classes of medications, Dr. Weber
adds, spironolactone17 has proven to be effec-
tive. Further research investigating treatment
combinations18 and pharamcogenomics19 may
result in effective tools for addressing true treatment-resistant
hypertension, as well as strategies for eliminating some of the
trial and error involved in selecting medications for all patients.
Early research focused on renal denervation, a procedure
involving the ablation of renal nerves, also has shown promise.20
It may turn out that this procedure is helpful in individuals
who are not responding to drugs, Dr. Weber says, or perhaps
more importantly for patients who are unable or unwilling to
take their medications reliably.
The Elderly, Women, and Groups Excluded From SPRINT
As the U.S. population continues to age, there will likely be a
growing focus on the treatment of hypertension in the elderly.
Results of the SPRINT trial have for the rst time shown that
targeting a systolic blood pressure of less than 120 mm Hg,
a normal blood pressure level, is safe and effective for prevent-
ing deaths and major cardiovascular events like heart failure
and myocardial infarctions in individuals 75 years of age and
older with hypertension.21 Earlier notable studies, such as
Hypertension in the Very Elderly (HYVET) and the Systolic
Hypertension in the Elderly Program (SHEP), which were not
designed to address questions regarding appropriate targets,
examined only the general effectiveness and tolerability of
Vol. 42 No. 2 February 2017 P&T
121
 Experts Provide a Glimpse of the New Post-SPRINT Era of Hypertension
hypertension treatment in the elderly, for whom treatment
poses some special risks.
Blood vessels in the elderly tend to be stiff, so that systolic ized to an ACE inhibitor or calcium-channel blocker. That is
blood pressure tends to be elevated, while diastolic blood
pressure actually tends to be lower than in younger people,
says Suzanne Oparil, MD, Professor of Medicine and Director
of the Vascular Biology and Hypertension Program at the
University of Alabama at Birmingham, who in 2016 received
the Excellence Award for Hypertension Research from the
AHA Council on Hypertension. Electrolyte abnormalities, or
low sodium and low potassium, also are a particular concern
in the elderly. Postural hypotension, which can lead to falls
and serious fractures, is another major concern in individuals
who are already frail and unsteady.
With targeted supplementary funding, SPRINT investigators
were able to address some of these concerns by recruiting
additional elderly participants, so that close to 30% of the result- effects of estrogen disappear as women age, she adds. It may
ing trial populationa subgroup called SPRINT seniorwere
older than 75 years of age.
The very frail elderly, such as those in assisted living or in
nursing homes, were excluded from the trial, Dr. Oparil says,
as were individuals with signs of cognitive
dysfunction or dementia. So we still lack infor-
mation about treatment in those individuals. But
SPRINT very clearly demonstrated that for the
reasonably high-functioning elderly, aggressive
treatment to targets as low as 120 mm Hg is safe
and effective, and that adverse events in this
population were comparable to those seen in
younger groups, which was quite surprising.
Consequently, many experts anticipate less
age stratication with regard to recommended
treatment targets in future hypertension
guidelines. These experts agree that follow-
up research examining further stratication of Suzanne Oparil, MD
this population by functional status, rather than
by age, would likely be of value. Currently, Dr. Oparil says, it
makes sense to avoid aggressive treatment of hypertension
in frail elderly patients who are already experiencing frequent
dizziness and falls.
Meanwhile, a component of the SPRINT trial called SPRINT-
MIND is addressing yet another important question regarding
elderly patients: the effects of intensive treatment of systolic
blood pressure on cognitive function. SPRINT-MIND investi-
gators will aim to discover whether intensive blood pressure
lowering to the 120 mm Hg target reduces cognitive decline
and the incidence of all-cause dementia.22
To date, hypertension guidelines have not offered specic
guidelines for women, even though women have several kinds
of high blood pressureincluding oral contraceptive- and
pregnancy-related hypertensionnot found in men. Likewise
SPRINT, which had a somewhat larger male population, was
not specically designed to detect gender-related differences
in response to hypertension treatment. However, recent meta-
analyses have shown that some antihypertensive medications
might be more benecial for women.
We know that thiazide diuretics more than other drug
classes are better for bone health in women, says Dr. Oparil,
coauthor of a recent analysis of ALLHAT,23 which indicated that
122 P&T February 2017 Vol. 42 No. 2
women randomized to receive chlorthalidone, a thiazide-type
diuretic, had signicantly fewer fractures than those random-
important because signicant fractures, such as hip and pelvic
fractures, require hospitalization and sometimes surgery and
can lead to life-ending complications.
Dr. Oparil adds that, compared with men, research also
has indicated that women tend to have a larger number of
adverse events while taking ACE inhibitors, such as cough
and angioedema. Future research is needed to detect other
gender-related differences and identify treatment strategies
that will offer greater protection to women. Basic science
research is also called for to further investigate the effect that
sex hormones, particularly estrogen, have on blood vessels
in women as they age.
Im particularly interested in examining why the benecial
be that there is a reduction in the number of estrogen receptors,
or it may be that with age receptor proteins are modied in
such a way that they dont signal properly. Perhaps estrogen
is metabolized differently with agewe dont yet know the
answers to these questions.
Questions also remain for a fairly wide range
of patients who were excluded from SPRINT,
including patients with diabetes, those with pre-
vious stroke, and those younger than 50 years
of age. Patients with diabetes were excluded
from SPRINT largely because of the ACCORD
trial; however, experts continue to be uncertain
about appropriate blood pressure targets in
these patients because of a number of factors
that served to confound ACCORD data.24
SPRINT excluded patients with prior stroke
largely because of the Secondary Prevention
of Small Subcortical Strokes (SP3) trial, which
examined whether an SBP target of less than
130 mm Hg would reduce recurrent stroke in patients who
had experienced recent lacunar stroke.25 Consequently, the
impact of intensive blood pressurelowering on patients with
recent stroke was left unanswered by SPRINT.
The literature clearly indicates that stroke is the outcome
that is generally most sensitive to blood pressurelowering
more so than heart attack and heart failure. And yet, largely
because of its inclusion and exclusion criteria, we didnt nd
that in SPRINT. We found that heart failure was reduced more
than any other single outcome, Dr. Oparil says.
In patients at high risk for stroke and in those with previous
stroke, further research is needed to identify best treatment
approaches and the extent to which other variables, including
the lowering of cholesterol, play a relevant role in the risk for
future stroke.
A need also exists for smaller studies that more closely
examine the effects of hypertension treatment on other high-
risk patient populations, including individuals with a wide
range of chronic diseases who were excluded from SPRINT.
Research has shown, for example, that individuals with
HIV [human immunodeciency virus infection] tend to have
accelerated vascular disease and also tend to have increased
nocturnal hypertension. We dont yet know why such
 Experts Provide a Glimpse of the New Post-SPRINT Era of Hypertension
differences exist in these patients. Are they related to choles-
terol? Or perhaps to inammation? We also dont yet know
whether these individuals will respond as well to aggressive
blood pressurelowering.
Two other important groups excluded from SPRINT, which
many hypertension experts feel have been unduly neglected in
hypertension literature, are children and young adults at high
risk for hypertension, as well as low-risk individuals of all ages.
Although the incidence of hypertension in children is increasing,
Dr. Oparil says that research designed to determine the best
treatment for these patients has yet to be conducted. A closer
examination of low-risk individuals also will be increasingly impor-
tant, in part to gain a better understanding of the mechanisms
of hypertension. Answers to all of these questions will almost
certainly require the development of new research methods.
Its unlikely that we will able to answer these questions with
other large-scale trials such as SPRINT because such trials are
prohibitively expensive, Dr. Oparil says. As we move into the
future, questions will more likely be addressed using big data-
bases, such as those drawn from electronic medical records.
The American Heart Association, for example, is using large
databases in a study designed to answer some larger questions
about cardiovascular diseasea study that will likely provide
some valuable information about hypertension.26
Observational trials, and studies that rely on telemonitoring
perhaps making use of the growing trend toward home blood
pressure monitoringwill likely play a role in study designs that
may replace traditional randomized clinical trials in the guidance
of antihypertensive treatment in the future, Dr. Oparil adds.
REFERENCES
1. Campbell NR, Khalsa T, Lackland DT, et al. High blood pres-
sure 2016: why prevention and control are urgent and impor-
tant. The World Hypertension League, International Society of
Hypertension, World Stroke Organization, International Diabetes
Foundation, International Council of Cardiovascular Prevention
and Rehabilitation, International Society of Nephrology. J Clin
Hypertens (Greenwich) 2016;18(8):714717.
2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guide-
line for the management of high blood pressure in adults: report
from the panel members appointed to the Eighth Joint National
Committee (JNC 8). JAMA 2014;311:507520.
3. The SPRINT Research Group. A randomized trial of intensive
versus standard blood-pressure control. N Engl J Med
2015;373:21032116.
4. Weber MA, Lackland DT. Contributions to hypertension public
policy and clinical practice: a review of recent reports. J Clin
Hypertens (Greenwich) 2016;18(10):10631070.
5. Chobanian AV. Time to reassess blood-pressure goals. N Engl J
Med 2015;373(22):20932095.
6. The ACCORD Study Group. Effects of intensive blood-pressure
control in type-2 diabetes mellitus. N Engl J Med 2010;362(17):
15751582.
7. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of
the Joint National Committee on prevention, detection, evaluation,
and treatment of high blood pressure: the JNC 7 Report. JAMA
2003;289:25602572.
8. Sica DA, Phillips RA, White WB, et al. Translational medicine:
transforming SPRINT ndings into clinical practice. J Am Soc
Hypertens 2016;10(5):382386.
9. Myers M, Stergiou G. White coat phenomenon: removing the
stigma of hypertension. Hypertension 2016;67(6):11111113.
10. Armstrong D, Matangi M, Brouillard D, Myers MG. Automated
ofce blood pressurebeing alone and not location is what
matters most. Blood Press Monit 2015;20(4):204208.
11. Myers MG, Kaczorowski J, Dolovich L, et al. Cardiovascular risk in
relation to achieved automated blood pressure in clinical practice.
Hypertension 2016;68(4):866872.
12. Myers MG. The great myth of ofce blood pressure measurement.
J Hypertens 2012;30(10):18941898.
13. World Health Organization. NCD Global Monitoring Framework:
ensuring progress on noncommunicable diseases in countries.
Available at: www.who.int/nmh/global_monitoring_framework/
en. Accessed January 5, 2017.
14. Ruzicka M, Akbari A, Bruketa E, et al. How accurate are home
blood pressure devices in use? A cross-sectional study. PLoS One
2016;11(6):e0155677.
15. Hofmann B, Riemer M, Erbs C, et al. Carotid to femoral pulse
wave velocity reects the extent of coronary artery disease. J Clin
Hypertens (Greenwich) 2014;16(9):629633.
16. Siu AL; U.S. Preventive Services Task Force. Screening for high
blood pressure in adults: U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med 2015;163(10):778786.
17. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus
placebo, bisoprolol, and doxazosin to determine the optimal treat-
ment for drug-resistant hypertension (PATHWAY-2): a randomised,
double-blind, crossover trial. Lancet 2015;386(10008):20592068.
18. Taddei S. Combination therapy in hypertension: what are the
best options according to clinical pharmacology principles
and controlled clinical trial evidence? Am J Cardiovasc Drugs
2015;15(3):185194.
19. Fontana V, Luizon MR, Sandrim VC. An update on the pharmaco-
genetics of treating hypertension. J Hum Hypertens 2015;29(5):
283291.
20. Mahfoud F, Brilakis N, Bhm M, et al. Long-term (3-year) safety
and effectiveness from the Global SYMPLICITY Registry of renal
denervation in a real-world patient population with uncontrolled
hypertension. J Am Coll Cardiol 2016;68(18S):B308.
21. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs.
standard blood pressure control and cardiovascular disease out-
comes in adults aged 75 years: a randomized clinical trial. JAMA
2016;315(24):26732682.
22. National Institute on Aging. Systolic blood pressure intervention
trial: memory and cognition in decreased hypertension (SPRINT-
MIND). Available at: www.nia.nih.gov/alzheimers/clinical-trials/
systolic-blood-pressure-intervention-trial-memory-and-cognition-
decreased. Accessed January 5, 2017.
23. Puttnam R, Davis BR, Pressel SL, et al. Association of three
different antihypertensive medications with hip and pelvic fracture
risk in older adults: secondary analysis of a randomized clinical
trial. JAMA Intern Med 2017;177(1):6776.
24. Brunstrm M, Carlberg B. Effect of antihypertensive treatment at
different blood pressure levels in patients with diabetes mellitus:
systematic review and meta-analyses. BMJ 2016;352:i717.
25. Benavente OR, White CL, Pearce L, et al. The Secondary
Prevention of Small Subcortical Strokes (SPS3) study. Int J Stroke
2011;6(2):164175.
26. Benjamin I, Brown N, Burke G, et al. American Heart Association
Cardiovascular Genome-Phenome Study: foundational basis and
program. Circulation 2015;131(1):100112. Q
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 Effect of Intravenous Acetaminophen on
Post-Anesthesia Care Unit Length of Stay, Opioid
Consumption, Pain, and Analgesic Drug Costs
After Ambulatory Surgery
Moteb A. Khobrani, PharmD; James M. Camamo, PharmD; and Asad E. Patanwala, PharmD
ABSTRACT
Objectives: The primary objective was to assess whether
the use of intravenous acetaminophen (APAP) in the ambula-
tory surgery setting is associated with a decreased length of
stay in the post-anesthesia care unit (PACU). The secondary
outcomes evaluated were pain scores, opioid consumption,
and total cost of analgesics used in the PACU.
Methods: This was a retrospective cohort study conducted
in adult patients (18 years of age or older) who received an eye,
ear, nose, or throat (EENT) procedure at an outpatient surgery
center between January 2014 and January 2015. Patients were
consecutively included until the desired sample was reached
during two six-month time periods: 1) intravenous APAP
available on the formulary (APAP group) and 2) intravenous
APAP not available on the formulary (non-APAP group).
Results: The cohort included 174 patients who received an
EENT procedure (87 patients in the APAP group and 87 patients
in the non-APAP group). The median PACU length of stay was
66 minutes (interquartile range [IQR], 4892) in the APAP
group and 71 minutes (IQR, 5289) in the non-APAP group
(P = 0.269). Mean pain score categories in the APAP versus
non-APAP group were mild (85% versus 53%, respectively;
P < 0.001), moderate (13% versus 33%, respectively; P = 0.002),
and severe (2% versus 14%, respectively; P = 0.005). The
median opioid consumption in morphine equivalents was 9 mg
(IQR, 513) in the APAP group and 8 mg (IQR, 512) in the
non-APAP group (P = 0.081). The total cost of analgesics used
in the PACU was signicantly greater in the APAP group
($15 versus $1; P < 0.001).
Conclusions: Intravenous APAP use in EENT ambulatory
surgery is not associated with decreased PACU length of stay.
However, it may decrease postoperative pain following EENT
procedures.
Keywords: acetaminophen, pain, ambulatory surgical
procedures, analgesics
Dr. Khobrani is a Postdoctoral Pharmacy Fellow in the Department
of Pharmacy Practice and Science at the College of Pharmacy of
the University of Arizona in Tucson, Arizona, and a Lecturer in
the Department of Pharmacy Practice and Science of the College of
Pharmacy at King Khalid University in Abha, Saudi Arabia.
Dr. Camamo is a Pharmacist in the Department of Pharmacy Services
at Banner University Medical Center in Tucson. Dr. Patanwala is
an Associate Professor in the Department of Pharmacy Practice and
Science at the College of Pharmacy of the University of Arizona in
Tucson.
INTRODUCTION
Most surgeries today are conducted in the outpatient setting.1
From 1992 to 2012, the proportion of surgeries performed at
ambulatory centers in the United States increased from 54%
to 65%.2 Historically, opioids have been the primary analge-
sics used for postoperative pain control in these patients.
However, opioids have adverse effects, such as central nervous
system and respiratory depression, which limit their use. Thus,
guidelines suggest that multimodal analgesia should be used
to minimize opioid consumption, increase effectiveness of
postoperative analgesic therapy, and decrease drug-induced
adverse effects.3 The concept of multimodal analgesia is the
simultaneous provision of different classes of analgesics with
different mechanisms to produce an additive or synergistic
analgesic effect.4 Intravenous acetaminophen (APAP) is one
treatment option for postoperative pain that can be used as part
of a multimodal treatment regimen. Intravenous APAP does
not have central nervous system or respiratory depressant
properties and may reduce postoperative opioid requirements
because of its analgesic effect. This has the potential to improve
patient recovery after surgery.
In the ambulatory surgery setting, intravenous APAP has
unique properties that make it an appealing adjunctive agent. It
is relatively safe with few adverse effects, and the intravenous
formulation as opposed to the oral formulation allows for drug
administration soon after surgery to control postoperative pain
when patients are unable to take tablets.5 Intravenous APAP
has a half-life of 2.4 hours and a dosing interval of six hours.
It is theorized that the use of a single postoperative dose of
intravenous APAP would enable earlier patient recovery, which
would facilitate an earlier discharge from the post-anesthesia
care unit (PACU).
Although previous studies have evaluated postoperative
pain control and opioid consumption, none have evaluated
the effect on earlier discharge from the PACU. In one trial,
intravenous APAP reduced opioid consumption after outpatient
sinus surgery.6 In this study, the use of rescue analgesics
(i.e., oxycodone) occurred in 71% of patients in the placebo
group and only 25% of patients in the intravenous APAP group.
However, the effect on length of stay was not evaluated. Most
other trials have been performed in patients undergoing
major surgery during hospitalization.713 In hospitalized post-
operative patients, some studies have shown that the use of
intravenous APAP decreased pain, reduced opioid consumption,
Disclosures: Dr. Patanwala has received grant funding from Mallinckrodt
Pharmaceuticals, the makers of intravenous acetaminophen. The other
authors report no commercial or nancial interests in regard to this article.
Vol. 42 No. 2 February 2017 P&T 125
Effect of IV Acetaminophen on PACU Length of Stay, Opioid Consumption, Pain, and Costs
and resulted in a faster recovery.10,11 But there is a gap in the
literature pertaining to ambulatory surgery.
Our primary objective was to assess whether intravenous
APAP use in the ambulatory surgery setting is associated with a
decreased length of stay in the PACU. The usual length of stay
can vary but is typically less than three hours in the ambulatory
surgery setting. We hypothesized that there would be a reduced
length of stay with the use of intravenous APAP. The secondary
objectives were to evaluate the effect of intravenous APAP on
pain scores, opioid consumption, and analgesic drug costs.
METHODS
Study Design and Setting
This was a retrospective cohort study conducted at an
ambulatory surgery center afliated with a university hospi-
tal in the United States. The surgery center did not have any
written protocol in place for postoperative pain management, so
analgesic provision was based on provider preference. Providers
had access to opioids, ketamine, intravenous and oral APAP,
lidocaine, and ketorolac. None of the patients in the study
used patient-controlled analgesia in the PACU. Intravenous
APAP was routinely used in all eye, ear, nose, or throat
(EENT) procedures because this set of providers considered
that this drug would improve recovery and decrease PACU
length of stay. This was the primary rationale that EENT physi-
cians used to justify the medications costs and its retention
on the formulary. No providers other than EENT physicians
utilized intravenous APAP at the facility. In addition to intra-
venous APAP, pain in the PACU was primarily managed using
intermittent intravenous boluses of opioids.
In July 2014, the institution removed intravenous APAP from
the formulary due to a cost increase from the manufacturer.
After this, all EENT procedures were performed without the
use of intravenous APAP for postoperative pain. At the time
of removal from the formulary, the EENT providers were
notied that other analgesics, such as ketamine, lidocaine,
and ketorolac, could be used instead of intravenous APAP.
In addition, oral APAP could be used when possible. The
universitys institutional review board approved the study prior
to data collection.
Patient Selection
Consecutive adult patients (at least 18 years of age) who
received an EENT procedure in the ambulatory surgery center
were included until the desired sample of 87 patients was reached
in each group. A list of all patients who underwent a procedure was
generated, and EENT procedures were identied. We selected
a population of patients who received only EENT procedures
to provide a relatively homogenous population. This was also
the only population of patients for whom intravenous APAP was
routinely used. Patients in the APAP group were included during
the period when the medication was available on the formulary
(January 2014 to June 2014). Patients in the non-APAP group
were included during the period when it was not available on
formulary (July 2014 to January 2015). Patients were included
chronologically until the desired sample size was reached for
each period. In other words, the rst 87 patients in each period
were included consecutively. There were no exclusion criteria
other than the age limits and procedure type listed above.
126 P&T February 2017 Vol. 42 No. 2
Study Variables and Data Collection
Data were collected from electronic medical records by one
of the investigators and entered into an online data capture
system using a standardized form. Research Electronic Data
Capture (REDCap) was used for data collection. Data col-
lected included demographics, comorbidities, surgery type,
pain scores, analgesic consumption (opioid and nonopioid),
adverse effects, and PACU length of stay. Pain was measured
on a numerical rating scale of 0 to 10 (0 = no pain, 10 = worst
possible pain). We collected all pain scores documented in the
PACU after administration of intravenous APAP, which was
given immediately after surgery. The mean pain score was
then calculated and used for analysis. Three or more scores
were documented for most patients. The only nonsteroidal
anti-inammatory agent used in these patients was intravenous
ketorolac. All opioids were converted to intravenous morphine
equivalents for our outcome of opioid consumption in the PACU.
The institutions average acquisition cost was used to derive
total analgesic cost in the PACU, with all costs represented
in 2014 U.S. dollars.
Data Analysis
Continuous data were reported as means with standard
deviations if normally distributed. Data that were not nor-
mally distributed were reported as medians with interquartile
ranges (IQRs). The distribution of data for each variable was
evaluated visually via histograms. Because length of stay is
typically skewed, this variable was also reported as medians.
An unpaired Students t-test or the Wilcoxon rank-sum test
was used to compare continuous data between groups as
appropriate. Categorical data were reported as percentages
and compared between groups using the Fishers exact test
or chi-square test as appropriate. The mean pain scores were
highly skewed, thus this variable was categorized as mild
pain (score 03), moderate pain (score 46), and severe pain
(score 710). An a priori alpha of 0.05 was used for all analyses.
All data analyses were conducted in Stata 13 (StataCorp LP,
College Station, Texas).
Based on previous studies conducted in outpatient surgery
settings, we considered a mean PACU length of stay of approxi-
mately 120 minutes for the APAP group and 150 minutes for
the non-APAP group with a common standard deviation of
70 minutes.14 This reduction of 30 minutes was based on what
we considered to be clinically meaningful and on estimates
of the EENT providers at our institution to justify the use of
intravenous APAP. Using an alpha of 0.05 and power of 80%,
we established a sample size of 87 patients in each group.
RESULTS
The overall cohort included 87 patients who received intra-
venous APAP in the PACU and 87 patients who did not receive
intravenous APAP. Because the initial list we obtained included
only EENT ambulatory surgeries, no patients were excluded.
The mean age was 49 19 years, 94 patients (54%) were men,
and mean weight was 81 19 kg. Comparisons between groups
with regard to demographic and clinical variables appear in
Table 1 along with the types of EENT surgeries performed. The
two groups were similar with respect to demographic catego-
ries and most comorbid conditions. There were more patients
Effect of IV Acetaminophen on PACU Length of Stay, Opioid Consumption, Pain, and Costs
with coronary artery disease, chronic obstructive pulmonary
Table 1 Demographic and Clinical Data
disease (COPD), and anxiety disorders in the non-APAP group
APAP Non-APAP P Value than in the APAP group. The majority of patients in the APAP
(n = 87) (n = 87) group received 1,000 mg APAP intravenously as a single dose
Demographics (n = 84 of 87, 97%). None of the patients in the study had
respiratory depression requiring the use of naloxone.
Age (mean SD) 46 20 51 19 0.13 The median PACU length of stay was 66 minutes
Weight (kg) (mean SD) 79 19 83 18 0.20 (IQR, 4892) in the APAP group and 71 minutes (IQR, 5289)
Male (n [%]) 44 (51) 50 (58) 0.45 in the non-APAP group (P = 0.269) (Table 2). Mean pain
score categories in the APAP versus non-APAP groups were
Comorbid conditions (n [%]) mild (85% versus 53%, respectively; P < 0.001), moderate (13%
Heart failure 3 (3) 0 (0) 0.25 versus 33%, respectively; P = 0.002), and severe (2% versus
14%, respectively; P = 0.005). The median opioid consumption
Coronary artery disease 6 (7) 16 (18) 0.04
in intravenous morphine equivalents was 9 mg (IQR, 513) in
Diabetes 10 (12) 12 (14) 0.82 the APAP group and 8 mg (IQR, 512) in the non-APAP group
Chronic obstructive 2 (2) 10 (12) 0.03 (P = 0.081). The use of some adjunctive medications differed
pulmonary disease between the APAP and non-APAP groups. Intravenous lidocaine
(31% versus 83%; P < 0.001) and oral APAP (8% versus 29%;
Asthma 18 (21) 17 (20) 1.00 P < 0.001) were used less in the intravenous APAP group
Chronic kidney disease 2 (2) 3 (4) 1.00 compared with the non-APAP group. The median dose of
Chronic pain condition 23 (26) 16 (18) 0.28 lidocaine used was 100 mg (IQR, 90100). Ketamine was used
more often in the APAP group (9%) versus the non-APAP
Depression 12 (14) 10 (12) 0.82 group (1%) (P = 0.018). The median dose of ketamine used
Bipolar/psychosis 2 (2) 6 (7) 0.28 was 50 mg (IQR, 3050). Intravenous ketorolac use was similar
in the APAP (14%) and non-APAP groups (12%) (P = 0.820).
Anxiety disorder 6 (7) 18 (21) 0.01
With the exception of three patients who received ketorolac
Fibromyalgia 0 (0) 1 (1) 1.00 15 mg, all patients received a single dose of 30 mg. There was
Diabetic neuropathy 1 (1) 0 (0) 1.00 no use of other nonsteroidal anti-inammatory agents or any
rectal APAP. The total cost of analgesics used in the PACU
Cancer 6 (7) 10 (12) 0.43 was signicantly greater in the APAP group compared with
Procedures (n [%]) the non-APAP group ($15 versus $1; P < 0.001).
Cataract surgery 10 (12) 4 (5) 0.16
DISCUSSION
Cornea transplant/ 7 (8) 10 (12) 0.61 The key nding of this study is that the use of intravenous
conjunctiva excision APAP in the PACU did not reduce length of stay in patients
Entropion repair/ 3 (4) 3 (4) 1.00 undergoing EENT surgery at our institution. The primary
blepharoplasty rationale of the providers for use of intravenous APAP in this
setting was that it would reduce opioid consumption in the
Rectus recession 2 (2) 9 (10) 0.06
Glaucoma valve insertion 4 (5) 1 (1) 0.37 Table 2 Results
Vitrectomy 1 (1) 1 (1) 1.00 APAP Non-APAP P Value
(n = 87) (n = 87)
Nasal surgery 31 (36) 30 (35) 1.00
Post-anesthesia care unit 66 71 0.27
Sinus surgery 10 (12) 20 (23) 0.07 length of stay in minutes (4892) (5289)
Mastoidectomy 3 (4) 0 (0) 0.25 (median [IQR])
Ear exploration/ 3 (4) 0 (0) 0.25 Pain score categories (n [%])*
tympanoplasty Mild (03) 73 (85) 46 (53) < 0.01
Moderate (46) 11 (13) 28 (33) < 0.01
Tonsillectomy 8 (9) 4 (6) 0.37
Severe (710) 2 (2) 12 (14) < 0.01
Other 1 (1) 2 (2) 1.00
Opioid consumption (intra- 9 (513) 8 (512) 0.08
Adjunctive analgesics (n [%]) venous morphine equivalents
Ketorolac 12 (14) 10 (12) 0.82 in milligrams) (median [IQR])
Oral acetaminophen 7 (8) 34 (29) < 0.01 Total cost of analgesics ($) 15 (1416) 1 (13) < 0.01
(median [IQR])
Ketamine 9 (10) 1 (1) 0.02
APAP = intravenous acetaminophen; IQR = interquartile range.
Lidocaine 27 (31) 72 (83) < 0.01 * Pain was measured on a numerical rating scale of 0 to 10 (0 = no pain, 10 =
APAP = intravenous acetaminophen worst possible pain). One patient in each group had missing pain scores.

Vol. 42 No. 2 February 2017 P&T 127

Effect of IV Acetaminophen on PACU Length of Stay, Opioid Consumption, Pain, and Costs
PACU and thus decrease recovery time, enabling patients to
be discharged home sooner.1 However, our ndings suggest
that opioid consumption was not reduced, and PACU length of
stay was similar between groups. A signicant nding is that
the use of intravenous APAP was associated with better pain
control in the PACU. There were also greater analgesic drug
costs associated with the use of intravenous APAP ($15 versus
$1). This was primarily attributed to the cost of intravenous
APAP. The drugs cost doubled at our institution, which led
to its removal from the formulary. Thus, this disparity in drug
costs is expected to be greater today than reported in our study.
In a previous randomized controlled study (N = 74) conducted
in patients undergoing endoscopic sinus surgery, patients
received a single dose of 1 g intravenous APAP or placebo.6
Within four hours after surgery, fewer patients in the APAP
group required rescue opioid analgesia (25% versus 71%;
P = 0.001). There were also fewer patients in the APAP group
who reported signicant pain (31% versus 58%; P = 0.018). The
authors dened this as a score greater than 3 on 010 numeri-
cal rating scale at any time during the study. In our study, we
showed a reduction in pain, but opioid consumption was not
reduced. This could result from differences in the types of
EENT procedures in our population or differences in the use
of other adjunctive analgesics.
The use of intravenous APAP has been studied after a variety
of surgeries, such as abdominal, cardiac, orthopedic, dental,
otolaryngologic, and others.15 However, the evidence is greatest
for major surgeries, such as those involving the abdomen. In one
systematic review involving seven randomized controlled trials,
intravenous APAP was associated with an opioid-sparing effect,
involving a 20% reduction in morphine use via patient-controlled
analgesia.10 However, it did not reduce morphine-related adverse
effects. Some studies have shown a decrease in hospital length
of stay with the use of intravenous APAP.8,16 In patients under-
going abdominal hysterectomy, the mean hospital length of stay
was decreased from 6.4 days to 5.2 days (P < 0.05).8 Similarly,
in patients undergoing laparoscopic colorectal resection, mean
hospital length of stay decreased from ve days to three days
(P < 0.05). However, these trials have been conducted in
European countries, limiting extrapolation to the United States
because of different processes and conditions that determine
eligibility for discharge. Our study is unique because it was in
a population that has not been studied as extensively. Given the
increasing trend toward ambulatory surgery, this study helps
evaluate the use of intravenous APAP in a population where
there is increasing interest in its utilization. When the decision
was made to remove intravenous APAP from the formulary
due to budgetary implications, proponents for its use argued
that the increase in cost was justied because the medication
decreased resource use by reducing PACU length of stay. We
did not see an increased length of stay after intravenous APAPs
removal from the formulary. This suggests that other adjunctive
agents (e.g., oral APAP, lidocaine, ketorolac, ketamine) may
be adequate as part of multimodal regimens in this setting.
However, the increase in pain scores that occurred after removal
of intravenous APAP from the formulary is concerning.
The study has a few important limitations inherent in the
retrospective design. The study was conducted in a single
institution in the United States, which may limit the generaliza-
128 P&T February 2017 Vol. 42 No. 2
tion of these results. There was an imbalance between groups
with regard to a few comorbidities, such as coronary artery
disease, COPD, and anxiety disorder. Patients in the non-APAP
group were more likely to have anxiety disorder, which has the
potential to inuence pain and opioid consumption.17 However,
the comorbidities we considered to be most important per-
tained to the presence of chronic pain conditions, which were
similar between groups. There were also differences between
groups with regard to the use of adjunctive analgesic agents.
For instance, the intravenous APAP group was less likely to
receive oral APAP. This is intuitive because after removal of
intravenous APAP from the formulary, the staff was provided
with information regarding available alternatives, such as oral
APAP. A few patients in the intravenous APAP group also were
more likely to receive intravenous ketamine, and patients in
the non-APAP group were more likely to receive intravenous
lidocaine. Although the increased use of lidocaine was expected,
the decrease in the use of ketamine was surprising. However, it
should be noted that there were very few patients overall who
received ketamine, and this difference could be attributed to
random variation. This occurred because the staff decided to
use other intravenous options instead of APAP. We can only
speculate regarding how these differences affected pain scores
and opioid consumption. It is possible that the use of these
other adjunctive agents instead of intravenous APAP resulted
in minimizing potential differences in length of stay. We did not
collect information regarding the timing of pain scores in the
PACU. Thus we could not plot the time course of pain to gain a
better understanding for this measure in the PACU. However,
because the stay in the PACU is only for a few hours, we did
not consider this to be necessary. At the time of the study
there was no protocol in place for postoperative pain, and this
management was at the discretion of the physician. As a result,
there could have been variation among patients with regard
to their analgesic provision. However, we have no reason to
believe that this variation would be any different between the
two study phases. We did not collect data regarding provid-
ers, which would have inuenced the selection of analgesics.
Finally, we considered PACU length of stay to be more mean-
ingful as an outcome than discharge from the surgical center.
This is because PACU length of stay inuences throughput in
the surgical center. Discharge from the surgical center itself
can be attributed to nonmedical issues, such as availability of
transport, so it was not used as our outcome.
CONCLUSION
Intravenous APAP use in ambulatory surgery patients under-
going EENT procedures is not associated with decreased PACU
length of stay. However, intravenous APAP may decrease
postoperative pain in this setting. Analgesic drug costs are
signicantly greater when intravenous APAP is used.
REFERENCES
1. Crews JC. Multimodal pain management strategies for ofce-based
and ambulatory procedures. JAMA 2002;288:629632.
2. Wier LW, Steiner CA, Owens PL. Surgeries in hospital-owned
outpatient facilities. Healthcare Cost and Utilization Project. AHRQ
Statistical Brief #188. 2015. Available at: www.hcup-us.ahrq.gov/
reports/statbriefs/sb188-Surgeries-Hospital-Outpatient-Facili-
ties-2012.pdf. Accessed October 2, 2015.
continued on page 139
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Vol. 42 No. 2 February 2017 P&T

129
PIPELINE PLUS
New Schizophrenia Treatments
Address Unmet Clinical Needs
Chris Fellner
S
chizophrenia is a chronic brain dis-
order primarily characterized by
delusions, hallucinations, difculty
with thinking and concentration, and
lack of motivation. The disorder affects
approximately 1% of the U.S. population.1
The precise cause of schizophrenia is
unknown, but some investigators have
suggested that it may begin in utero.2,3
Genetic, environmental, and social factors
have also been implicated.4,5
Although there is no cure for schizo-
phrenia,1 numerous drugs are available
for initial and maintenance therapy,
with the goal of controlling symptoms.6
According to the American Psychiatric
Association, second-generation (atypical)
antipsychoticswith the exception of clo-
zapineare the agents of choice for the
rst-line treatment of schizophrenia.7 Clo-
zapine is not recommended because of
its risk for causing agranulocytosis or sei-
zures.2,8 All of the atypical antipsychotic
drugs offer comparable efcacy.9,10 After
patients have recovered from their acute
psychotic episode, maintenance therapy
is initiated.11
Most schizophrenia patients (approxi-
mately 80% to 90%) experience a relapse
during the course of their illness.12
Breakthrough psychotic episodes may
result from nonadherence to mainte-
nance therapy, persistent substance use,
poorer premorbid adjustment, or stressful
life events.13 Long-acting injectable anti-
psychotics are commonly used to prevent
relapse.14 In addition, adjunctive psycho-
social interventionsincluding family
psychosocial education, social skills train-
ing, and cognitive behavioral therapy
have been shown to prevent relapse and
to improve medication adherence.7,15
Approximately 10% to 30% of schizo-
phrenic patients are treatment resis-
tant.7 The optimal management of these
patients may require switching to the
atypical antipsychotic clozapine or aug-
menting current therapy with other
approaches.16,17 Augmentation treat-
Chris Fellner is a medical writer and the
Editor of PTCommunity.com.
130 P&T February 2017 Vol. 42 No. 2
ments include the use of electroconvul-
sive therapy or repetitive transcranial
magnetic stimulation.18,19
Table 1 lists the leading schizophrenia
treatments in the United States.6
Analysts have identied ve unmet
needs in the schizophrenia marketplace.
They include:6
Drugs that enhance cognition
Drugs that treat negative symptoms
(such as lethargy, apathy, and social
withdrawal)
Drugs that provide improved options
for treatment-resistant patients
Drugs with enhanced safety proles
Drugs that increase compliance
With these needs in mind, pharmaceu-
tical companies are working to develop
several novel schizophrenia drugs
(Table 2). These investigational thera-
pies are discussed below.
ALKS 3831 (Alkermes) is a xed-dose
combination of samidorphan, a mu-opioid
receptor antagonist, and the atypical
antipsychotic drug olanzapine (generic
Zyprexa).6 The combination treatment
uses the action of samidorphan to reduce
the weight gain and metabolic adverse
events associated with olanzapine while
maintaining olanzapines antipsychotic
efcacy.6
ALKS 3831 was evaluated in a 12-week,
phase 2, randomized, double-blind, active-
controlled, dose-ranging study involving
300 adults with schizophrenia. Alkermes
reported top-line results from this trial in
January 2015. ALKS 3831 achieved the
studys primary efcacy endpoint, demon-
strating equivalence to olanzapine in the
reduction from baseline in Positive and
Negative Syndrome Scale (PANSS) total
scores. ALKS 3831 also met the studys
principal secondary endpoints, demon-
strating a 37% lower mean weight gain
compared with olanzapine at week 12 in
the full study population (P = 0.006) and
a 51% lower mean weight gain compared
with olanzapine at week 12 in a subset of
patients who gained weight in the one-
week olanzapine lead-in (P < 0.001).20
Based on these positive ndings,
Alkermes has moved ALKS 3831 into a
phase 3 clinical development program
consisting of two trials: ENLIGHTEN-1
and ENLIGHTEN-2. In the rst study,
ALKS 3831 is being compared with olan-
zapine alone and placebo in an estimated
390 patients with schizophrenia. The
primary endpoint is the change in the
PANSS score after four weeks of treat-
ment. The study began in December 2015
and has an anticipated completion date of
April 2018.21 The second trial is evaluat-
ing weight gain during treatment with
ALKS 3831 compared with olanzapine
in adults with schizophrenia. The study
has two primary endpoints: the percent
change from baseline in body weight at
24 weeks and the proportion of patients
with 10% or greater weight gain at the
same time point. The study was initi-
ated in February 2016, with a projected
completion date of March 2018.22
If ALKS 3831 is approved by the Food
and Drug Administration (FDA), it is
expected to be launched in the U.S. in
the third quarter of 2019.6
AVN-211 (Avineuro Pharmaceuticals)
is an oral, small-molecule antagonist of
the 5-hydroxytryptamine 6 (5-HT6) family
of serotonin receptors that has received
attention as a potential adjunctive treat-
ment for the cognitive impairments asso-
ciated with schizophrenia. There are no
marketed drugs with this indication.6
In 2015, however, AVN-211 failed
to demonstrate statistically signicant
results in a phase 2 pilot study, which
evaluated the efcacy of AVN-211 in
amplifying the effects of antipsychotic
drugs in 80 patients with schizophrenia
in incomplete remission receiving stable
antipsychotic therapy. AVN-211 was not
signicantly different from placebo on
the studys primary efcacy endpoint.23
Moreover, as a drug discovery and
development company, Avineuro may
lack the sales and marketing expertise
required for a successful launch of AVN-
211. Therefore, the company may need
to attract a partner or forge a licensing
agreement to maximize the drugs com-
 PIPELINE PLUS

Table 1 Leading Atypical Antipsychotics for the Treatment of Schizophrenia Patients in the U.S.6
Drug Brand Primary Indication U.S. Primary Patent or
Developer Launch Exclusivity Expiry
Aripiprazole Abilify Schizophrenia in adults and adolescents (ages 1317 years); 2002 April 2015
Otsuka agitation associated with schizophrenia
Abilify Maintena Schizophrenia in adults 2013 October 2024
Aripiprazole lauroxil Aristada Schizophrenia in adults 2015 October 2033
Alkermes
Asenapine Saphris Schizophrenia in adults 2009 October 2026
Organon/Merck
Brexipiprazole Rexulti Schizophrenia in adults 2015 February 2027
Otsuka/Lundbeck
Cariprazine Vraylar Schizophrenia 2016 December 2028
Allergan
Clozapine Clozaril Treatment-resistant schizophrenia; reduction in risk of recurrent 1989 Numerous
Novartis suicidal behavior in schizophrenia and schizoaffective disorder generics
Iloperidone Fanapt Schizophrenia in adults 2010 November 2016
Vanda
Lurasidone Latuda Schizophrenia in adults 2011 July 2018
Dainippon Sumitomo
Olanzapine Zyprexa Schizophrenia in adults and adolescents (ages 1317 years); 1996 October 2011
Lilly agitation associated with schizophrenia
Olanzapine pamoate Zyprexa Relprevv Schizophrenia in adults 2009 September 2018
Lilly
Paliperidone Invega Schizophrenia in adults and adolescents (ages 1217 years) 2006 April 2012
Janssen
Paliperidone palmitate Invega Sustenna Schizophrenia in adults 2009 May 2019
Janssen Invega Trinza Schizophrenia in adults after receiving Invega Sustenna for four months 2015 May 2018
Quetiapine Seroquel Schizophrenia in adults and adolescents (ages 1317 years) 1997 March 2012
AstraZeneca/Astellas Seroquel XR Schizophrenia in adults and adolescents (ages 1317 years) 2007 November 2017
Risperidone Risperdal Schizophrenia in adults and adolescents (ages 1317 years) 1994 June 2008
Janssen Risperdal Consta Schizophrenia in adults 2003 2023
Ziprasidone Geodon Schizophrenia in adults; agitation associated with schizophrenia 2001 March 2012
Pzer

mercial potential. At the present time, the
future of AVN-211 remains uncertain.6
ITI-007 (Intra-Cellular Therapies) is
a selective 5-HT2A receptor antagonist
that is in phase 3 clinical development
for the treatment of patients with acute
or residual schizophrenia.6 At increased
doses, the drug may provide additional
benets, including modest dopamine
receptor modulation and modest inhibi-
tion of serotonin transporters.24
A phase 3 study of ITI-007 in schizo-
phrenia patients was completed in
September 2015, with positive results.
Once-daily ITI-007 60 mg met the studys
primary endpoint, demonstrating anti-
psychotic efcacy with statistically signi-
cant superiority over placebo at week 4
(the study endpoint), as measured by
the change from baseline in PANSS total
score (P = 0.022). Moreover, ITI-007
60 mg showed signicant antipsychotic
efcacy as early as week 1, which was
maintained throughout the study.25
However, in a second phase 3 trial of
ITI-007 in schizophrenia patients, the
drug did not differ signicantly from
placebo in its effect on the primary
endpoint (the change from baseline in
the PANSS score), whereas the active
control, risperidone, did separate from
placebo. Intra-Cellular Therapies blamed
ITI-007s poor showing on an unusually
high placebo response rate (even though
this response did not affect risperidone).26
If ITI-007 gains FDA approval, analysts
anticipate that it will be launched in the
U.S. in the rst half of 2018.6
Lu AF35700 (Lundbeck) is an antago-
nist of the D1, 5-HT2A, and 5-HT6 recep-
tors. Based on its pharmacological prole,
the drug is expected to reduce the occur-
rence of adverse events associated with
the use of several antipsychotics, includ-
ing extrapyramidal symptoms, elevated
prolactin levels, dysphoria/anhedonia,
and depressed mood.6,27
Two doses of Lu AF35700 (10 mg and

Vol. 42 No. 2 February 2017 P&T 131

PIPELINE PLUS

Table 2 Promising Compounds in Clinical Development for the Treatment of Schizophrenia in Adults6
Drug Description Targeted Indication(s) Expected Anticipated U.S.
Developer Pricing Strategy Launch Date
Atypical Antipsychotics
ALKS 3831 Fixed-dose combination of Schizophrenia Priced at premium to Third quarter
Alkermes mu-opioid receptor antagonist (acute exacerbations olanzapine (Zyprexa, Lilly) of 2019
(samidorphan) and atypical or stable disease)
antipsychotic (olanzapine)
AVN-211 5-HT6 receptor antagonist Cognitive impairments Undetermined Undetermined
Avineuro Pharmaceuticals associated with schizophrenia
ITI-007 5-HT2A receptor antagonist Acute and residual Priced at premium to currently First half
Intra-Cellular Therapies schizophrenia marketed oral antipsychotics of 2018
Lu AF35700 D1, 5-HT2A, and 5-HT6 receptor Treatment-resistant Undetermined Undetermined
Lundbeck antagonist schizophrenia
MIN-101 5-HT2A and sigma-2 receptor Schizophrenia Priced at premium to currently 2019
Minerva Neurosciences antagonist marketed oral antipsychotics
RBP-7000 Sustained-release risperidone Schizophrenia (acute or Priced at premium to Fourth quarter
Indivior maintenance treatment) Risperdal Consta (Janssen) of 2017
Risperidone implant Six-month, nonbiodegradable, Schizophrenia Priced at 15% premium to Second quarter
Braeburn Pharmaceuticals drug-eluting stent (maintenance treatment) annual cost of therapy with of 2018
Risperdal Consta
Risperidone ISM Once-monthly IM formulation Schizophrenia or Priced at premium to Fourth quarter
Rovi Pharmaceutical based on ISM delivery system schizoaffective disorder Risperdal Consta of 2019
Laboratories
Hyperammonemia Agent
Sodium benzoate (NaBen) D-amino acid oxidase inhibitor Pediatric schizophrenia Undetermined Undetermined
SyneuRx International Refractory schizophrenia (in
(Taiwan) Corp. combination with clozapine)
Adjunctive therapy for
schizophrenia in adults
5-HT = 5-hydroxytryptamine; IM = intramuscular; ISM = in situ microparticles.

20 mg) are being evaluated in a phase 3
trial involving an estimated 964 adults
with treatment-resistant schizophrenia.
The primary endpoint is the change from
baseline to study week 10 in the PANSS
total score. The study began in March
2016, with an estimated completion date
of May 2018.28,29
MIN-101 (Minerva Neurosciences) is
a rst-in-class 5-HT2A and sigma-2 recep-
tor antagonist. These receptors play a
role in regulating mood, sleep, cognition,
and anxiety. By blocking 5-HT2A recep-
tors, MIN-101 is believed to minimize
the hallucinations, delusions, agitation,
and thought and movement disorders
associated with schizophrenia. Moreover,
antagonism of sigma-2 receptors modu-
lates dopamine, a neurotransmitter that
has been implicated in the pathophysiol-
ogy of schizophrenia. It also increases
intracellular calcium levels in brain
neurons, which can result in enhanced
memory.30
Positive results were reported from a
12-week, phase 2b, prospective, random-
ized, double-blind, placebo-controlled,
parallel-group trial that evaluated
MIN-101 versus placebo in 244 patients
with negative symptoms of schizophre-
nia (i.e., disruptions to normal emotions
and behaviors). The study achieved its
primary endpoint, demonstrating a statis-
tically signicant benet of MIN-101 over
placebo in improving negative symptoms,
as measured by the PANSS. The effect
was observed for both the 32-mg and
64-mg doses of MIN-101 (P 0.022 and
P 0.003, respectively).31
Phase 3 testing of MIN-101 is expected
to begin in 2017.32 If the drug is approved,
its anticipated launch date is 2019.6
RBP-7000 (Indivior) is a monthly
sustained-release formulation of ris-
peridone, one of the most frequently
prescribed atypical antipsychotics for
schizophrenia.6 The product consists of
a two-syringe system in which the contents
are mixed immediately before adminis-
tration. One syringe contains a delivery
system (Atrigel), and the other contains
powdered risperidone.33 The mixture is
injected subcutaneously as a liquid into the
patients abdomen, where it subsequently
solidies, resulting in the prolonged
release of risperidone for one month
before it eventually biodegrades.34
In May 2015, Indivior reported posi-
tive results from a pivotal phase 3 study
of RBP-7000 (90 mg and 120 mg once
monthly) in patients with schizophrenia.
The study met its primary endpoint of pro-
viding statistically signicant reductions
in the symptoms of acute schizophrenia,
as determined by PANSS scores, com-
pared with placebo during the eight-week

132 P&T February 2017 Vol. 42 No. 2


treatment period. RBP-7000 also met the
key secondary endpoint with signicant
improvements in the Clinical Global
ImpressionSeverity scale compared with
placebo during the eight-week treatment
period, as indicated by the change from
baseline to the end of treatment.33
Indivior subsequently announced
that it was weighing the options for the
nal stages of clinical development and
commercialization of RBP-7000. These
options included potential partnerships,
outlicensing or outright sale of the
product, and maintaining ownership of
the product.34,35
Analysts anticipate that RBP-7000
will be launched in the U.S. in the
fourth quarter of 2017, with an indica-
tion for acute and maintenance treat-
ment of patients with schizophrenia. It
is expected, however, to meet strong
competition from generic risperidone.6
Braeburn Pharmaceuticals is develop-
ing an implantable six-month formula-
tion of risperidone, which it acquired
from Endo Pharmaceuticals. The non-
biodegradable, drug-eluting implant
is designed to deliver risperidone for
maintenance treatment of schizophrenia
patients.6,36
A 48-week, phase 3, open-label study
is evaluating the safety and tolerability
of risperidone implants as maintenance
therapy in 145 adults (18 to 70 years of
age) with schizophrenia. The studys
primary outcome measure is the number
of participants with treatment-related
adverse events. The study began in April
2016 and is expected to be completed in
November 2017.37
As of December 2016, no efcacy data
for the risperidone implant have been
published. If the product is approved,
analysts expect a 2018 launch.6
Risperidone is also being developed in
the form of in situ microparticles (ISM) by
a Spanish company, Rovi Pharmaceutical
Laboratories. Risperidone ISM consists of
two syringesone containing a polymer
and the active ingredient in a solid state,
and the other containing the solvent
needed for reconstitutionfor once-
monthly intramuscular administration.38
Rovi completed a phase 2 pharmaco-
kinetics and tolerability study of risperi-
done ISM in schizophrenia patients in
March 201539 and presented the results to
the 24th European Congress of Psychia-
try in March 2016.40 Shortly afterward,
Rovi submitted the PRISMA-2 data, along
with ndings from previous studies, to
the FDA in order to request guidance
on the design of a phase 3 trial of risperi-
done ISM. The company predicted that
recruitment for such a study would be
under way by the third quarter of 2016.40
If approved, risperidone ISM is
expected to be launched in the U.S. in
the fourth quarter of 2019 for the treat-
ment of patients with schizophrenia or
schizoaffective disorder.6
NaBen (sodium benzoate, SyneuRx
International [Taiwan] Corp.) is a
D-amino acid oxidase inhibitor under
clinical development as a schizophrenia
treatment.6 It was granted orphan drug
status for the treatment of schizophre-
nia patients with refractory disease in
combination with clozapine in December
2011 and for the treatment of schizophre-
nia in pediatric patients in July 2012.41
In December 2014, NaBen also won a
breakthrough therapy designation as an
adjunctive treatment for schizophrenia
in adults.42
A phase 2, randomized, double-blind,
placebo-controlled trial was conducted
in Taiwan to determine the clinical and
cognitive efcacy of add-on treatment
with sodium benzoate in patients with
schizophrenia who had been stabilized
with antipsychotic medications for at least
three months. Fifty-two patients received
six weeks of add-on treatment with 1 g
daily of sodium benzoate or placebo.
Sodium benzoate was associated with
a 21% improvement in the PANSS total
score compared with placebo. Signi-
cantly greater improvements were also
observed in Scales for the Assessment of
Negative Symptoms20 items, the Global
Assessment of Function, the Quality
of Life Scale, and the Clinical Global
Impression in patients receiving add-on
sodium benzoate treatment compared
with placebo treatment.43
SyneuRx led a proposed phase 2b/3
study of sodium benzoate with the
National Institutes of Health in Sep-
tember 2014, but as of December 2016,
no subjects have been recruited. The
multicenter, prospective, randomized,
placebo-controlled, sequential paral-
lel comparison design trial is expected
to enroll an estimated 240 adults with
schizophrenia. The study will consist of
a 19-week double-blind phase followed by
a 26-week open-label extension phase.44
PIPELINE PLUS
In summary, several products are
being developed to address the signi-
cant unmet needs that exist in the schizo-
phrenia marketplace. For example, three
potential treatmentsITI-007 (Intra-
Cellular Therapies), MIN-101 (Minerva
Neurosciences), and NaBen (SyneuRx)
are aimed at managing the negative symp-
toms of the disease. In addition, AVN-211
(Avineuro Pharmaceuticals) is in late-
stage development as a treatment for the
cognition impairments associated with
schizophrenia, and Lu AF35700 (Lund-
beck) addresses treatment resistance
in schizophrenia patients. Finally, three
formulations of risperidonerisperidone
implant (Braeburn Pharmaceuticals), ris-
peridone ISM (Rovi), and RBP-7000 (Indi-
vior)are expected to offer improved
safety proles.6
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November 28, 2016. Q
 MEETING HIGHLIGHTS
American Society of Hematology
Annual Meeting and Exposition
Walter Alexander
Billed as the worlds premier event in malignant and
nonmalignant hematology, this years American Society
of Hematology (ASH) meeting hosted more than 27,000
hematology professionals December 36 in San Diego.
We review below key sessions on pharmacotherapy
clinical trials across a wide span of disease states,
including leukemia, graft-versus-host disease, myelobrosis,
multiple myeloma, and sickle cell disease.
Minimal Residual Disease Negative Complete
Remissions Following Anti-CD22 Chimeric
Antigen Receptor Therapy in Children and
Young Adults with Relapsed/Refractory
Acute Lymphoblastic Leukemia
Terry J. Fry, MD, National Cancer Institute, Bethesda,
Maryland
A National Cancer Institute (NCI) phase 1 study of anti-
CD22 chimeric antigen receptor (CAR) therapy in children
and young adults with relapsed/refractory acute lymphoblastic
leukemia (ALL) revealed complete remissions without severe
or irreversible neurotoxicity.
Not all relapsed/refractory ALL patients respond to anti-CD19
CAR therapy, and CD19-negative escape has been observed,
Dr. Fry said at an ASH press brieng. He noted that CD22,
which is widely expressed in ALL, represents an ideal target.
The NCI trial tested anti-CD22 CAR therapy to determine the
feasibility of producing anti-CD22 CAR cells and the safety
of administering escalating doses of anti-CD22 CAR T cells.
Preliminary assessment of antileukemia effects, a secondary
endpoint, was also conducted.
Anti-CD22 CAR T-cell therapy, in which a patients own
genetically altered T cells track down and kill cancer cells
expressing CD22, plus udarabine 25 mg/m2 was given to
16 patients 1 to 30 years of age with relapsed/refractory CD22-
positive hematologic malignancies. All patients had CD22
expression on more than 99% of their malignancy, with a median
site density of 2,589 molecules per cell (range, 84613,452).
All had previously undergone at least one allogeneic stem
cell transplant, and a majority of participants (11 of 16) had
relapsed after receiving anti-CD19 CAR T-cell therapy before
entering the trial.
Among the 10 participants treated at a higher dose
(comparable to that used by current CD19 CAR programs),
eight attained a complete remission without evidence of residual
disease after one month of their infusion. Two patients had
mild cytokine release syndrome. Three patients are in ongoing
The author is a freelance writer living in New York City.
sustained remission with durations of more than one year,
six months, and three months.
Relapses were associated with changes in CD22 expression
level. Weve been able to show that you can give a second
CAR therapy that is directed against a different antigen and
have it be safe and effective, Dr. Fry said, noting that a single
antigen-directed CAR immunotherapy probably wont be suf-
cient for long-term durable remissions in many patients. The
potential for targeting multiple cancer-related proteins (also
called bispecic targeting) is suggested by this feature, he said.
This is the rst successful salvage CAR therapy for
CD19-negative B-ALL, he concluded.
Chronic Myeloid Leukemia Patients With
Stable Molecular Responses May Safely
Decrease the Dose of Their Tyrosine Kinase
Inhibitor: Data from the British DESTINY Study
Mhairi Copland, MD, PhD, University of Glasgow, Glasgow,
United Kingdom
Like patients with deep molecular responses, most chronic
myeloid leukemia (CML) patients with stable responses
(molecular response with a 3.0 log reduction [MR3]; BCRABL
protein level less than 0.1%) can safely cut their tyrosine kinase
inhibitor (TKI) dose in half. The consequence, according to
Dr. Copland, is fewer side effects and reduced cost.
Reporting ndings from the DESTINY study at an ASH press
brieng, Dr. Copland noted that several studies report 50% to
60% of CML patients with enduring good responses can stop
TKI therapy. All of these studies, however, are restricted to
patients with very deep responses (less than MR4; BCRABL
less than 0.01%). Dr. Copland asked, What about patients with
less deep responses? Could they manage on reduced-dose
treatment? This might improve side effects and save money.
One of the challenges in CML, she added, is how to manage
patients with side effects.
DESTINY included CML patients in MR4 or better and in
MR3. They were assigned half-dose therapy with imatinib
(Gleevec, Novartis) 200 mg once daily (n = 148), nilotinib
(Tasigna, Novartis) 200 mg twice daily (n = 16), or dasatinib
(Sprycel, Bristol-Myers Squibb) 50 mg once daily (n = 10).
Individual TKI side effects such as lethargy, diarrhea, rash,
nausea, periorbital edema, and hair thinning improved in the
rst one to two months of de-escalation, but plateaued there-
after. Quality-of-life measures were optimal at the trial outset,
however, and were not impacted.
Molecular relapses, dened as loss of MR3 on two consecutive
samples, were reported for 12 patients between study months 2
and 12. The molecular relapse rate was higher in patients with
less deep molecular responses at the outset (MR4 in three of
125 patients [2.4%]; MR3 in nine of 49 patients [18.4%]).
Vol. 42 No. 2 February 2017 P&T
135
 MEETING HIGHLIGHTS: American Society of Hematology
According to Dr. Copland, halving treatment led to a 46.7%
cost savings of 1,943,364 (US $1,530,204) from an expected TKI
budget (without de-escalation) of 4,156,969 (US $3,273,197).
In CML patients with stable MR3 or better, decreasing
TKI treatment to half the standard dose appears safe and
is associated with improvement in TKI-related side effects,
implying that many patients with stable responses are being
overtreated, Dr. Copland concluded. Studies of more
ambitious de-escalation are warranted.
Cessation of Tyrosine Kinase Inhibitor
Treatment in Chronic Myeloid Leukemia
Patients with Deep Molecular Response:
Results of the EURO-SKI Trial
Francois-Xavier Mahon, MD, PhD, University of Bordeaux,
Bordeaux, France
In a clinical trial with a large cohort of chronic myeloid
leukemia (CML) patients, stopping tyrosine kinase inhibitor
(TKI) therapy was feasible and safe, according to ndings from
the EURO-SKI trial, which were discussed by Dr. Mahon in
an ASH press brieng.
The feasibility of stopping TKI treatment has been dem-
onstrated previously,13 and the concept of treatment-free
remission was validated in the STIM study.1 While it has
been established that a sustained deep molecular remission
on long-term TKI therapy is necessary prior to an attempt at
treatment-free remission, the exact preconditions for stopping
CML treatments are not dened.
The EURO-SKI trial included 821 patients treated at 61 sites
in 11 countries. All were chronic-phase CML patients who
had received imatinib (Gleevec, Novartis), nilotinib (Tasigna,
Novartis), or dasatinib (Sprycel, Bristol-Myers Squibb) for
three years or more without treatment failure. All were in
deep molecular response (molecular response with a 4.0 log
reduction [MR4]; BCRABL protein level less than 0.01% on
the international scale) for at least one year.
Molecular recurrence in the EURO-SKI study was dened
by the loss of the major molecular response (BCRABL less
than 0.1% on the international scale) at any point. Loss of
major molecular response among the 755 evaluable patients
occurred in 373 patients. That loss occurred within the rst
six months in 78.3% of patients (n = 292). Median follow-up
was 14.9 months for the entire group and 26.0 months among
the 383 patients who did not experience loss of response.
Molecular recurrence-free survival was 61% at six months,
52% at 18 months, and 47% at 36 months.
While gender, age, or any other variable did not predict the
probability of successful therapy cessation, longer duration
of imatinib therapy (optimally 5.8 years or longer) prior to
TKI cessation correlated with a higher probability of relapse-
free survival. In addition, each additional year of TKI therapy
increased a patients chances of successful TKI discontinuation
by about 16%. Resumption of TKI therapy for patients with
molecular recurrence led to regaining prior remission levels
in most patients, and none progressed to advanced disease.
With about half of the enrolled patients remaining in
remission two years after stopping their TKI therapy,
136 P&T February 2017 Vol. 42 No. 2
Dr. Mahon concluded, With inclusion and relapse criteria less
strict than in many previous trials, and with decentralized but
standardized PCR [polymerase chain reaction] monitoring,
stopping of TKI therapy in a large cohort of CML patients
appears feasible and safe.
Multicenter, Open-Label, Phase 2 Study
Of Ibrutinib in Chronic Graft-Versus-Host
Disease After Failure of Corticosteroids
David Miklos, MD, Stanford University, Palo Alto, California
Data from a multicenter, open-label, phase 2 study of
ibrutinib (Imbruvica, Pharmacyclics/Janssen) support the
kinase inhibitors use in patients with steroid-refractory
chronic graft-versus-host disease (GVHD), Dr. Miklos said in a
late-breaking clinical trials session.
He described GVHD as a complication of allogeneic stem cell
transplantation that affects approximately 4,000 of the 10,000
individuals in the United States who undergo allogeneic stem
cell transplantation each year. Immune-suppressing cortico-
steroids, the standard treatment, do not benet all patients. The
kinase inhibitor ibrutinib, which was recently granted break-
through therapy status by the Food and Drug Administration,
reduces the severity of chronic GVHD through its inhibition
of Bruton tyrosine kinase and interleukin-2inducible T-cell
kinase.4 Both B and T cells play a role in the pathophysiology
of chronic GVHD, Dr. Miklos said.
All 42 patients (median age, 56 years; range, 1974 years)
with chronic GVHD in Dr. Miklos study needed additional
therapy. Included patients had received prior regimens for
chronic GVHD and had erythematous rash over more than 25%
of their body surface or National Institutes of Health mouth
scores of greater than 4. All were treated daily with 420 mg
ibrutinib until unacceptable toxicity or disease progression.
The study evaluated the efcacy and safety of ibrutinib, with
changes in corticosteroid use among the secondary endpoints.
Median duration of chronic GVHD was 13.7 months at study
entry. The median number of prior regimens was two (range,
one to three). The overall response rate, after a median follow-up
of 13.9 months, was 67%. Complete responses were observed
in 45% of patients, with sustained responses of 20 weeks or
greater in 71% and 32 weeks or greater in 48%.
Curtailed or reduced corticosteroid use was facilitated
with ibrutinib, with low corticosteroid doses (less than
0.14 mg/kg per day) given in 75% of patients and complete
cessation of corticosteroid use while in response in
ve patients (12%). Clinician-assessed chronic GVHD median
severity scores decreased from 7 at baseline to 4 at week 49.
Score improvements using the Lee chronic GVHD symptom
scale were reported overall in 61% of the 28 responders versus
11% in nine nonresponders.
Adverse events, consistent with those previously observed
for ibrutinib in B-cell malignancies and chronic GVHD,
were experienced in 45% of patients. The most common
adverse events were fatigue (57%), diarrhea (36%), muscle
spasms (29%), nausea (26%), and bruising (24%). Two fatal
events (multilobular pneumonia and bronchopulmonary
aspergillosis) were reported.
 MEETING HIGHLIGHTS: American Society of Hematology
Dr. Miklos underscored the importance of active monitoring
to manage ibrutinib-related adverse events. He commented
that analysis of biomarker changes shows that ibrutinib has a
positive effect on immune cell subsets.
I think clinicians will nd these data support the use of
ibrutinib in patients with steroid-refractory chronic GVHD,
Dr. Miklos concluded.
Results of the PERSIST-2 Phase 3
Study of Pacritinib Versus Best
Available Therapy, Including Ruxolitinib,
In Patients With Myelobrosis and Platelet
Counts Less Than 100,000 per mcL
John Mascarenhas, MD, Tisch Cancer Institute, Icahn School
of Medicine at Mount Sinai, New York, New York
Among patients with myelobrosis (MF) and platelet counts
of less than 100,000 per mcL, pacritinib was signicantly more
effective than best available therapy (BAT)(including ruxoli-
tinib [Jaka, Incyte]) for spleen volume reduction. A trend
toward improved total symptom score was also observed,
according to an ASH late-breaking clinical trial presentation
by Dr. Mascarenhas.
A life-threatening hematologic malignancy characterized by
splenomegaly and debilitating constitutional symptoms, MF
presents with thrombocytopenia, platelet counts of less than
50,000 per mcL (associated with reduced quality of life), heavier
symptom burden, and likelihood of shortened overall survival
in 25% of patients. The Janus kinase 1 (JAK1)/JAK2 inhibi-
tor ruxolitinib has been shown to reduce splenomegaly and
related symptoms. However, it is associated with dose-limiting
cytopenias and is not indicated for patients with platelet counts
of less than 50,000 per mcL. Pacritinib is an oral kinase inhibitor
with specicity for JAK2, FMS-like tyrosine kinase-3, inter-
leukin-1 receptor-associated kinase 1, and colony-stimulating
factor 1 receptors.
In the PERSIST-1 trial, which compared pacritinib to BAT
(excluding JAK2 inhibitors), pacritinib demonstrated sus-
tained spleen volume reduction and symptom control in MF
patients regardless of baseline platelet counts. The PERSIST-2
phase 3 trial tested two doses of pacritinib (400 mg once daily
[QD] and 200 mg twice daily [BID]) versus BAT (including
ruxolitinib). The coprimary endpoints were the number of
patients achieving spleen volume reductions of 35% or greater
and reductions in total symptom score of 50% or greater at
week 24. The 1:1:1 randomization included 75 patients receiving
pacritinib QD, 74 receiving pacritinib BID, and 72 receiving
BAT. Mean age was approximately 68 years, and 57% of the
patients were men. Median spleen length was approximately
14 cm. Approximately 44% of patients had received prior treat-
ment with ruxolitinib. BAT most commonly consisted of rux-
olitinib (45%) and hydroxyurea (19%). The safety and overall
survival analysis included approximately 100 patients per arm.
The PERSIST-2 study was truncated by a Food and Drug
Administration (FDA)-mandated full clinical hold ordered
after interim analysis revealed patient deaths related to intra-
cranial hemorrhage, cardiac arrest, and heart failure. At the
time of the clinical hold, there had been 15 deaths in the QD
arm (14%), 10 deaths in the BID arm (9%), and 14 deaths
(14%) in the BAT arm. The rates for the primary endpoint
of spleen volume reduction at 24 weeks were signicantly
improved for both pacritinib arms versus BAT (QD, 14.7%,
P = 0.017; BID, 21.6%, P = 0.001). Percentages of patients with
50% or greater total symptom score reductions were signi-
cantly higher only for the pacritinib BID arm versus BAT (32.4%
versus 13.9%; P = 0.011).
Overall survival was censored at the clinical hold date. It was
slightly higher with pacritinib versus BAT in the QD group
(hazard ratio [HR] = 1.18) but was lower in the BID group
(HR = 0.68). The need for red blood cell transfusions at
week 24 was reduced in the pacritinib arms, especially the
BID arm (0.67 units per month versus 1.33 in the BAT arm).
Serious cardiac events and bleeding events were comparable
among all groups and were relatively rare. The most common
adverse events with pacritinib were diarrhea, vomiting, nausea,
anemia, and low platelet count.
Despite study truncation due to the clinical hold, pacri-
tinib QD and BID was signicantly more effective than best
available therapy, including ruxolitinib, for spleen volume
reduction with a trend toward improved total symptom score,
Dr. Mascarenhas said. He also noted that the pacritinib BID
benetrisk prole appeared to be better than that of BAT,
including ruxolitinib.
The FDA recommended that the manufacturer conduct
dose-exploration studies for pacritinib in patients with MF and
should submit nal study reports and datasets for PERSIST-1
and PERSIST-2.
SUSTAIN: A Multicenter, Randomized,
Placebo-Controlled, Double-Blind, 12-Month
Study to Assess Safety and Efficacy of
SEG101 With or Without Hydroxyurea
Therapy in Sickle Cell Disease Patients
With Sickle CellRelated Pain Crises
Kenneth I. Ataga, MD, University of North Carolina at Chapel
Hill, Chapel Hill, North Carolina
High-dose SEG101 (crizanlizumab, formerly SelG1, Novartis)
resulted in a statistically signicant and clinically meaning-
ful reduction in the frequency of sickle cellrelated pain
crises (SCPCs) in patients with sickle cell disease, according
to SUSTAIN clinical trial results presented at an ASH press
brieng. SEG101 is a rst-in-class humanized anti-P-selectin
antibody given as an intravenous infusion over 30 minutes.
Upregulation of P-selectin, an adhesion molecule expressed
on activated vascular endothelial cells and platelets, plays a key
role in the pathogenesis of SCPC, Dr. Ataga said.
In sickle cell disease, pain is caused by tissue ischemia
created when sickled red blood cells and leukocytes adhere
to the endothelium and lead to vaso-occlusion. SCPCs occur
unpredictably and often require hospitalization, Dr. Ataga
explained. While hydroxyurea is known to decrease SCPC
frequency in sickle cell anemia, many patients receiving
hydroxyurea continue to experience acute painful episodes.
Vol. 42 No. 2 February 2017 P&T
137
 MEETING HIGHLIGHTS: American Society of Hematology
In SUSTAIN, investigators randomized sickle cell patients
double-blind to placebo (n = 65), SEG101 2.5 mg/kg (n = 66),
or SEG101 5.0 mg/kg (n = 67). Patients received an initial dose,
one dose 14 days later, and then one dose every four weeks
through week 50 for a total of 14 doses. The primary efcacy
endpoint was the annual rate of SCPC in the 5.0-mg/kg SEG101
group versus placebo. An SCPC was dened as acute sickle
cellrelated pain that resulted in a visit to a medical facility and
required a parenteral or oral narcotic or parenteral nonsteroidal
anti-inammatory drug. The primary endpoint was the median
rate of SCPC per year.
Median patient age was 28 years, 45% of patients were male,
and approximately 93% were African-American. Concomitant
hydroxyurea was being taken by 62% of patients.
For patients receiving the higher SEG101 dose, the median
rate of SCPC per year was 1.63. For those receiving the lower
dose, it was 2.01, and for patients receiving placebo, it was 2.98.
In the high-dose group, 24 patients were SCPC-free. Twelve in
the low-dose SEG101 group were SCPC-free over the course
of the study, as were 12 in the low-dose group and 11 in the
placebo group. Median time to the rst and second SCPC
events was signicantly longer in the high-dose SEG101 group
(4.07 months and 10.32 months, respectively; P = 0.001) than
in the placebo group (1.38 months and 5.09 months, respec-
tively; P = 0.022). Differences between the low-dose SEG101
group and placebo group were not signicant. Adverse event
incidence with SEG101 was low.
Treatment with high-dose SelG1 [SEG101] resulted in a
statistically signicant and clinically meaningful reduction in
the frequency of SCPC in patients with sickle cell disease,
Dr. Ataga concluded.
A Phase 1b Study of Vadastuximab Talirine
In Combination With 7+3 Induction Therapy
For Patients With Newly Diagnosed
Acute Myeloid Leukemia
Harry P. Erba, MD, PhD, University of Alabama at
Birmingham, Birmingham, Alabama
Vadastuximab talirine (VDT) can be safely combined with
standard 7+3 chemotherapy in patients with newly diagnosed
acute myeloid leukemia (AML), according to preliminary
results of an ongoing phase 1b trial. Standard induction treat-
ment for this population has been 7+3 (cytarabine for 7 days
with an anthracycline for 3 days) for 30 years, Dr. Erba said
in an ASH press brieng.
VDT is an antibody that targets the cell surface antigen
CD33. CD33 is expressed in about 90% of AML and leads to
cell death. Remissions brought about by adding VDT to 7+3
chemotherapy could be enhanced and deeper than those with
standard chemotherapy alone, leading to minimal residual
disease (MRD) status. Achieving MRD-negative remission
postinduction correlates with improved survival, Dr. Erba said.
The safety and antileukemic activity of VDT added to
the 7+3 regimen with induction on days 1 and 4 of a 28-day
treatment cycle are being evaluated in Dr. Erbas trial. The
study includes 42 patients (36% male; mean age, 45.5 years)
with previously untreated AML. Most patients have
138 P&T February 2017 Vol. 42 No. 2
intermediate (50%) or adverse (36%) cytogenetic risk, and 17%
of patients have secondary AML.
Adverse event rates with VDT are acceptable, according to
Dr. Erba. Among hematologic treatment-related adverse events,
grade 3 febrile neutropenia has been reported in approximately
65% of patients, and grade 4 thrombocytopenia, as expected, was
reported in all patients. Nonhematologic toxicities were similar
to those seen with 7+3 alone and most commonly included
grades 1 and 2 nausea (60%), diarrhea (36%), and constipation
(33%). No grade 3 or higher nonhematologic events have been
observed in 15% or more of patients. The 30-day mortality
rate is 2%. No veno-occlusive disease, sinusoidal obstruction
syndrome, or signicant hepatotoxicity has been observed.
Dr. Erba reported that complete remissions (CRs) have
been achieved in 60% of patients, with 30 of 32 (94%) achiev-
ing CR within one cycle of therapy. Among these, 25 of
32 patients (78%) are MRD-negative. An additional 17% have
CRs with incomplete platelet recovery. Dr. Erba observed that
CRs tracked closely with cytogenic risk (favorable = 100%;
intermediate = 67%; adverse = 40%).
Vadastuximab talirine can be safely combined with 7+3,
Dr. Erba concluded, adding that the recommended dose is
20+10 mcg/kg on days 1 and 4. An alternate schedule of single-
day dosing on day 1 is under investigation, and a randomized
phase 2 trial of vadastuximab talirine plus 7+3 versus 7+3
alone is planned.
Survival Following Allogeneic Hematopoietic
Cell Transplantation in Older High-Risk Acute
Myeloid Leukemia Patients Initially Treated
With CPX-351 Liposome Injection Versus
Standard Cytarabine and Daunorubicin:
Subgroup Analysis of a Large Phase 3 Trial
Jeffrey E. Lancet, MD, Moftt Cancer Center and Research
Institute, Tampa, Florida
Treatment with CPX-351 for older patients with high-risk
acute myeloid leukemia (AML) leads to better outcomes after
allogeneic hematopoietic cell transplantation (HCT), according
to an exploratory analysis of an open-label, parallel-arm study.
This liposomal formulation of cytarabine and daunorubicin may
also provide a bridge to successful transplant in poor-risk older
AML patients, Dr. Lancet said in an ASH press conference.
Remission rates in patients older than 60 years of age are
lower and induction mortality is higher compared with younger
patients. CPX-351s 5:1 molar ratio is said to maximize the
synergy between cytarabine and daunorubicin, leading to
preferential drug uptake into leukemic cells. In earlier phase 3
trial reporting, survival was superior in newly diagnosed older
patients with secondary AML versus standard 7+3 cytarabine
and daunorubicin.
Among older patients, Dr. Lancet observed, few can be
cured with chemotherapy alone. He conducted an explor-
atory analysis among those patients who received allogeneic
HCT after induction treatment. The study included patients
60 to 75 years of age with newly diagnosed secondary
AML. Patients with complete responses (CRs) or CRs
 MEETING HIGHLIGHTS:
American Society of Hematology
with incomplete platelet or neutrophil recovery (CPX-351,
n = 73; 7+3, n = 52) were considered for allogeneic HCT based
on institutional criteria.
CRs (with and without platelet/neutrophil recovery) were
more frequent with CPX-351 than with 7+3 (47.7% versus 33.3%).
Also, median survival landmarked from time of transplant
was not reached in the CPX-351 patients (n = 52) and was
10.25 months for the 7+3 patients (n = 39) (hazard ratio, 0.46,
favoring CPX-351; P = 0.0046).
While cautioning that the analysis is exploratory, Dr. Lancet
underscored that the reduction in deaths was 53%, with all-cause
mortality by day 100 after transplant at 9.6% in the CPX-351
group and 20.5% in the 7+3 group.
Outcomes after allogeneic transplant in older patients with
high-risk AML appear superior in patients treated with CPX-
351, he concluded. The ndings of lower-inductionrelated
morbidity and more patients in CR suggest that patients are
transplanted in better condition, he commented.
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139
 RESEARCH BRIEFS
Prevention Efforts Have Mixed
Results for Injection-Drug Users
More people who need them are using syringe services
programs (SSPs), but they still arent always using sterile needles,
according to a Centers for Disease Control and Prevention
(CDC) Vital Signs report. Thus, theyre still at risk for human
immunodeciency virus (HIV), hepatitis B, and hepatitis C
(HCV) infection.
Researchers conducted a study of people who inject drugs in
22 U.S. cities with a high number of HIV cases. In 2015, more
than half of people who inject drugs said they used an SSP in
the previous year, compared with about one-third in 2005. But
the percentage of people who received at least one syringe from
an SSP and shared syringes was about the same as those who
had not received any syringes from SSPs (31% versus 38%).
The good news is that annual acquired immunodeciency
syndrome (AIDS) diagnoses among people who inject drugs
have dropped by a stunning 90%. Nonetheless, about 9% of
HIV infections diagnosed each year are due to injecting drugs.
Injection drug use has also contributed to a 150% rise in acute
cases of HCV infections.
But prevention efforts are paying off in the African-American
and Latino communities, says Eugene McCray, MD, Director
of the CDCs Division of HIV/AIDS Prevention. The number
of African-Americans getting all syringes from SSPs was up by
48%, and the number sharing syringes was down 34% from 2005.
The number of HIV diagnoses among African-Americans who
inject drugs declined by 60% from 2008 to 2014.
Syringe sharing was also down 12% among Latinos, and HIV
diagnoses dropped by 50% from 2008 to 2014 in that population.
In contrast, whites who inject drugs continue to share at
similar levels45% in 2005 versus 43% in 2015. The number
receiving all syringes from sterile sources remained unchanged
at 22%, and HIV diagnoses remained stable from 2012 to 2014.
Recent trends indicate that heroin use and injection drug use
among whites are on the rise; that, coupled with high rates of
syringe sharing, might challenge the decades of progress in HIV
prevention, the researchers say. They also point to obstacles
such as a potential lack of sufcient sterile equipment, too few
SSPs in rural areas, and absence of legal support in many states.
Decisions about SSPs are made at state and local levels, the
report notes. In 2015, Congress gave states and local commu-
nities the opportunity to use federal funds to support certain
components of comprehensive SSPs, which also offer or refer
people to prevention, care, and treatment.
Until now, the nation has made substantial progress in pre-
venting HIV among people who inject drugs, but this success
is threatened, says Jonathan Mermin, MD, MPH, Director of
the CDCs National Center for HIV/AIDS, Viral Hepatitis, STD,
and TB Prevention. Syringe services programs work, and their
expansion is pivotal for progress in the coming decades.
Source: CDC, December 2016
140 P&T February 2017 Vol. 42 No. 2
Even Just A Few Cigarettes
Have Long-Term Consequences
There is no safe level of smokingthats the conclusion
of National Cancer Institute researchers, based on data from
290,215 adults in the 20042005 NIH-AARP Diet and Health
Study. Smoking even a small number of cigarettes per day
has substantial negative health effects, said lead author Maki
Inoue-Choi, PhD.
The participants responded to a questionnaire that assessed
lifetime smoking intensity. Those who smoked between one and
10 cigarettes a day had an 87% higher risk of earlier death. But
even people who smoked an average of less than one cigarette
per day over their lifetimes still had a 64% higher risk of earlier
death compared with never-smokers.
The researchers also looked at specic causes of death.
Not surprisingly, they found a particularly strong associa-
tion for lung cancer mortality. But again, even people who
consistently averaged less than one cigarette per day over their
lifetimes had nine times the risk of dying from lung cancer
than never-smokers. Among those who smoked between one
and 10 cigarettes a day, the risk of dying from lung cancer was
nearly 12 times higher.
People who smoked between one and 10 cigarettes a day
also had more than six times the risk of dying from respiratory
disease and about one and a half times the risk of dying of
cardiovascular disease compared with never-smokers.
The younger people were when they quit smoking, the lower
their risk of early death.
Source: National Institutes of Health, December 2016
Multiple Myeloma and Stroke: Whats the Risk?
Some 20% to 40% of patients with multiple myeloma have
renal impairment and may also be taking drugs that raise the
risk of venous thromboembolism (VTE). Are those the factors
responsible for the higher risk of arterial thrombosis in this
patient group? Researchers from the University of Arkansas
and Ohio State University conducted a large retrospective,
comparative case-control study to nd out.
The patients were all enrolled in total therapy protocols
that tested varying combinations of thalidomide, bortezomib,
lenalidomide, and dexamethasone. Of 1,148 patients, 46 (4%)
had strokes, usually ischemic stroke (33 patients or 72%).
Hypercoagulability, atrial brillation, and small-vessel occlusion
were common mechanisms. While other research has found a
higher risk of arterial thrombosis from activated prothrombotic
factors, especially during the early period of chemotherapy, in
this study, vascular events occurred even months later.
Seven patients died in the hospital (15% compared with a
national average of 5%). Although six of those deaths were
stroke-related, most patients (78%similar to the national
average) were discharged home or to a rehabilitation facility;
two were discharged to a long-term nursing facility. During a
 RESEARCH BRIEFS
median follow-up of 10 years, six patients had another stroke.
The cumulative risk of recurrent stroke was 15% compared
with 5% for the general population.
Stage I and II cancer and renal insufciency independently
predicted stroke. Also noteworthy, the researchers said, is
that patients with multiple myeloma who developed renal
insufciency had worse clinical outcomes despite improve-
ment in their renal function or lack of signicant difference
in their baseline renal functions between various treatment
protocols. Thus, the increased risk of stroke, recurrent stroke,
and mortality could partly be due to renal disease, which might
or might not have resulted from myeloma.
Use of combination chemotherapy has markedly improved
clinical outcomes for multiple myeloma patients, the research-
ers said, but those drugs have also been associated with an
increased risk of VTE, especially during the rst months of
chemotherapy. Thalidomide alone did not increase the risk of
VTE, nor did lenalinomide on its own. However, thalidomide
combined with multiagent chemotherapy increased VTE risk
as much as 34% in newly diagnosed patients, and lenalinomide
with dexamethasone boosted risk as high as 75%.
The researchers found no signicant relationship between
mortality and use of thalidomide. Median survival was
103 months for a thalidomide-based regimen and 78 months
for a regimen without thalidomide.
Interestingly, the researchers noted, the patients developed
strokes despite a trend toward coagulopathy, to the extent that
half were ineligible for immediate use of antiplatelet agents.
The study ndings heightened our awareness, the research-
ers said, that aggressive preventive measures can help reduce
the incidence of stroke in patients with renal insufciency.
Source: PLoS One, November 2016
Hospital-Acquired Conditions on the Decline
Hospital-acquired conditions (HACs) are still trending down-
ward, with 3 million fewer adverse eventsa 21% dropover
a ve-year period, according to the recently released National
Scorecard on Rates of Hospital-Acquired Conditions. Thanks in
part to provisions of the Patient Protection and Affordable Care
Act, the Department of Health and Human Services (HHS)
says, about 125,000 fewer patients died due to HACs, and more
than $28 billion in health care costs were saved.
Agency for Healthcare Research and Quality (AHRQ)
researchers used national data systems to analyze the
incidence of 28 HACs that occurred from 2010 to 2015. The
list included adverse drug events, catheter-associated urinary
tract infections, central-lineassociated bloodstream infec-
tions, pressure ulcers, and surgical-site infections, selected as
focus areas because theyre common and considered
preventable.
AHRQs Comprehensive Unit-based Safety Program (CUSP)
is one of the tools used most often to cut down on HACs. Its a
proven method, HHS says, that combines improvement in safety
culture, teamwork, and communications with evidence-based
practices to protect patients. AHRQ has worked hand-in-hand
with front-line clinicians to help them use CUSP in a series of
highly effective nationwide projects.
AHRQ has been building a foundation of patient safety
research for the last decade and a half at the request
of Congress, said AHRQ Director Andy Bindman, MD.
Now were seeing these investments continue to pay off in
terms of lives saved, harm avoided, and safer care delivery
overall.
Source: HHS, December 2016
When Work Puts Employees at Risk for Asthma
As many as 2.7 million American workers might have asthma
that their work has caused or worsened, say Centers for Disease
Control and Prevention (CDC) researchers. Data from the
20062007 Behavioral Risk Factor Surveillance System Asthma
Call-back Survey of 208,788 adults in 33 states revealed that
nearly half of adult asthma might be related to work, and thus
potentially preventable.
Of the respondents employed in the previous year, 7.7% had
asthma, ranging from 5% in Mississippi to 10% in Michigan.
Among the 21 states that collected information on industry and
occupation, prevalence was highest among workers in health
care support occupations in Michigan (21.5%). In fact, health
care ranked rst among the ve industries with the highest
asthma prevalence, and health care practitioners ranked second
among the ve occupational groups with the highest asthma
prevalence.
Different industries and occupations have different irritants.
In health care, for instance, cleaning and disinfection products,
powdered latex gloves, and aerosolized medications have
doubled the likelihood of new-onset asthma, the report notes.
But its possible to make a big dent in the illness prevalence
with evidence-based changes. The researchers say powder-
free natural rubber latex or nonlatex gloves, for instance,
considerably reduced workplace asthma in the health care
industry.
The researchers say their ndings might help physicians
and state public health ofcials identify workers who should
be evaluated for work-related asthma in order to plan and
target interventions.
Source: CDC, December 2016 Q
Vol. 42 No. 2 February 2017 P&T
141
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