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

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 Macrovascular Outcomes: There have been no clinical studies
establishing conclusive evidence of macrovascular risk reduction
In male and female rats, dulaglutide causes a dose-
with Trulicity or any other antidiabetic drug.
related and treatment-duration-dependent increase in
the incidence of thyroid C-cell tumors (adenomas and The most common adverse reactions reported in 5% of
carcinomas) after lifetime exposure. It is unknown whether Trulicity-treated patients in placebo-controlled trials (placebo,
Trulicity causes thyroid C-cell tumors, including medullary Trulicity 0.75 mg, and Trulicity 1.5 mg) were nausea (5.3%, 12.4%,
thyroid carcinoma (MTC), in humans as human relevance 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
of dulaglutide-induced rodent thyroid C-cell tumors has
(1.6%, 4.9%, 8.6%), dyspepsia (2.3%, 4.1%, 5.8%), and fatigue
not been determined.
(2.6%, 4.2%, 5.6%).
Trulicity is contraindicated in patients with a personal or Gastric emptying is slowed by Trulicity, which may impact
family history of MTC and in patients with Multiple absorption of concomitantly administered oral medications.
Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel Use caution when oral medications are used with Trulicity.
patients regarding the potential risk of MTC with use of Drug levels of oral medications with a narrow therapeutic
Trulicity and inform them of symptoms of thyroid tumors index should be adequately monitored when concomitantly
(eg, mass in the neck, dysphagia, dyspnea, persistent administered with Trulicity. In clinical pharmacology studies,
hoarseness). Routine monitoring of serum calcitonin or Trulicity did not affect the absorption of the tested, orally
using thyroid ultrasound is of uncertain value for early administered medications to a clinically relevant degree.
detection of MTC in patients treated with Trulicity. Pregnancy: There are no adequate and well-controlled studies
of Trulicity in pregnant women. Use only if potential benet
Trulicity is contraindicated in patients with a personal or family outweighs potential risk to fetus.
history of MTC or in patients with MEN 2, and in patients with Nursing Mothers: It is not known whether Trulicity is excreted in
a prior serious hypersensitivity reaction to dulaglutide or any human milk. A decision should be made whether to discontinue
of the product components. nursing or to discontinue Trulicity, taking into account the
Risk of Thyroid C-cell Tumors: Cases of MTC in patients treated importance of the drug to the mother.
with liraglutide, another GLP-1 receptor agonist (GLP-1 RA), Pediatric Use: Safety and effectiveness of Trulicity have not
have been reported in the postmarketing period; the data in been established and use is not recommended in patients
these reports are insufcient to establish or exclude a causal less than 18 years of age.
relationship between MTC and GLP-1 RA use in humans.
Please see Brief Summary of Prescribing Information, including
If serum calcitonin is measured and found to be elevated or
Boxed Warning about possible thyroid tumors including
thyroid nodules are noted on physical examination or neck
thyroid cancer, on following page.
imaging, the patient should be further evaluated.
Please see Instructions for Use included with the pen.
Pancreatitis: Has been reported in clinical trials. Observe
patients for signs and symptoms including persistent severe DG HCP ISI 20APR2015
abdominal pain. If pancreatitis is suspected, discontinue Trulicity is a registered trademark owned or licensed by Eli Lilly and Company,
Trulicity promptly. Do not restart if pancreatitis is conrmed. its subsidiaries, or affiliates. Trulicity is available by prescription only.
Consider other antidiabetic therapies in patients with a history References
of pancreatitis. 1. Trulicity [Prescribing Information]. Indianapolis, IN: Lilly USA, LLC; 2015.
Hypoglycemia: The risk of hypoglycemia is increased when 2. Trulicity [Instructions for Use]. Indianapolis, IN: Lilly USA, LLC; 2014.
Trulicity is used in combination with insulin secretagogues 3. Glaesner W, Vick AM, Millican R, et al. Engineering and characterization
(eg, sulfonylureas) or insulin. Patients may require a lower dose of the long-acting glucagon-like peptide-1 analogue LY2189265, an
of the sulfonylurea or insulin to reduce the risk of hypoglycemia. Fc fusion protein. Diabetes Metab Res Rev. 2010;26(4):287-296.
Hypersensitivity Reactions: Systemic reactions were observed 4. Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus
in patients receiving Trulicity in clinical trials. Instruct patients once-daily liraglutide in metformin-treated patients with type 2 diabetes
who experience symptoms to discontinue Trulicity and promptly (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial
[published correction appears in Lancet. 2014;384:1348]. Lancet.
seek medical advice.
2014;384:1349-1357.
Renal Impairment: In patients treated with GLP-1 RAs, there 5. Umpierrez G, Tof Povedano S, Prez Manghi F, et al. Efcacy and
have been postmarketing reports of acute renal failure safety of dulaglutide monotherapy versus metformin in type 2
and worsening of chronic renal failure, sometimes requiring diabetes in a randomized controlled trial (AWARD-3). Diabetes Care.
hemodialysis. A majority of reported events occurred in 2014;37:2168-2176.
patients who had experienced nausea, vomiting, diarrhea, 6. Giorgino F, Benroubi M, Sun JH, et al. Efcacy and safety of once-weekly
or dehydration. In patients with renal impairment, use caution dulaglutide versus insulin glargine in patients with type 2 diabetes on
when initiating or escalating doses of Trulicity and monitor metformin and glimepiride (AWARD-2). Diabetes Care. 2015;38(12):2241-
renal function in patients experiencing severe adverse 2249.
gastrointestinal reactions. 7. Blonde L, Jendle J, Gross J, et al. Once-weekly dulaglutide versus
Severe Gastrointestinal Disease: Use of Trulicity may be bedtime insulin glargine, both in combination with prandial insulin lispro,
associated with gastrointestinal adverse reactions, sometimes in patients with type 2 diabetes (AWARD-4): a randomised, open-label,
severe. Trulicity has not been studied in patients with severe phase 3, non-inferiority study. Lancet. 2015;385:2057-2066.
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.


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


65
CONTENTS
February 2017

Cover: Scanning electron micrograph FEATURES


of a white blood cell from a patient
with chronic lymphocytic leukemia
(CLL). A review of the latest treatment
FDA Flags Inconsistent Hospital Reporting
strategies for CLL starts on page 106. Of Medical Device Problems 97
(Credit: Aaron Polliack/Science Source) 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
DEPARTMENTS events. However, participants using the new system will incur signicant capital costs.
Stephen Barlas
Medication Errors 74
The impact of disrespectful New Pharmacotherapies in Chronic Lymphocytic Leukemia 106
workplace behavior and how The authors present the clinical outcomes and therapeutic application of
to address it newly approved pharmacotherapies for chronic lymphocytic leukemia and
highlight emerging investigational therapeutic options.
Prescription: Washington 76 Jacqueline L. Olin, MS, PharmD, BCPS, CDE, FASHP, FCCP; Katherine Canupp, BS,
21st Century Cures bill may PharmD Candidate; and Morgan B. Smith, PharmD, BCOP
lead to faster drug/device
approvals Experts Provide a Glimpse of the
New Post-SPRINT Era of Hypertension 118
Drug and Device News 78 In advance of the new guidelines being published this year, the author discusses
Approvals, new indications, treatment targets, diagnostics, and public policy with three hypertension experts.
regulatory activities, and more Susan L. Worley
Pharmaceutical Effect of Intravenous Acetaminophen on Post-Anesthesia Care
Approval Update 90
Prasterone (Intrarosa) for the
Unit Length of Stay, Opioid Consumption, Pain, and Analgesic
treatment of dyspareunia due Drug Costs After Ambulatory Surgery 125
to menopause; crisaborole A retrospective cohort study conducted in adult patients nds that intravenous
(Eucrisa) for the topical acetaminophen use in certain ambulatory procedures is not associated with
treatment of atopic dermatitis; decreased PACU length of stay, but it may decrease postoperative pain.
and tenofovir alafenamide Moteb A. Khobrani, PharmD; James M. Camamo, PharmD; and
(Vemlidy) for once-daily Asad E. Patanwala, PharmD
treatment of chronic hepatitis
B virus infection PIPELINE PLUS
New Schizophrenia Treatments
Drug Forecast 92 Address Unmet Clinical Needs 130
Brivaracetam (Briviact): We present several novel drugs in development for enhancing cognition, treating
a novel adjunctive therapy negative symptoms, and providing improved options for treatment-resistant patients.
for partial-onset seizures Drug makers aim to enhance safety proles and increase patient compliance to therapy.
Chris Fellner
Author Guidelines 124
MEETING HIGHLIGHTS
Research Briefs 140
American Society of Hematology
Annual Meeting and Exposition 135
Back issues are available on Key sessions on pharmacotherapy clinical trials across a wide span of disease states,
the PubMed Central archive. including leukemia, graft-versus-host disease, myelobrosis, multiple myeloma, and
Visit www.pubmedcentral.nih.gov sickle cell disease, are reviewed.
Walter Alexander

The digital edition does not contain some of the advertising pages that appear in the print edition.
Editor-in-Chief Associate Editor-in-Chief
David B. Nash, MD, MBA Karl A. Matuszewski, MS, PharmD
Dr. Raymond C. and Vice President
Doris N. Grandon Professor First Databank, Inc.
The Jefferson College of Population Health Clinical and Editorial
Philadelphia, Pennsylvania Knowledge Base Services
South San Francisco, California
EDITORIAL BOARD
Richard Afable, MD, MPH Marvin M. Goldenberg, PhD, RPh, MS Luke A. Probst, PharmD, BCPS
President and Chief Executive Ofcer President, Pharmaceutical and Scientic Director of Pharmacy Services
Hoag Memorial Hospital Presbyterian Services Upstate University Hospital/
Newport Beach, California Marvin M. Goldenberg, LLC Downtown Campus
Westeld, New Jersey Clinical Assistant Professor, Departments
Robert L. Barkin, MBA, PharmD of Pediatrics and Medicine
Professor, Faculty of Anesthesiology, Nancy Greengold, MD, MBA SUNY Upstate Medical University
Family Medicine, and Pharmacology Chief Medical Ofcer Syracuse, New York
Rush Medical College of Rush University Sharp Grossmont Hospital/Sharp
Chicago, Illinois HealthCare Sheldon M. Retchin, MD, MSPH
Clinical Pharmacologist La Mesa, California Executive Vice President of Health
North Shore University Health System
Sciences, The Ohio State University
Pain Centers
Matthew Grissinger, RPh, FASCP Chief Executive Ofcer, OSU Wexner
Skokie and Evanston, Illinois
Director, Error Reporting Programs Medical Center
Institute for Safe Medication Practices Columbus, Ohio
Mark J. Baumel, MD, MS Horsham, Pennsylvania
President/Chief Executive Ofcer
Colon Health Centers of America, LLC Vitalina Rozenfeld, PharmD, BCPS
Mendenhall, Pennsylvania Rusty Hailey, PharmD, DPh, MBA, FAMCP Medical Affairs
President, Pharmaceutical Operations AstraZeneca
Thomas Biancaniello, MD Senior Vice President, HealthSpring, Inc. Wilmington, Delaware
Clinical Professor of Pediatrics Nashville, Tennessee
Columbia University Fadia T. Shaya, PhD, MPH
College of Physicians and Surgeons Steven D. Hanks, MD, MMM, FACP Professor and Vice-Chair for Academic
Division of Pediatric Cardiology Executive Vice President Affairs
New York, New York and Chief Medical Ofcer University of Maryland School of Pharmacy
The Hospital of Central Connecticut Associate Director
Joseph E. Biskupiak, PhD, MBA New Britain, Connecticut Center on Drugs and Public Policy
Research Associate Professor Baltimore, Maryland
Department of Pharmacy Practice Michele B. Kaufman, PharmD, BCGP, RPh
Director, Pharmacotherapy Outcomes Pharmacist, New YorkPresbyterian
Research Center Arthur F. Shinn, PharmD, FASCP
Lower Manhattan Hospital, Pharmacy
College of Pharmacy, University of Utah President
Department
Salt Lake City, Utah Managed Pharmacy Consultants, LLC
New York, New York
Palm City, Florida
David A. Casey, MD Grant D. Lawless, RPh, MD
Vice Chairman, Department of Psychiatry Associate Professor of Clinical Pharmacy, Brian Swift, PharmD, MBA
University of Louisville Pharmaceutical Economics and Policy Vice President/Chief of Pharmacy
Louisville, Kentucky Director, Master of Science Program in and Accreditation
Healthcare Decision Analysis Thomas Jefferson University Hospital
Alan Caspi, PhD, PharmD, MBA School of Pharmacy Associate Dean of Professional Affairs
President, Caspi & Associates University of Southern California Jefferson College of Pharmacy
New York, New York Los Angeles, California Philadelphia, Pennsylvania

Burke A. Cunha, MD Burton Orland, BS, RPh F. Randy Vogenberg, RPh, PhD
Professor of Medicine President Partner
State University of New York at Stony Brook BioCaRe Consultants Access Market Intelligence and National
Chief, Infectious Disease Division Westport, Connecticut Institute of Collaborative Healthcare
Winthrop-University Hospital Greenville, South Carolina
Mineola, New York
Fred Joseph Pane, RPh, BS, FASHP, FABC
Joseph C. English III, MD Senior Director, Customer Engagement Scott W. Yates, MD, MBA, MS
Professor of Dermatology The Medicines Company Center for Executive Medicine
Clinical Vice Chairman Parsippany, New Jersey Plano, Texas
for Quality and Innovation
Founding Director of Teledermatology Lawrence Charles Parish, MD
University of Pittsburgh Dermatologist, Editor-in-Chief
Department of Dermatology Clinics in Dermatology
Pittsburgh, Pennsylvania Philadelphia, Pennsylvania

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 Why Disrespectful Behavior Arises unclear whether poor working conditions
board member of P&T, is Disrespectful behavior can arise in create an environment where the behav-
Director of Error Reporting any health care setting, and both the iors are tolerated or if the disrespectful
Programs at the Institute for stressful nature of the environment and behaviors create the unfavorable
Safe Medication Practices human nature play roles in this destruc- environment.7,8
(ISMP) in Horsham, Penn- tive behavior. We are driven to function in Organizations have largely failed to
sylvania (www.ismp.org). survival mode when forced to cope with address disrespectful behavior for a
difcult personal frustrations and system variety of reasons. First, the behavior
In our last column, we published the failures. Disrespectful behavior is often typically occurs daily but often goes
results of an Institute for Safe Medication survival behavior gone awry.2 Although unreported due to fear of retaliation
Practices (ISMP) survey, which clearly personal frustrations and system failures and the stigma associated with whistle
exposed health cares continued tolerance do not excuse disrespectful behavior, blowing. Disrespectful behaviors are
of and indifference to disrespectful behav- they often create a tipping point by which difcult to measure, so without robust
ior.1 Widespread disrespectful behavior an individual is pushed over the edge systems of environmental scanning to
in health care persists unchecked and into full-blown disrespectful behavior. uncover the behavior, leaders may be
is found at all levels of the organization Characteristics of the individual, such as ignorant of the problem.9 Leaders may
and among all disciplines of staff. The insecurity, anxiety, depression, aggres- also be unaware of the behavior if man-
stubborn strength of this problem lies siveness, and narcissism, can also kick agers shield them from this informa-
in its quiet ability to undermine critical in and serve as a form of self-protection tion because they view it as a personal
conversations.2 In Part 2, we delve into the against feelings of inadequacy.5 Cul- failure.9 If disrespectful behaviors are
impact of disrespectful behavior, why it tural, generational, and gender biases, known, leaders may be reluctant to con-
arises and persists, and how to address it. and current events inuencing mood, front individuals if they are powerful or
attitude, and actions, also contribute to high-revenue producers, or they may not
Impact of Disrespectful Behavior disrespectful behavior.4 know how to handle the problem. Its not
Disrespectful behavior chills communi- Differences in communication styles a topic taught in training programs, so
cation and collaboration, undercuts indi- and power dynamics can also play a leaders may hesitate to take on a problem
vidual contributions to care, undermines role.5,6 For example, physicians may get for which there is no obvious solution.9
staff morale, increases staff resignations frustrated when nurses present informa-
and absenteeism, creates an unhealthy or tion in more detail than they believe is Addressing Disrespectful Behavior
hostile work environment, causes some to necessary. Nurses may get frustrated 1. Set the Stage
abandon their profession, and ultimately when physicians do not seem interested Establish a steering committee of
harms patients. These behaviors have in the information provided. These differ- trustees, senior leaders, middle manag-
been linked to adverse events, medical ences in communication styles can lead ers, physicians, pharmacists, nurses, and
errors, compromises in patient safety, and to disrespectful behavior. The hierarchi- other staff. Have the committee educate
even patient mortality.3,4 Disrespect causes cal nature of health care and a sense of itself about disrespectful behavior, dene
the recipient to experience fear, anger, privilege and status can lead those at the the behavior, list examples of the many
shame, confusion, uncertainty, isolation, top of a hierarchy to treat others lower on forms it can take, and establish an action
self-doubt, depression, and a whole host the hierarchy with disrespect. plan that species how to identify dis-
of physical ailments, such as insomnia, respectful behavior, respond to it, and
fatigue, nausea, and hypertension.5 These Why Disrespectful Behavior Persists measure the success of organizational
feelings diminish a persons ability to think Health care organizations have fed efforts. Responsibility for addressing the
clearly, make sound judgments, and speak the problem of disrespectful behavior problem belongs to the leaders, who need
up regarding questions or concerns. Dis- for years by ignoring it, thereby tacitly to raise awareness of the problem, inspire
respectful behavior is also at the root of accepting such behaviors.2 The health others to change, communicate respect
difculties encountered in developing care culture has permitted a certain as a core value, articulate their commit-
team-based approaches to improving degree of disrespect while considering ment to achieving it, and create a sense
care.5 Patient condence has also been this a normal style of communication.5 of urgency around doing so.
undermined by disrespectful behaviors, Studies have shown that disrespectful Establish a no retribution policy for
making patients less likely to ask questions behaviors are tolerated most often in those who report disrespectful behavior.
or provide important information. unfavorable work environments, but it is This policy must be established at the

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


MEDICATION ERRORS

very onset of organizational efforts to I statements and nonjudgmental nication, hand-offs, physical hazards,
reduce disrespectful behaviors. terminology; specify or inquire and environmental stressors. Individual
Open the dialogue about disrespect- about an alternate course of action; behaviors can also be altered through
ful behavior by surveying staff about discuss both positive and negative system improvements.2
the issue using surveys from ISMP consequences
(www.ismp.org/survey/disrespectful) TeamSTEPPS (http://teamstepps. 6. Train Staff
or the Agency for Healthcare Research ahrq.gov): Team Strategies and Provide mandatory hospital-wide
and Quality (www.ismp.org/sc?id=343). Tools to Enhance Performance and education for all staff about the impact of
Incorporate questions about disrespect- Patient Safety, an evidence-based disrespectful behavior and appropriate
ful behavior in safety rounds. Hold focus teamwork system to improve com- professional behavior as dened by the
groups where frank discussions can be munication and teamwork skills code of conduct.12,14 Provide skill-based
held with objective facilitators to keep among health care professionals. training in communication methods,
the conversation productive. However relationship building, business etiquette,
uncomfortable, dialogue on this issue is 4. Manage Conicts behavioral techniques to confront and
crucial to the development of more effec- An escalation policy must be estab- address disrespect, conict resolution,
tive and respectful ways of interacting lished to manage conicts about the assertiveness training, team training, and
with each other. safety of an order when the standard how to report disrespectful behaviors.
communication process fails to resolve Use role-playing, vignettes, or aggression
2. Establish a Code of Conduct an issue. Staff must know whom to call scenarios to strengthen skills associated
Create a code of conduct (or code of to aid in getting a satisfactory resolution. with assertive communication, conict
professionalism) that serves as a model Be sure the process provides an avenue resolution, and interpersonal interactions.
of interdisciplinary collegial relationships for resolution outside the typical chain of One health system provides leaders with a
(different but equal) and collaboration command in case the conict involves a toolkit that includes talking points regard-
(mutual trust and respect that produces subordinate and his or her supervisor. ing the impact of disrespectful behavior,
willing cooperation).10 Clearly articulate the code of conduct, denitions, surveys,
the standard of behavior desired as well 5. Establish Interventions communication/teamwork guides, key
as unacceptable behaviorsdont assume Develop an intervention policy that has articles and intranet resources, no retri-
staff know this, so be clear.9 Addressing full leadership support to consistently bution policy, and a letter from the chief
disrespectful behavior must start with address disrespectful behaviors. An executive ofcer outlining full leadership
an absolute belief by all staff that no one effective policy includes zero tolerance support.9
deserves to be treated with disrespect. for disrespectful behaviors regardless of
Furthermore, the code of conduct should the offenders standing in the organiza- 7. Encourage Reporting/
not allow any exemptions. As long as tion, fairness to all parties, consistency in Surveillance
those who generate the most revenue enforcement, a tiered response to infrac- Implement a condential reporting/
are excused from responsibility for their tions, a restorative process to help people surveillance program for detecting dis-
actions, the code of conduct will have change their behavior, and surveillance ruptive behavior and measuring compli-
little impact on anyone elses behavior.11 mechanisms.12 Levels of interventions ance with the code of conduct. A formal
might start with coaching and proceed reporting program and an informal
3. Establish a Communication to progressive discipline as warranted. process for unwritten reports should be
Strategy The intervention policy should clearly offered, and anyone who experiences or
Establish a standard, assertive com- articulate the behaviors or repeated witnesses disruptive behavior should be
munication process for health care staff behaviors that will be referred for dis- encouraged to report the event.13 The no
who must convey important informa- ciplinary action, and how and when the retribution policy for reporting should
tion. Stating the problem along with its disciplinary process will start.13 The focus be well known to staff and upheld. Peri-
rationale and a potential solution can of an intervention should be on building odic updates should be provided to those
improve assertive communication. trust and holding staff accountable for who make reports about addressing
Numerous communication techniques making better behavioral choices. The disrespectful behaviors, but individual
are available to help staff accomplish this, importance of a prompt, predictable, and details should remain condential.
including: appropriate response to an alleged viola- No organization should assume that
tion cannot be overemphasized.10 In all the absence of reports of disrespectful
SBAR (www.ismp.org/sc?id=344): cases, those who report or cooperate in behavior means it is not occurring. Other
the person communicating the the investigation should be protected means of surveillance to identify dis-
crucial information covers the situa- against retaliation.12 respectful behaviors should be employed,
tion, background, assessment, and The intervention policy should also including feedback from patients and
recommendations require addressing any system issues that families, staff and patient surveys, focus
D-E-S-C script (www.ismp.org/ amplify and perpetuate the disrespectful groups, informal dialogue, peer and team
sc?id=345): Describe in objective behavior. Common system problems evaluations, and making direct inquiries
terms what you observed, heard, or include issues that affect workloads, at routine intervals (e.g., during safety
perceived; express concerns using stafng, budgeting, education, commu- 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 real-world evidence (RWE) and surro- determines aids drug development and
writer in Washington, gate endpoints, such as biomarkers. The regulatory review for purposes of this
D.C., who covers issues term RWE refers to ndings about a drug section.1 Dr. Dhruva also worries about
inside the Beltway. Send that are gleaned by looking at patient the FDA moving away from requiring
ideas for topics and your health records, whether obtained in a drug manufacturers to prove that a drug
comments to sbarlas@ clinical trial or not, and marrying them actually benets a patient by making
verizon.net. with health insurance claims data and/or his or her life longer and/or better. He
product registries to reach a conclusion cites the controversial use of endpoints
about whether an already-approved drug in the recent FDA approval of eteplirsen
cynic might say that it is hard to should be approved for a new indication. (Exondys 51, Sarepta Therapeutics)

A take the mammoth 21st Century


Cures bill seriously. It passed
Congress at the very end of the session in
The FDA already issued a guidance docu-
ment on RWE used for medical device
approval in 2016,2 so it is not clear what
based on the use of a surrogate measure
(in this case, muscle dystrophin levels).
In an article published by the Journal of
December, the culmination of four years the bill requires the FDA to do that it the American Medical Association, Aaron
of discussion. So in one sense, many of its is not already doing. Moreover, the top S. Kesselheim, MD, JD, MPH, of the
provisions were vetted, at least politically, leaders of the FDA published an article in Program on Regulation, Therapeutics,
which is another way of saying they didnt the New England Journal of Medicine on and Law (PORTAL) at Harvard Medical
raise serious objections in any quarter. December 8, 2016,3 committing to move School, and similarly situated colleague
The votes in the House (39226) and forward with the use of RWE, including Jerry Avorn, MD, wrote:
Senate (945) were testimony to that. It publishing draft guidance on pharma-
can often be said that, when it comes to ceuticals as a follow-on to its guidance However, the accelerated approval pathway
congressional legislation, no controversy on medical devices. The provision in the through which eteplirsen was authorized
equals minimal signicance. bill simply requires the FDA to evaluate requires that a surrogate endpoint must be
The nearly 1,000-page bill is a hodge- the use of RWE. reasonably likely to predict clinical benet
podge of loosely worded speculative The bill denes RWE as data regard- of the drug, and this standard is challenged
provisions across many health care/ ing the usage, or the potential benets by the minimal changes seen in the dys-
federal programs, most of them at the or risks, of a drug derived from sources trophin levels. Speeding drugs to market
Food and Drug Administration (FDA) other than randomized clinical trials.1 based on such biomarker outcomes can
and National Institutes of Health (NIH).1 The implication that randomized clinical actually lead to a worse outcome for patients,
When the House Energy and Commerce trials can be done away with concerns even those with life-threatening diseases, if
Committee began holding hearings on some health researchers, such as Sanket a product confers no meaningful benet
the bill four years ago, the legislation was Dhruva, MD, FACC, a cardiologist and and carries a risk of adverse effects and a
viewed as a vehicle for allowing, or, if one health services researcher at the Yale high cost. Immediately after approval, the
prefers, forcing the FDA to permit phar- University School of Medicine. Speci- manufacturer announced a price of $300,000
maceutical companies to gain approval of cally saying that clinical trials, the gold per year for eteplirsen.4
new indications for existing drugs with standard in drug and medical device
evidence assembled short of expensive approval, do not have to be used takes The FDA approval process measures
clinical trials and short of conventional a step in the wrong direction, he says. were sought by the Pharmaceutical
endpoints. Over the years, the vehicle There certainly is tremendous poten- Research and Manufacturers of America
was expanded to include funding for the tial with RWE, but we must validate the (PhRMA) and the Advanced Medical Tech-
Cancer Moonshot supported by Vice evidence as being rigorously collected nology Association, the drug and medical
President Joe Biden and some other pro- and reliable. device manufacturers trade groups, and
grams at the NIH. As the bill lumbered Dr. Dhruva worries about the bills some patient groups, too. The PhRMA
toward passage in early December, it was endorsement of the use of drug develop- released a statement saying:
larded with new provisions in areas such ment tools in the drug approval process.
as mental health and opioid addiction. Here, the bill denes those tools as: a) a The legislation includes pro-patient, science-
The FDA provisions are the most biomarker; b) a clinical outcome assess- based reforms, which enhance the com-
ballyhooed and are where the bill started. ment; and c) any other method, mate- petitive market for biopharmaceuticals and
Here, the legislation encourages the rial, or measure that the [Department of drive greater efciency in drug develop-
FDA to approve new drugs based on Health and Human Services] Secretary ment. It also increases FDAs regulatory

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


PRESCRIPTION: WASHINGTON

capabilities to foster the timely review and that identies, measures, or describes the REFERENCES
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No: 114255. Available at: www.congress.
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Were this done, FDA would acquire a bestowing too many of what might be 316(22):23572358. Q
large number of new responsibilities, viewed as rich gifts on the drug industry.
but the agency would not receive net
additional funds, the Alliance says. Seen
another way, FDA might nd itself with a and communication defects on patient
signicant budget cut imposed upon the MEDICATION ERRORS safety. Jt Comm J Qual Patient Saf 2008;
34(8):464471.
agencys non-Cures activities. continued from page 75 4. McNamara SA. Incivility in nursing:
There might be a similar scenario affect- 8. Create a Positive Environment unsafe nurse, unsafe patients. AORN J
ing funding for the NIH. The Cures bill Certain aspects of the workplace envi- 2012;95(4):535540.
provides $4.8 billion in new funding for ronment are key to combatting disrespect, 5. Leape LL, Shore MF, Dienstag JL, et al.
Perspective: a culture of respect, part 1:
the NIH over the next 10 years to pursue including a fair and just culture, respectful
the nature and causes of disrespectful
a moonshot to cure cancer, investi- management of serious adverse events, behavior by physicians. Acad Med 2012;
gate brain chemistry, and develop indi- and transparency so staff members feel 87(7):845852.
vidualized or precision medicine. Even if safe talking about disrespectful behavior 6. Gessler R, Rosenstein A, Ferron L. How
Congress continues to increase annual without fear of reprisal.12 Another factor to handle disruptive physician behavior.
Am Nurse Today 2012;7(11):810.
appropriations for the NIH at approxi- is visible leadership commitment to a 7. Lamontagne C. Intimidation: a concept
mately the same rate it has beenbetween respectful culture, which requires leading analysis. Nurs Forum 2010;45(1):5465.
1% and 2% per yearthe extra $4.8 billion by example. Leaders should set the tone 8. Budin WC, Brewer CS, Chao YY, et al.
over 10 years probably wont keep NIH with an attitude of mutual respect for the Verbal abuse from nurse colleagues
and work environment of early career
spending increases even with ination. contributions of all staff, remain open to
registered nurses. J Nurs Scholarsh
Many other provisions are worth questions and new ideas, and reward 2013;45(3):308316.
noting, though it will not be clear for some outstanding examples of collaborative 9. Porto G, Deen J. Drawing the line. Effec-
time whether they are signicant or not. teamwork, respectful communication, tive management strategies for disruptive
The Academy of Managed Care Pharmacy and positive interpersonal skills. Using behavior. Patient Saf and Qual Healthcare
2008 Nov/Dec:2024,2628.
was glad to see a provision included in the key communication tools, such as email 10. Kramer M, Schmalenberg C. Securing
bill that it says will be a plus for formulary blasts, leaders can maintain an ongoing good nurse physician relationships.
decision-makers. Specically, it loosens dialogue about respectful behaviors with Nurs Manage 2003; 34(7):3438.
the current FDA standard dictating what the entire organization to help assure 11. Leape LL, Shore MF, Dienstag JL, et al.
Perspective: a culture of respect, part 2:
kind of health care economic information staff that leadership commitment to a
creating a culture of respect. Acad Med
a manufacturer can share with a health respectful culture is not eeting.2 2012;87(7):853858.
insurers P&T committee. The intention is 12. Pennsylvania Patient Safety Author-
to allow drug companies to share informa-
REFERENCES ity. Chain of command: when disruptive
1. Grissinger M. Unresolved disrespect- behavior affects communication and
tion about a drug beyond what is on the
ful behavior in health care: practi- teamwork. Pa Patient Saf Advis 2010;16(7)
drugs label. The bill denes health care tioners speak up (again)part 1. (suppl 2):S4S13.
economic information as: P T 2017;42(1):45,23. 13. DuPree E, Anderson R, McEvoy MD,
2. Zimmerman T, Amori G. The silent et al. Professionalism: a necessary ingredi-
... any analysis, including the clinical data, organizational pathology of insidious ent in a culture of safety. Jt Comm J Qual
intimidation. J Healthc Risk Manag 2011; Patient Saf 2011;37(10):447455.
inputs, clinical or other assumptions, 30(3):56,815. 14. The Joint Commission. Behaviors that
methods, results, and other components 3. Rosenstein AH, ODaniel M. A survey undermine a culture of safety. Sentinel
underlying or comprising the analysis of the impact of disruptive behaviors Event Alert 2008;40:13. Q

Vol. 42 No. 2 February 2017 P&T


77
NEW DRUG APPROVALS Synjardy ER for Diabetes NEW BIOLOGIC APPROVAL
Rubraca for Ovarian Cancer The FDA has given the green light Maci for the Repair of
The FDA has granted accelerated to Synjardy XR (empagliozin and met- Knee Cartilage Defects
approval to rucaparib (Rubraca, Clovis formin hydrochloride extended-release The FDA has approved Maci (auto-
Oncology) to treat women with advanced tablets, Boehringer Ingelheim/Eli Lilly) logous cultured chondrocytes on a
ovarian cancer who have been treated for the treatment of adults with type-2 porcine collagen membrane, Vericel
with two or more chemotherapies and diabetes (T2D). When used along with Corporation) for the repair of symptom-
whose tumors have a specic gene muta- diet and exercise, Synjardy XR is indi- atic, full-thickness cartilage defects of
tion (deleterious BRCA), as identied by cated to improve blood sugar in adults the knee in adults. Maci is the rst FDA-
an FDA-approved companion diagnostic with T2D when both empagliflozin approved product that applies the process
test. and metformin can be taken. Standard of tissue engineering to grow cells on
The agency also approved the Synjardy tablets were approved in 2015. scaffolds using healthy cartilage tissue
FoundationFocus CDxBRCA (Founda- Empagliflozin, a sodium-glucose from the patients own knee.
tion Medicine, Inc.) companion diagnos- cotransporter 2 inhibitor, removes excess Each Maci implant consists of a small
tic for use with rucaparib. The test detects glucose through the urine by blocking cellular sheet containing 500,000 to
the presence of deleterious BRCA gene glucose reabsorption in the kidney. Met- 1,000,000 cells per square centimeter
mutations in the tumor tissue of ovar- formin, a commonly prescribed initial treat- (approximately 0.16 square inches). The
ian cancer patients. If one or more of the ment forT2D, lowers glucose production by amount of Maci administered depends
mutations are detected, the patient may the liver and its absorption in the intestine. on the size of the cartilage defect, and
be eligible for treatment with rucaparib. Source: Eli Lilly, December 12, 2016 the membrane is trimmed to ensure that
Source: FDA, December 19, 2016 the damaged area is completely covered.
Adynovate Antihemophilic Factor Multiple implants may be used if there is
Spinraza for Spinal The FDA has approved Adynovate more than one defect.
Muscular Atrophy (antihemophilic factor [recombinant], Source: FDA, December 13, 2016
Nusinersen (Spinraza, Biogen/Ionis PEGylated, Shire), an extended circulating
Pharmaceuticals) has received FDA half-life recombinant factor VIII treatment Generic Approvals and Launches
approval as the rst drug to treat children for pediatric patients under 12 years of age Epinephrine Injection
and adults with spinal muscular atrophy with hemophilia A. The FDA also approved Mylan has launched an authorized
(SMA), a rare and often fatal genetic Adynovate for use in surgical settings in generic for the EpiPen autoinjector (epi-
disease affecting muscle strength and both adult and pediatric patients. Adyno- nephrine injection, USP) at a wholesale
movement. Nusinersen is an injection vate is built on the full-length Advate (anti- acquisition cost (WAC) of $300 per epi-
administered into the uid surrounding hemophilic factor [recombinant]) mole- nephrine injection two-pack, which is
the spinal cord. cule, a leading treatment for patients with more than 50% lower than the WAC of
The efcacy of nusinersen was inves- hemophilia A, with more than 13 years of the companys EpiPen 2-Pak autoinjec-
tigated in a study of 121 patients with real-world patient experience. tors. The authorized generic has the same
infantile-onset SMA who were diagnosed Source: Shire, December 27, 2016 drug formulation and device functionality
before 6 months of age and who were less as the EpiPen autoinjector and is admin-
than 7 months old at the time of their Eucrisa Ointment for Eczema istered the same way.
rst dose. The FDA asked the sponsor to Crisaborole ointment (Eucrisa, Ana- Source: Mylan, December 16, 2016
conduct an interim analysis as a way to cor Pharmaceuticals) has secured
evaluate the study results as early as pos- FDA approval to treat mild-to-moderate Oseltamivir Phosphate Capsules
sible; 82 patients were eligible for this eczema (atopic dermatitis) in patients Alvogen has launched the rst generic
analysis. Forty percent of the patients 2 years of age and older. Crisaborole, equivalent to Tamiu (oseltamivir phos-
treated with nusinersen achieved applied topically twice daily, is a phos- phate capsules, HoffmanLa-Roche) in
improvements in motor milestones as phodiesterase 4 inhibitor, although its the United States. The product is available
dened in the study, whereas none of the specic mechanism of action in atopic in 30-mg, 45-mg, and 75-mg strengths.
control patients did. dermatitis is not known. Alvogen expects this generic equivalent
Source: Biogen, December 27, 2016 Source: FDA, December 14, 2016 to Tamiu to deliver savings for patients

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


and health providers of up to $500 million to the rst occurrence of CV death, non- Stivarga for Liver Cancer
during the 20162017 u season. fatal heart attack, or nonfatal stroke) by The FDA has granted priority review
Source: Alvogen, December 12, 2016 14% compared with placebo (hazard ratio status to a supplemental new drug
[HR], 0.86); the absolute risk reduction application for regorafenib (Stivarga,
NEW INDICATIONS was 1.6% for empagliozin compared with Bayer) for the second-line treatment of
Lucentis for Eye Disorder placebo. This primary nding was driven patients with unresectable hepatocellular
The FDA has approved ranibizumab by a signicant 38% reduction in the risk carcinoma (uHCC).
(Lucentis, Genentech) 0.5-mg injec- of CV death (HR, 0.62); the absolute risk The regulatory submission was based
tion for the treatment of patients with reduction was 2.2% for patients treated on data from the phase 3 RESORCE
myopic choroidal neovascularization with empagliozin compared with those trial, which investigated regorafenib
(mCNV), a complication of severe near- given placebo. There was no change in in patients with uHCC whose disease
sightedness that can lead to blindness. the risk of nonfatal heart attack (HR, 0.87) had progressed during treatment
In the United States, ranibizumab was or nonfatal stroke (HR, 1.24). with sorafenib (Nexavar, Bayer/Onyx
previously approved for the treatment Source: Boehringer Ingelheim, Pharmaceuticals). Regorafenib signi-
of patients with wet age-related macu- January 5, 2017 cantly improved overall survival (OS)
lar degeneration; macular edema after compared with placebo (hazard ratio,
retinal vein occlusion; diabetic macular FDA REVIEW ACTIVITIES 0.63; P < 0.001), which represented a
edema (DME); and diabetic retinopathy Priority Review Designations 37% reduction in the risk of death for
in people with DME. Niraprib for Ovarian Cancer patients who received regorafenib plus
The new approval was based on results The FDA has granted priority review best supportive care (BSC) compared
from the phase 3, randomized, double- of the new drug application for niraparib with patients treated with placebo plus
blind, active-controlled RADIANCE trial, (Tesaro, Inc.). Niraparib is a poly(ADP- BSC. The median OS was 10.6 months
which compared the efcacy and safety ribose) polymerase inhibitor that is in patients treated with regorafenib
of ranibizumab injection (0.5 mg) with being evaluated as a potential new treat- plus BSC compared with 7.8 months in
that of verteporn photodynamic therapy ment option for patients with recurrent patients who received placebo plus BSC.
(vPDT) in 276 patients with visual impair- epithelial ovarian, fallopian tube, or Source: Bayer, January 4, 2017
ment due to mCNV. At month 3, two primary peritoneal cancer after respond-
ranibizumab groups had a mean change ing to platinum-based chemotherapy. The Betrixaban for VTE
in best corrected visual acuity (BCVA) FDA has established a target action date The FDA has accepted a new drug
of +12.1 and +12.5 letters from baseline, of June 30, 2017. application granting priority review for
respectively, compared with a mean BCVA The niraparib application was sup- betrixaban (Portola Pharmaceuticals),
change of +1.4 letters in the vPDT group. ported by data from a phase 3, double- an oral, once-daily factor Xa-inhibitor
Source: Genentech, January 5, 2017 blind, placebo-controlled, international anticoagulant, for extended-duration
trial that enrolled 553 patients with recur- prophylaxis of venous thromboembolism
Jardiance for Diabetic CV Risk rent ovarian cancer who had achieved (VTE) in acute medically ill patients with
The FDA has approved a new indication either a partial response or a complete risk factors for VTE. The application for
for empagliozin (Jardiance, Boehringer response to their most-recent platinum- betrixaban, an FDA-designated fast-
Ingelheim/Eli Lilly) to reduce the risk of based chemotherapy. Among patients track investigational drug, has a Prescrip-
cardiovascular (CV) death in adults with who were germline BRCA mutation car- tion Drug User Fee Act action date of
type-2 diabetes (T2D) and established riers, median progression-free survival June 24, 2017.
CV disease. Empagliozin is the rst T2D (PFS) for those treated with niraparib was Source: Portola Pharmaceuticals,
treatment with this additional indication 21.0 months compared with 5.5 months December 23, 2016
and the only oral T2D medication shown for control (P < 0.0001). Among patients
in a clinical trial to provide a life-saving CV in the nongermline BRCA mutant cohort, Durvalumab for Bladder Cancer
benet, according to the manufacturers. the median PFS for patients treated with The FDA has accepted a biolog-
In the EMPA-REG OUTCOME trial, niraparib was 9.3 months compared with ics license application for durvalumab
empagliozin signicantly reduced the 3.9 months for control (P < 0.0001). (AstraZeneca/MedImmune) and has
combined primary endpoint (the time Source: Tesaro, December 20, 2016 granted the medication priority review

Vol. 42 No. 2 February 2017 P&T


79
status, with the Prescription Drug User Breakthrough Therapy Status The visual cycle is the process by which
Fee Act action date set for the second Neridronic Acid for CRPS vitamin A is recycled in the eye; vitamin A
quarter of 2017. The FDA has granted a breakthrough is crucial to the visual process. Emixustat
Durvalumab is an investigational therapy designation to neridronic acid modulates the visual cycle by inhibiting
human monoclonal antibody directed (Grnenthal/Abiogen Pharma), an inves- a critical enzyme of this pathway, retinal
against programmed death ligand-1 tigational medication for the treatment pigment epithelium protein 65. Slowing
(PD-L1). PD-L1 is expressed by tumors of patients with complex regional pain the visual cycle reduces the availabil-
to evade detection by the immune system syndrome (CRPS), a serious, disabling ity of vitamin A derivatives (11-cis- and
through binding to programmed death-1 orphan disease. CRPS is characterized all-trans-retinal) to form precursors of
(PD-1) proteins on cytotoxic T lympho- by severe, continuous, burning pain that A2E and related compounds. In animal
cytes. Durvalumab blocks the PD-L1 inter- often occurs in an extremity after injury models of Stargardt disease and retinal
action with PD-1, thereby countering the or surgery. degeneration, emixustat was found to stop
tumors immune-evading tactics. Source: Grnenthal, December 20, and reverse the accumulation of A2E and
Source: AstraZeneca, December 9, 2016 2016 to preserve the integrity of the retina.
Source: Acucela, January 5, 2017
Fast-Track Designations Sublingual Cyclobenzaprine for PTSD
APL-2 for PNH The FDA has granted breakthrough RG7916 for Spinal Muscular Atrophy
The FDA has granted a fast-track therapy status to cyclobenzaprine sub- RG7916 (PTC Therapeutics) has
designation to the development program lingual tablets (TNX-102 SL, Tonix received an FDA orphan drug designa-
for APL-2 (Apellis Pharmaceuticals), a Pharmaceuticals) for the treatment of tion for the treatment of patients with
complement C3 inhibitor, for the treat- patients with post-traumatic stress dis- spinal muscular atrophy (SMA). SMA
ment of patients with paroxysmal noctur- order. A phase 3 study is expected to is a rare genetic disorder that results in
nal hemoglobinuria (PNH) who continue begin in the rst quarter of 2017. neuromuscular disability beginning in
to experience hemolysis and require Source: Tonix Pharmaceuticals, infancy and is the leading inherited cause
transfusions of red blood cells despite December 19, 2016 of mortality in infants and young children.
receiving therapy with eculizumab. RG7916 is an oral small-molecule splic-
PNH is a rare, acquired, potentially life- Orphan Drug Designations ing modier that directly targets the under-
threatening disease characterized by MGD006 for AML lying molecular deciency of SMA by
complement-mediated hemolytic ane- The FDA has granted an orphan drug modulating SMN2 splicing to increase the
mia. APL-2 is a synthetic cyclic peptide designation to MGD006 (MacroGenics, expression of stable full-length SMN pro-
that binds specically to C3 and C3b, Inc.), a dual-afnity retargeting molecule teins from the SMN2 gene. The compound
effectively blocking all three pathways that recognizes both CD123 and CD3, for is under investigation in two clinical stud-
of complement activation. the investigational treatment of patients ies: SUNFISH, a trial in childhood-onset
Source: Apellis Pharmaceuticals, with acute myeloid leukemia (AML). (type 2/3) SMA patients, and FIREFISH, a
December 20, 2016 MGD006 is being evaluated in the United trial in infant-onset (type 1) patients.
States and Europe in a phase 1 dose- Source: PTC Therapeutics, January 6,
ASP0892 Vaccine forPeanut Allergy escalation study designed to determine 2017
The drug candidate ASP0892 (Astellas the safety and tolerability of the molecule
Pharma/Immunomic Therapeutics), a in patients with relapsed/refractory AML CX-4945 for Cholangiocarcinoma
DNA vaccine for the mitigation of severe or myelodysplastic syndrome. The FDA has granted an orphan drug
hypersensitivity reactions due to peanut Source: MacroGenics, January 5, 2017 designation to CX-4945 (Senhwa Bio-
allergy, has been granted FDA fast-track sciences) for the treatment of patients
status. A phase 1 clinical trial has been Emixustat for Stargardt Disease with cholangiocarcinoma. CX-4945 is a
initiated to evaluate the safety, tolerabil- Emixustat hydrochloride (Acucela Inc.) small-molecule drug that inhibits protein
ity, and immune response of ASP0892 in has received orphan drug status for the kinase CK2, which plays a key role in
adults who are allergic to peanuts. treatment of patients with Stargardt dis- the DNA damage repair mechanisms of
Source: Astellas Pharma, December ease, the most common form of inherited cancer cells. CX-4945 has demonstrated
20, 2016 juvenile macular degeneration. favorable safety, pharmacokinetic, and

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


pharmacodynamic characteristics in the tions in the RPGR gene. Males with XLRP lateral sclerosis (ALS), also known as Lou
treatment of patients with advanced chol- caused by mutations in RPGR typically Gehrigs disease.
angiocarcinoma, according to the devel- have night blindness in their rst decade BHV-0223 is a sublingually absorbed
oper. This cancer is difcult to detect in of life, followed by the progressive reduc- dissolving tablet formulation of rilu-
its early stages, and the ve-year survival tion of their visual eld and the loss of zole. It was designed to address some
rate is approximately 20%. visual acuity. By the end of their fourth of the shortcomings associated with
Source: Senhwa Biosciences, January decade, most patients are legally blind. the solid oral dosage form of riluzole,
4, 2017 Source: MeiraGTx, December 20, 2016 which ALS patients have difculty swal-
lowing. Because BHV-0223 is systemi-
PIKA Rabies Vaccine Nintedanib for Mesothelioma cally absorbed through the oral mucosa
The FDA has granted an orphan drug The FDA has granted an orphan drug rather than through the gastrointestinal
designation for a polyinosinicpolycyti- designation to nintedanib (Boehringer system, it is expected to eliminate the
dylic acid-based adjuvant (PIKA) rabies Ingelheim) for the treatment of patients negative food effect associated with rilu-
vaccine (Yisheng Biopharma) that is in with mesothelioma. Nintedanib is an oral zole, to bypass rst-pass metabolism, and
phase 2 clinical development. The vaccine triple angiokinase inhibitor that simul- to deliver effective doses of the drug at
uses a proprietary Toll-like receptor-3 acti- taneously inhibits vascular endothelial lower concentrations.
vation technology. growth factor receptor, platelet-derived Source: Biohaven, December 9, 2016
Source: Yisheng Biopharma, January growth factor receptor, and broblast
4, 2017 growth factor receptor signaling path- Refusal to File Letter
ways. These three angiokinase recep- Bupivacaine Implants for Pain
ES-3000 for AML tors, which are not targeted by available Innocoll has received a refusal to le
ES-3000 (Escend Pharmaceuticals) therapies, play an important role in angio- letter from the FDA for Xaracoll (bupi-
has received orphan drug status from genesis, tumor growth, and metastases. vacaine HCl collagen-matrix implants)
the FDA for the treatment of patients with Source: Boehringer Ingelheim, for the treatment of postsurgical pain.
acute myeloid leukemia (AML). The FDA December 14, 2016 After a preliminary review, the FDA
previously granted ES-3000 an orphan determined that the application, which
drug designation for the treatment of ABTL0812 for Pancreatic Cancer was submitted in October 2016, was not
patients with chronic myeloid leukemia. ABTL0812 (Ability Pharmaceuticals) sufciently complete to permit a sub-
ES-3000 is an orally bioavailable small has received orphan drug status from stantive review. The FDA indicated,
molecule that ablates leukemic stem cells the FDA for the treatment of patients among other things, that Xaracoll should
by reducing beta-catenin expression. The with pancreatic cancer. The investiga- be characterized as a drug/device com-
Wnt/beta-catenin pathway is critical for tional compound, now in phase 2 clini- bination, which would require Innocoll
the survival of cancer stem cells. ES-3000 cal development, causes cell death by to submit additional information. Xara-
is also in development for the treatment of autophagy through the overexpression coll is a surgically implantable and bio-
patients with triple-negative breast cancer. of TRIB3, an endogenous Akt regulator. resorbable bupivacaine-collagen matrix
Source: Escend Pharmaceuticals, It is a rst-in-class, fully differentiated, that uses a proprietary collagen-based
December 28, 2016 oral, targeted anticancer compound delivery technology.
inhibiting the PI3K/Akt/mTOR pathway Source: Innocoll, December 29, 2016
A004 for Retinitis Pigmentosa without being a direct kinase inhibitor.
The FDA has granted orphan drug Source: Ability Pharmaceuticals, Complete Response Letter
status to A004 (MeiraGTx), an adeno- December 14, 2016 Lutathera for Neuroendocrine Tumors
associated virus-mediated gene therapy The FDA has issued a complete
product candidate containing the retinitis BHV-0223 for ALS response letter (CRL) regarding
pigmentosa GTPase regulator (RPGR) The FDA has granted orphan drug the new drug application (NDA) for
gene for the treatment of patients with status to BHV-0223 (Biohaven Pharma- Lutathera (lutetium Lu 177 dotatate,
X-linked retinitis pigmentosa (XLRP). ceutical Holding Company), an orally dis- Advanced Accelerator Applications), a
More than 70% of XLRP cases and up solving tablet being developed for the Lu 177labeled somatostatin analogue
to 20% of RP cases are caused by muta- treatment of patients with amyotrophic peptide, for the treatment of adults with

Vol. 42 No. 2 February 2017 P&T


81
gastroenteropancreatic neuroendocrine with the unexposed cohort were 2.72 for longer than three hours or if multiple pro-
tumors. The CRL referred to issues with samples submitted from the community cedures are required in children younger
the format, traceability, uniformity, and and 1.28 for samples submitted from than 3 years of age.
completeness of the NETTER-1 and hospitals. Source: FDA, December 14, 2016
Erasmus clinical datasets that were pre- Source: Wiley, January 5, 2017
venting FDA reviewers from perform- Pioglitazone and Bladder Cancer
ing the required independent analysis Chantix Boxed Warning Dropped As a result of an updated review, the
of these clinical studies. In addition, the The FDA has approved updates to the FDA has concluded that the use of the
CRL requested analyses for gender, age, labeling for varenicline (Chantix, Pzer), type-2 diabetes medication pioglitazone
and racial subgroups, as well as other including removal of the boxed warn- (Takedas Actos, Actoplus Met, Acto-
stratication factors and disease charac- ing regarding serious neuropsychiatric plus Met XR, Duetact, and Oseni) may
teristics. A safety update on clinical and events. The removal of the boxed warn- be linked to an increased risk of blad-
nonclinical studies was also requested. ing was based on results from a pivotal der cancer. The labels of pioglitazone-
Finally, the CRL noted that observations smoking-cessation trial in patients with containing medications already include
made during inspections of manufactur- and without a history of psychiatric dis- warnings about this risk, but the FDA has
ing facilities supporting the NDA must orders, and was consistent with recent approved new label updates to describe
be resolved before the NDA could be recommendations from the FDAs additional study data.
approved. Psychopharmacologic Drugs Advisory Source: FDA, December 12, 2016
Source: Advanced Accelerator Committee and its Drug Safety and Risk
Applications, December 21, 2016 Management Advisory Committee. CLINICAL TRIAL NEWS
Additional labeling revisions based Contrave for Obesity
DRUG SAFETY ISSUES on the EAGLES trial include updates to The phase 3, randomized, open-label
Acid-Suppressant Drugs the corresponding warning regarding IGNITE trial was designed to evaluate the
Linked to GI Infections neuropsychiatric safety and the addition use of Contrave (naltrexone and bupro-
In a population-based study conducted of information on the superior efcacy of pion extended-release tablets, Orexigen
in Scotland, the use of commonly pre- varenicline compared with bupropion or Therapeutics) in combination with a com-
scribed acid-suppressant medications a transdermal nicotine patch. mercially available lifestyle-intervention
(ASMs), such as proton pump inhibi- Source: FDA, December 19, 2016 program compared with usual care in
tors (PPIs), has been linked to an a real-world weight-loss setting. The
increased risk of intestinal infections with Anesthesia and Sedation in results showed that treatment with Con-
Clostridium difcile and Campylobacter Children and Pregnant Women trave, when used in a manner consis-
bacteria, which can cause serious ill- The FDA has warned that repeated tent with prescribing information in the
ness. The study involved 188,323 patients or lengthy use of general anesthetic and United States, resulted in a signicant
exposed to PPIs and H2 receptor antago- sedation drugs during surgeries or pro- reduction in body weight compared with
nists (H2RAs) and 376,646 controls who cedures in children younger than 3 years usual care. After 26 weeks of treatment,
were not exposed to ASMs between 1999 of age or in pregnant women during participants in the Contrave group lost
and 2013. their third trimester may affect the signicantly more weight compared with
Compared with individuals in the com- development of childrens brains. the usual-care group (9.5% versus 0.9%,
munity who did not take acid-suppressant The agency has been investigating respectively; P < 0.0001).
drugs, those who did had 1.7-times and the potential adverse effects of general Source: Orexigen Therapeutics,
3.7-times increased risks for C. difcile anesthetic and sedation drugs on chil- January 6, 2017
and Campylobacter infections, respec- drens brain development since the rst
tively. Among hospitalized patients, those animal study on this topic was published Humira Biosimilar
using acid-suppressant medications had in 1999. Health care providers are advised The comparative, confirmatory
1.4-times and 4.5-times increased risks, to balance the benets of appropriate REFLECTIONS B538-02 study has met
respectively. The adjusted hazard ratios anesthesia in young children and preg- its primary endpoint by demonstrating
for culture-positive diarrhea for the PPI- nant women against the potential risks, the equivalent efcacy, as measured
and H2RA-exposed cohort compared especially for procedures that may last by the American College of Rheuma-

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


tology 20% response rate at week 12, pany also plans to initiate another study several cases of veno-occlusive disease,
of PF-06410293 (Pzer) and Humira of Sollupra in patients with EPI due to with four deaths.
(adalimumab, AbbVie), each adminis- cystic brosis. Vadastuximab talirine is an investiga-
tered with methotrexate, in patients with Source: Anthera Pharmaceuticals, tional antibodydrug conjugate targeted
moderate-to-severe rheumatoid arthritis. December 27, 2016 to the CD33 transmembrane receptor.
PF-06410293, a monoclonal antibody, is CD33 is expressed on most AML and
being developed as a potential biosimilar Biosimilar Trastuzumab myelodysplastic syndrome blast cells.
to Humira, which is approved in the For Breast, Gastric Cancers Vadastuximab is designed to be stable
United States for multiple indications, Phase 3 results have conrmed the in the bloodstream and to release a cell-
including rheumatoid arthritis, juvenile efcacy, safety, and immunogenicity of killing pyrrolobenzodiazepine dimer
idiopathic arthritis, psoriatic arthritis, MYL-1401O (Mylan/Biocon), a proposed agent after internalization into CD33-
ankylosing spondylitis, adult Crohns biosimilar trastuzumab, in comparison expressing cells.
disease, pediatric Crohns disease, ulcer- with that of branded trastuzumab (Her- Source: Seattle Genetics, December
ative colitis, plaque psoriasis, hidradenitis ceptin, Genentech). Herceptin is indi- 27, 2016
suppurativa, and uveitis. cated for the treatment of patients with
Source: Pzer, January 5, 2017 certain human epidermal growth factor Emicizumab for Hemophilia
receptor 2 (HER2)-positive breast and The primary endpoint has been reached
RHB-105 for H. Pylori Infection gastric cancers. in a pivotal phase 3 study evaluating pro-
RHB-105 (RedHill Biopharma) is an The HERITAGE trial was a double- phylactic treatment with emicizumab
investigational xed-dose oral combina- blind, randomized study designed to (Chugai Pharmaceutical/Roche/Genen-
tion therapy consisting of two antibiotics compare MYL-1401O with Herceptin in tech) in patients 12 years of age or older
and a proton pump inhibitor in a single patients with centrally conrmed, mea- with hemophilia A and inhibitors to fac-
capsule. The product has a planned indi- surable HER2-positive metastatic breast tor VIII. The study showed a statistically
cation for the treatment of patients with cancer who had not received chemo- signicant reduction in the number of
Helicobacter pylori infection. A phase 3 therapy or trastuzumab for metastatic bleeds over time in patients treated with
study of RHB-105 has met its primary disease. The results showed an overall emicizumab prophylaxis compared with
endpoint of superiority over the histori- response rate of 69.6% for MYL-1401O those receiving no prophylactic treatment.
cal standard-of-care (SoC) eradication compared with 64.0% for Herceptin at The study also met all secondary end-
rate of 70% (P < 0.001). The study results week 24 (the trials primary endpoint). points, including a statistically signicant
demonstrated 89% efcacy in eradicating Tumor progression, progression-free reduction in the number of bleeds over
H. pylori infection with RHB-105. Sub- survival, and overall survival were not time with emicizumab prophylaxis treat-
sequent open-label treatment with SoC statistically different between the two ment in patients who had received prior
therapies of patients in the placebo arm groups at week 48. bypassing-agent prophylaxis treatment.
demonstrated a 63% eradication rate. Source: Mylan, December 27, 2016 Emicizumab is an investigational
Source: RedHill Biopharma, January bispecic monoclonal antibody designed
4, 2017 Vadastuximab for AML to bring together factors IXa and X
Seattle Genetics has received notice proteins required to activate the natu-
Sollpura for Cystic Fibrosis from the FDA that a clinical hold or partial ral coagulation cascade and restore the
The SOLUTION trial of Sollpura clinical hold has been placed on several blood-clotting process. Emicizumab is
(Anthera Pharmaceuticals), a nonporcine early-stage trials of vadastuximab talirine administered via a subcutaneous injection
pancreatic enzyme replacement therapy in subjects with acute myeloid leukemia of a ready-to-use solution once weekly.
(PERT), in cystic brosis patients with (AML). The clinical holds were initiated Source: Roche, December 22, 2016
exocrine pancreatic insufciency (EPI) to evaluate the potential risk of hepato-
narrowly missed its noninferiority margin toxicity in patients who were treated with Sotagliozin for Type-1 Diabetes
versus a PERT comparator (Pancreaze, vadastuximab and who received alloge- A pivotal phase 3 trial of sotagliozin
Janssen). Anthera expects to release data neic stem cell transplant either before (Lexicon Pharmaceuticals) has met
from the extension phase of this study or after treatment. Six patients were its primary endpoint, demonstrating a
during the rst quarter of 2017. The com- identied with hepatotoxicity, including statistically significant reduction in

Vol. 42 No. 2 February 2017 P&T


83
hemoglobin A1C (HbA1C) at 24 weeks of switching virologically suppressed pared with a 9.82-letter improvement with
in patients with type-1 diabetes receiv- patients from a three- or four-drug ranibizumab alone in study OPH1003.
ing optimized insulin therapy. Patients antiretroviral regimen to the two-drug Pegpleranib is a 32-mer pegylated
treated with sotagliozin had mean HbA1C regimen of rilpivirine (Edurant, Janssen) DNA aptamer that selectively binds to
reductions from baseline of 0.39% with a and dolutegravir (Tivicay, ViiV Health- platelet-derived growth factor (PDGF)-
200-mg once-daily dosage of sotagliozin care) have met the primary endpoint of BB and PDGF-AB homo- and hetero-
(P < 0.001) and 0.37% with a 400-mg once- noninferiority at week 48. dimers, respectively, thereby disrupting
daily dosage of sotagliozin (P < 0.001) In both studies, the subjects achieved the interaction with their cognate tyrosine
compared with a reduction of 0.03% with plasma human immunodeficiency kinase receptors.
placebo after 24 weeks of treatment. virus-1 (HIV-1) RNA levels of less than Source: Novartis, December 12, 2016
Sotagliozin is a rst-in-class, oral dual 50 copies/mL. Regulatory submissions
inhibitor of two proteins responsible for for the investigational two-drug regimen Plecanatide for IBS
glucose regulationsodium-glucose of rilpivirine and dolutegravir as a single With Constipation
cotransporter types 1 and 2 (SGLT1 and tablet are expected in 2017. Positive results have been reported
SGLT2). SGLT1 is the primary trans- Rilpivirine is a prescription HIV from the rst of two pivotal phase 3
porter for absorption of glucose and medication that is used with other anti- trials evaluating the efcacy and safety of
galactose in the gastrointestinal tract, retroviral drugs to treat patients with plecanatide (Synergy Pharmaceuticals),
and SGLT2 is primarily responsible for HIV-1 infection who have never received an investigational once-daily, orally
glucose reabsorption by the kidneys. HIV medications and who have a viral administered compound, in adults with
Source: Lexicon Pharmaceuticals, load of no more than 100,000 copies/mL. irritable bowel syndrome with constipa-
December 21, 2016 Dolutegravir is an HIV-1 integrase strand tion (IBS-C). Both doses of plecanatide
transfer inhibitor indicated in combina- (3 mg and 6 mg) met the studys primary
Plazomicin for Infections tion with other antiretroviral agents for endpoint, showing statistical signifi-
Resistant to Multiple Drugs the treatment of HIV-1 infection in adults cance in the percentage of patients who
Plazomicin (Achaogen, Inc.), an anti- and pediatric patients weighing at least were overall responders compared with
biotic being developed to ght multidrug- 30 kg. placebo during the 12-week treatment
resistant bacterial infections, has met Source: Janssen, December 19, 2016 period (21.5% in the 3-mg group and 24.0%
the primary objective of noninferiority in the 6-mg group compared with 14.2%
compared with meropenem in a phase 3 Pegpleranibfor AMD in the placebo group; P = 0.009 for 3 mg
registration trial in patients with compli- Two pivotal phase 3 studies evaluat- and P < 0.001 for 6 mg).
cated urinary tract infections and acute ing the safety and efcacy of pegpleranib Plecanatide is a peptide made up of
pyelonephritis. (Novartis) in combination with ranibi- 16 amino acids. With the exception of a
In addition, in a phase 3 trial in patients zumab (Lucentis, Genentech) for the single amino acid substitution, it is identi-
with serious infections due to carbapenem- treatment of patients with neovascular cal to uroguanylin, an endogenous human
resistant Enterobacteriaceae (CRE), a age-related macular degeneration did gastrointestinal peptide that targets
lower rate of mortality or serious disease- not meet the primary endpoint of supe- receptors in the proximal small intestine.
related complications was observed for riority for the pegpleranib/ranibizumab Source: Synergy Pharmaceuticals,
plazomicin compared with colistin, one of combination therapy over ranibizumab December 9, 2016
the few remaining antibiotics for the treat- monotherapy.
ment of infections due to CRE. Achaogen At month 12, patients in the peg- Solanezumab for Alzheimers
plans to submit a new drug application pleranib/ranibizumab groups showed The monoclonal antibody solanezumab
for plazomicin to the FDA in the second a 10.74-letter improvement in best cor- (Eli Lilly) failed to meet the primary end-
half of 2017. rected visual acuity (BCVA) compared point in a pivotal phase 3 study involv-
Source: Achaogen, December 12, 2016 with a 9.82-letter improvement with ing patients with mild dementia due to
ranibizumab alone in study OPH1002. Alzheimers disease, and Lilly announced
Edurant/Tivicay for HIV Similarly, the pegpleranib/ranibizumab that it will not pursue regulatory sub-
Two phase 3 studies designed to evalu- combination treatment groups showed missions of the medication. Patients
ate the efcacy, safety, and tolerability a 9.91-letter BCVA improvement com- treated with solanezumab did not expe-

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


rience a statistically signicant slowing in FA Rating Scale at 26 weeks compared AeroForm Tissue Expander
cognitive decline compared with patients with placebo. FA is a degenerative neuro- For Breast Reconstruction
given placebo. This nding represented muscular disorder that affects approxi- The FDA has allowed the marketing
an 11% reduction in decline (P = 0.095), mately 4,000 to 6,000 people in the United of the AeroForm device (AirXpanders),
as measured by the Alzheimers Disease States. There are no approved treatments a system for soft-tissue expansion in
Assessment ScaleCognitive subscale. for the disease. two-stage breast reconstruction after
Source: Eli Lilly, December 8, 2016 Actimmune is currently indicated to mastectomy and in the treatment of
reduce the frequency and severity of seri- underdeveloped breasts and soft-tissue
Cimzia for Plaque Psoriasis ous infections associated with chronic deformities. The patient uses a dose
UCB and Dermira, Inc., have granulomatous disease, a genetic dis- controller to independently inate the
announced positive results from the order that affects the functioning of some expander.
phase 3, placebo-controlled CIMPASI-1 cells of the immune system. Actimmune The AeroForm device differs from
trial, which evaluated the efcacy and is also indicated to delay the time to dis- available saline-lled tissue expanders,
safety of certolizumab pegol (Cimzia) in ease progression in patients with severe, which are expanded by the surgeon, who
adults with moderate-to-severe chronic malignant osteopetrosis, a genetic dis- uses a needle to pierce the skin and inject
plaque psoriasis. order that affects normal bone formation. saline into the expander through a port or
A total of 234 patients were randomly Source: Horizon Pharma, December injection area. The AeroForm expander
assigned to three dosing arms: 400 mg 8, 2016 is lled with air; there is no need for a
every two weeks (n = 88); 400 mg at needle, and the patient has control over
weeks 0, 2, and 4 followed by 200 mg IDP-118 for Plaque Psoriasis slowly expanding the device at home.
every two weeks (n = 95); or placebo Positive results have been reported Source: AirXpanders, December 20,
every two weeks (n = 51). At week 16, the from a phase 3, double-blind, random- 2016
response rate for patients who achieved ized study that compared IDP-118 lotion
75% or greater disease improvement from (halobetasol propionate and tazarotene, Continuous Glucose
baseline, as measured by the Psoriasis Valeant Pharmaceuticals) with vehicle Monitoring System
Area and Severity Index, was 75.8% for in 215 patients with moderate-to-severe The FDA has expanded the approved
patients receiving the 400-mg dose every plaque psoriasis. use of the Dexcom G5 mobile continuous
two weeks and 66.5% for patients receiv- After 12 weeks of treatment, IDP-118 glucose monitoring system (Dexcom,
ing the 200-mg dose every two weeks, was signicantly more effective than vehi- Inc.) to allow the replacement of nger-
compared with 6.5% for patients receiving cle, with a 45.3% success rate (P < 0.001). stick blood glucose testing for treatment
placebo. The response rate for patients This pivotal study was preceded by a decisions in diabetes patients 2 years
achieving at least a two-point improve- phase 2 trial in which IDP-118 was clinically of age and older. This is the rst FDA-
ment to a nal score of clear or almost superior to halobetasol propionate and approved continuous glucose monitoring
clear skin on the Physicians Global tazarotene, with a success rate of 52.5%. system that can be used to make diabetes
Assessment scale at week 16 was 57.9% Source: Valeant, December 8, 2016 treatment decisions without conrma-
for the 400-mg dose-treated patients tion with a traditional nger-stick test.
and 47.0% for the 200-mg dose-treated DEVICE APPROVALS The system was previously approved to
patients, compared with 4.2% for the Aptima HIV-1 Assay complement, not replace, nger-stick
patients receiving placebo. The FDA has approved the Aptima testing for diabetes treatment decisions.
Source: UCB, December 8, 2016 HIV-1 Quant assay (Hologic, Inc.) for Source: Dexcom, December 20, 2016
monitoring the viral load in patients
Actimmune for Friedreichs Ataxia infected with human immunodeciency OneTouch Vibe Plus Insulin Pump
A phase 3 trial evaluating Actimmune virus 1 (HIV-1). The nucleic acid ampli- The FDA has cleared the OneTouch
(interferon gamma-1b, Horizon Pharma) cation test is designed for the quantita- Vibe Plus insulin pump and continu-
for the treatment of patients with Fried- tive detection of RNA from HIV in plasma ous glucose monitoring (CGM) system
reichs ataxia (FA) failed to meet its specimens. The assay is not approved for the treatment of diabetes patients
primary endpoint of a statistically signi- for HIV-1 diagnosis in the United States. 2 years of age and older. The OneTouch
cant change from baseline in the modied Source: Hologic, January 3, 2017 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 Tuberculosis (TB) infection has been reported. Observe
and neutropenia, which are each dose-related effects. patients taking Jakafi for signs and symptoms of active TB and
Perform a pre-treatment complete blood count (CBC) and manage promptly. Prior to initiating Jakafi, evaluate patients
monitor CBCs every 2 to 4 weeks until doses are stabilized, for TB risk factors and test those at higher risk for latent
and then as clinically indicated infection. Consult a physician with expertise in the treatment of
Manage thrombocytopenia by reducing the dose or temporarily TB before starting Jakafi in patients with evidence of active or
interrupting Jakafi. Platelet transfusions may be necessary latent TB. Continuation of Jakafi during treatment of active TB
should be based on the overall risk-benefit determination
Patients developing anemia may require blood transfusions
and/or dose modifications of Jakafi Progressive multifocal leukoencephalopathy (PML) has
occurred with ruxolitinib treatment for myelofibrosis. If PML is
Severe neutropenia (ANC <0.5 10 9/L) was generally reversible
suspected, stop Jakafi and evaluate
by withholding Jakafi until recovery
Advise patients about early signs and symptoms of herpes
Serious bacterial, mycobacterial, fungal and viral infections have
zoster and to seek early treatment
occurred. Delay starting Jakafi until active serious infections
have resolved. Observe patients receiving Jakafi for signs and Increases in hepatitis B viral load with or without associated
symptoms of infection and manage promptly 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
Jakafi is a registered trademark of Incyte Corporation.
2017, Incyte Corporation. All rights reserved. RUX-2054b 01/17
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 creatinine clearance, urine glucose, and urine protein is recom-
established in two placebo-controlled trials with a total of mended before initiating TAF therapy and during therapy as
1,522 participants ranging in age from 2 to 79 years with mild- clinically appropriate. TAF should be discontinued in patients
to-moderate atopic dermatitis. Patients had a 5% to 95% treatable who develop clinically signicant renal function decreases or
body surface area. Overall, participants receiving crisaborole evidence of Fanconi syndrome.
ointment achieved greater response, with clear or almost clear Drug interactions. TAF is a substrate of P-glycoprotein
skin after 28 days of treatment. (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP
Sources: Anacor Pharmaceuticals, Eucrisa prescribing activity may lead to changes in TAF absorption. Drugs that
information induce P-gp activity are expected to decrease the absorption of
TAF, resulting in decreased plasma TAF concentrations, which
Tenofovir Alafenamide (Vemlidy) Tablets may lead to loss of therapeutic effect. Coadministration of TAF
Manufacturer: Gilead Sciences, Inc., Foster City, California with other drugs that inhibit P-gp and BCRP may increase
Date of Approval: November 10, 2016 TAF absorption and increase the TAF plasma concentration.
Indication: Tenofovir alafenamide (TAF) tablets are indi- Because TAF is primarily excreted by the kidneys by a
cated as a once-daily treatment for adults with chronic hepa- combination of glomerular ltration and active tubular secre-
titis B virus (HBV) infection with compensated liver disease. tion, coadministration with drugs that reduce renal function or
Drug Class: HBV nucleoside reverse transcriptase inhibitor compete for active tubular secretion may increase concentra-
Uniqueness of Drug: TAF is a novel, targeted prodrug tions of tenofovir and other renally eliminated drugs; this may
of tenofovir that has demonstrated antiviral efcacy similar increase the risk of adverse reactions. Some examples of these
to and at a dose less than one-tenth that of the 300-mg teno- drugs include, but are not limited to, acyclovir, ganciclovir,
fovir disoproxil fumarate (TDF) tablet (Viread, Gilead). TAF valacyclovir, valganciclovir, aminoglycosides, and high-dose
has greater plasma stability and can more efciently deliver or multiple NSAIDs.
tenofovir to hepatocytes; therefore, it can be given at a lower Other established or potentially clinically signicant drug
dose, resulting in less circulating tenofovir. TAF, therefore, interactions are listed in the full prescribing information.
has improved renal and bone laboratory safety parameters No signicant drug interactions have been observed based on
compared with TDF. TAF drug interaction studies with ethinyl estradiol, itraconazole,
Warnings and Precautions: ketoconazole, ledipasvir/sofosbuvir, midazolam, norgestimate,
Boxed warning: lactic acidosis/severe hepatomegaly sertraline, sofosbuvir, and sofosbuvir/velpatasvir.
with steatosis. Lactic acidosis/severe hepatomegaly with Dosage and Administration: The recommended TAF
steatosis, including fatal cases, have been reported with the use dose is 25 mg (one tablet) taken orally once daily with food. No
of nucleoside analogues, including TAF, in combination with dosage adjustment is required in patients with mild, moderate,
other antiretrovirals. Most cases have been in women. Obesity or severe renal impairment or with mild hepatic impairment.
and prolonged nucleoside exposure may be risk factors. TAF TAF is not recommended in patients with end-stage renal
should be used with caution in any patient with known risk disease (estimated creatinine clearance less than 15 mL per
factors for liver disease; however, cases have also been reported minute) or with decompensated (ChildPugh B or C) hepatic
in patients with no known risk factors. TAF treatment should impairment.
be withheld in any patient who develops clinical or laboratory Commentary: The safety and efcacy of TAF is supported by
ndings suggestive of lactic acidosis or pronounced hepato- 48-week data from two randomized phase 3 studies (Studies 108
toxicity (which may include hepatomegaly and steatosis even and 110) in 1,298 treatment-nave and treatment-experienced
in the absence of marked transaminase elevations). adult patients with chronic HBV infection. Study 108 random-
Boxed warning: post-treatment severe acute exacerba- ized and treated 425 hepatitis B e antigen (HBeAg)-negative
tion of HBV. Discontinuation of anti-HBV therapy may lead patients with either TAF or TDF. Study 110 randomized and
to severe acute HBV exacerbations. Hepatic function should treated 873 HBeAg-positive patients with either TAF or TDF.
be closely monitored in patients who discontinue TAF. If Both studies met their primary endpoint of noninferiority to
appropriate, restarting of anti-HBV therapy may be warranted. TDF based on the percentage of patients with chronic hepa-
HBV and HIV-1 coinfection. TAF monotherapy is not titis B with plasma HBV DNA levels less than 29 IU/mL at
recommended for treating human immunodeciency virus 48 weeks of therapy. In an integrated analysis of both studies,
type-1 (HIV-1) infection because resistance may develop. TAF-treated patients showed improvements in certain bone
New onset or worsening renal impairment. Renal impair- and renal laboratory parameters compared with TDF-treated
ment, including acute renal failure and Fanconi syndrome patients. TAF-treated patients also had numerically higher
(renal tubular injury with severe hypophosphatemia), has been rates of normalization of blood serum alanine aminotransferase
reported with the use of tenofovir prodrugs in both animal levels (83% versus 75% [Study 108] and 72% versus 67% [Study
toxicology studies and human trials. In TAF clinical trials, 110]). Both analogues were generally well tolerated with a
no cases of Fanconi syndrome or proximal renal tubulopathy 1% adverse event discontinuation rate. The most common
were reported. Patients taking tenofovir prodrugs who have adverse events reported were abdominal pain, back pain, cough,
impaired renal function and those taking nephrotoxic agents, fatigue, headache, and nausea occurring in similar rates in both
including nonsteroidal anti-inammatory drugs (NSAIDs), are treatment groups.
at increased risk of developing renal-related adverse effects. Sources: Gilead, Vemlidy prescribing information, Food
Assessment of serum creatinine, serum phosphorus, estimated 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 with epilepsy are able to maintain sei- PHARMACOKINETICS


Epilepsy is the fourth most common zure control with one to two antiepileptic Brivaracetam exhibits linear and
neurological disorder and affects more drugs (AEDs), many individuals require time-independent pharmacokinetics at
than 65 million individuals worldwide.1 adjunctive therapy to achieve long-term its approved doses. It is freely soluble
This condition is marked by the presence remission. in water, ethanol, methanol, and glacial
of epileptic seizures, which result from an Brivaracetam (Briviact, UCB, Inc.), a acetic acid.3 The drug experiences near-
abnormal synchronous ring of excitatory propyl analogue of levetiracetam, an anti- complete absorption after oral adminis-
neurons in the brain.1,2 When neurons re convulsant and racetam derivative, was tration and is weakly bound to plasma
synchronously, a wave of depolarization granted Food and Drug Administration proteins.3 Brivaracetams volume of dis-
known as a paroxysmal depolarizing shift (FDA) approval as an add-on therapy in tribution is 0.5 L/kg, and it is rapidly and
occurs.2 During this period, the neurons February 2016. It is indicated as adjunc- evenly distributed in most tissues. In addi-
experience a lowered resistance to ring, tive therapy for treating POS in adults tion, the amide moiety of the drug mol-
leading to multiple action potentials that and adolescents 16 years of age or older.3 ecule undergoes hydrolysis via hepatic
generate abnormally increased electrical and extrahepatic amidase to a carboxylic
activity within the brain. MECHANISM OF ACTION acid metabolite.3 This reaction is medi-
There are various types of epilepsy Brivaracetam is a third-generation ated mainly by cytochrome P450 2C19
syndromes that are dened based on a antiepileptic racetam derivative and a (CYP2C19). Genetic polymorphisms
combination of symptoms. While general- 4-n-propyl analogue of levetiracetam.13 in CYP2C19 may cause production of
ized seizures begin in both hemispheres While the exact mechanism of action the metabolite to be decreased. Poor
of the brain, partial-onset seizures (POS) of brivaracetam is unknown, its anti- metabolizers or patients taking con-
(also called focal or localized seizures) convulsant effects are believed to be due current CYP2C19 inhibitors may require
and other forms of epilepsy originate in to its highly selective afnity for synaptic dose reduction. Finally, brivaracetam is
only one hemisphere. Patients presenting vesicle protein 2A (SV2A) in the brain. excreted primarily in the urine within
with new-onset seizures must be carefully The SV2A glycoprotein is a protein- 72 hours of intake.3
evaluated to determine if the seizures are coding gene implicated in synaptic signal
secondary to non-neurological causes; transduction.4 It is believed to play a role CLINICAL TRIALS
differential diagnoses may include hypo- in the regulation of neurotransmission The efcacy of brivaracetam as an
glycemia, alcohol withdrawal, or electro- by stimulating vesicle fusion and main- adjunctive therapy for POS was estab-
lyte abnormalities. Diagnosis of epilepsy taining a reserve of secretory vesicles.4 lished in several randomized controlled
involves ruling out these other etiologies Studies in SV2A-decient animals have trials. Phase 3 trial data follow. (See
via laboratory testing, brain imaging, and demonstrated an increased propensity Table 1 for a summary.)
an electroencephalogram. Patients with for seizures.5 Brivaracetams actions as an
epilepsy may have developed the con- SV2A ligand lend it broad-spectrum activ- Ryvlin et al.6
dition secondary to genetic factors or ity against POS. Its chemical structure is A phase 3, double-blind, randomized,
other pathologies, such as brain trauma, shown in Figure 1. placebo-controlled trial conducted across
malignancy, stroke, or neurological 88 centers throughout Europe and India
infection.1,2 While a majority of patients Figure 1 Chemical Structure evaluated brivaracetam versus placebo in
Of Brivaracetam3 399 adults with POS. The objective of the
Mr. Khaleghi is a PharmD candidate at Western study was to evaluate the efcacy, safety,
New England University College of Pharmacy and tolerability of brivaracetam versus
in Springeld, Massachusetts. Dr. Nemec is placebo in patients with uncontrolled POS
Director of Research and Assessment and despite adequate therapy with one or two
Clinical Associate Professor of Physician concomitant AEDs.
Assistant Studies at Sacred Heart University Eligible patients were randomized
in Faireld, Connecticut. Drug Forecast is a to receive brivaracetam 20 mg per day
regular column coordinated by Alan Caspi, (BRV20), 50 mg per day (BRV50), 100 mg
PhD, PharmD, MBA, President of Caspi and per day (BRV100), or placebo, admin-
Associates in New York, New York. istered twice daily in equal doses. The
primary endpoint was percent reduction
Disclosure: The authors report no nancial or in baseline-adjusted POS frequency per
commercial relationships in regard to this article. week over the 12-week treatment period

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


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

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


DRUG FORECAST

The study met both of its primary ef- Summary of Meta-Analyses was determined that the use of brivarace-
cacy endpoints. Percent reduction in POS Three meta-analyses reviewing tam at doses greater than 5 mg per day
frequency per 28 days over placebo was the efcacy and safety of brivarace- resulted in statistically signicant reduc-
22.8% for BRV100 (P < 0.001) and 23.3% tam as an adjunctive therapy for POS tions in seizure frequency with respect to
for BRV200 (P < 0.001). Similarly, the 50% were identied. The rst included six the 50% responder rate. Brivaracetam was
or greater responder rate was 21.6% for randomized, placebo-controlled, single- mostly well tolerated, with the exception
placebo, 38.9% for BRV100 (P < 0.001), or double-blind add-on trials involving of some irritability and somnolence asso-
and 37.8% for BRV200 (P < 0.001). 2,399 patients (1,715 receiving brivar- ciated with the 50-mg and 150-mg per day
Treatment-related adverse events acetam and 684 receiving placebo). The doses, respectively.10
occurred in 155 of 261 (59.4%) placebo following endpoints were assessed: 50% The third meta-analysis included
patients versus 340 of 503 (67.6%) or greater reduction in seizure frequency, ve randomized, placebo-controlled,
brivaracetam patients. (Table 2) Dis- seizure freedom, incidence of treatment- single- or double-blind add-on trials
continuation rates due to treatment- related adverse events, and treatment that investigated the efficacy and
related adverse effects were 3.8% for withdrawal. In regard to all of the primary safety of brivaracetam at varying
placebo, 8.3% for BRV100, and 6.8% endpoints, an x2 test indicated no signi- doses. The following endpoints were
for BRV200. The study concluded that cant statistical heterogeneity between assessed: 50% or greater reduction
adjunctive therapy with BRV100 and the trials. It was determined that 45% of in seizure frequency and seizure-
BRV200, without the concomitant use of levetiracetam-nave patients responded free rates. Overall, the 50% responder
levetiracetam, was benecial in reduc- to brivaracetam and 19% to placebo, sug- rates of patients receiving brivarace-
ing POS frequency in patients with focal gesting a 25% real response rate that was tam 20, 50, or 100 mg per day were sig-
seizures, without resulting in signicant not attributable to placebo. Brivaracetam nicantly higher than those receiving
safety or tolerability issues. was found to be more effective than pla- placebo (20 mg: risk ratio [RR] = 1.63,
cebo in reducing seizure frequency by P = 0.003; 50 mg: RR = 2.00, P < 0.00001;
Kwan et al.9 50% or more when added to concomitant 100 mg: RR = 1.80, P = 0.01). In addition,
A phase 3, double-blind, randomized, AEDs in patients with refractory partial patients in all brivaracetam groups expe-
placebo-controlled, exible-dose trial epilepsy. While there was insufcient rienced higher seizure-free rates when
conducted across 74 sites in 15 coun- data to perform a doseresponse regres- compared with placebo regardless of
tries throughout Europe and Asia evalu- sion analysis, the results of the trials dosage (RR = 4.11, P = 0.01). Patients
ated varying doses of brivaracetam suggest that a dose-dependent effect receiving brivaracetam of any dosage
versus placebo in 480 patients with saturated when the dose of brivarace- experienced signicantly higher rates
uncontrolled epilepsy (431 with POS, 49 tam reached 50 mg per day. The authors of adverse effects compared with those
with generalized epilepsy). concluded that brivaracetam was effec- receiving placebo, specically somno-
Eligible patients were randomized to tive as an add-on treatment in adults with lence (P = 0.02) and fatigue (P = 0.009).
receive placebo or brivaracetam, admin- refractory focal epilepsy and may offer The authors concluded that brivaracetam
istered twice daily in equal doses. The additional benets in those patients who demonstrated efcacy as an adjunctive
brivaracetam was initiated at BRV20 and are levetiracetam-nave.1 treatment for refractory POS, as indicated
increased, as needed, to BRV150 during The second meta-analysis included by its statistically signicant increases in
an eight-week period. This dose-nding ve randomized, double-blind, placebo- the 50% responder rate (P < 0.00001) and
period was followed by an eight-week controlled, parallel-group trials that seizure-free rate (P = 0.01).11
fixed-dose maintenance period. The assessed the efcacy and safety of bri-
primary efcacy endpoint was percent varacetam compared with placebo as WARNINGS AND PRECAUTIONS
reduction in baseline-adjusted POS adjunctive therapy for patients with AEDs may increase the risk of
frequency per week. POS. Patients in the trials must have suicidal behaviors or thoughts in patients
From October 2007 through December received at least one concomitant AED taking these medications for any indica-
2008, 90.0% of BRV-treated patients and at a stable and optimal dosage prior to tion. Patients taking brivaracetam should
91.7% of placebo-treated patients com- study commencement. Brivaracetam at be monitored for depression, suicidal
pleted the study. Baseline characteris- doses of 20, 50, 100, and 150 mg per day ideations, or any unusual changes in
tics were largely similar between the two was associated with signicantly higher mood and behavior.3
treatment groups. The study met its pri- 50% responder rates. Brivaracetam 5 mg Brivaracetam may also cause dose-
mary efcacy endpoint. In patients with per day was not associated with any sig- dependent increases in somnolence and
POS, percent reduction in POS frequency nicant difference in 50% responder rate adverse effects such as fatigue, malaise,
from baseline was 26.9% for brivaracetam when compared with placebo. In addi- sedation, and lethargy. In the phase 3
versus 18.9% for placebo (P = 0.070). The tion, treatment-related adverse events controlled, adjunctive epilepsy trials,
study concluded that adjunctive therapy varied depending on the dose. Brivar- these adverse effects were seen in 25%
with brivaracetam given at individualized acetam dosed at 150 mg per day was of patients randomized to receive at least
doses ranging from 20150 mg per day more associated with somnolence than 50 mg per day of brivaracetam compared
was well tolerated and effective at reduc- any other dose. Similarly, fatigue and with 14% of patients receiving placebo.3
ing seizure frequency in patients with irritability were associated with brivar- Treatment with brivaracetam is associ-
uncontrolled epilepsy. acetam 50 mg per day. In conclusion, it ated with dizziness and disturbances in

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


DRUG FORECAST

olite, carbamazepine-epoxide. Renal and Hepatic Impairment


Table 2 Safety Data for Brivaracetam
While existing data did not reveal Patients with impaired renal function
(100 mg per day) any safety concerns in patients do not require dose adjustments of brivar-
Adverse Event Rate (%) receiving concomitant treatment acetam. However, the medication is not
(Incidence 5%) Ryvlin et al.6 Klein et al.8 with carbamazepine, the dose of recommended in patients with end-stage
carbamazepine may need to be renal disease receiving dialysis because
Somnolence 8.0 19.4 reduced if tolerability issues arise there are no data in this patient popula-
Dizziness 5.0 10.3 during therapy.3 tion. For patients with any stage of hepatic
Because brivaracetam may impairment, the recommended starting
Fatigue 8.0 7.5
increase the plasma concentra- dose of brivaracetam is 25 mg twice daily
Headache 9.0 6.7 tions of phenytoin, phenytoin and the recommended maximum dose is
Urinary tract infection N/R 5.1 levels should be monitored 75 mg twice daily.3
when brivaracetam is added
Nasopharyngitis 1.0 N/R
to or removed from ongoing DOSAGE AND ADMINISTRATION
Vertigo 2.0 N/R phenytoin therapy.3 The recommended starting dose for
Nausea 1.0 N/R When coadministered brivaracetam is 50 mg twice daily (100 mg
with levetiracetam, brivarace- total daily dose).3 Gradual dose escala-
Irritability 5.1 N/R tam provided no additional tion is not necessary when initiating
N/R = not reported. therapeutic benet.3 treatment. The dosage may be adjusted
down to 50 mg daily or up to 200 mg daily
gait and coordination, such as vertigo, SPECIAL POPULATIONS depending on patient tolerability and
ataxia, and nystagmus. In the phase 3 Pregnancy and Lactation therapeutic response.2 Brivaracetam is
controlled adjunctive epilepsy trials, these Brivaracetam is in pregnancy available as an oral tablet (10 mg, 25 mg,
adverse reactions were reported in 16% of category C, and there are currently 50 mg, 75 mg, and 100 mg), oral solution
patients randomized to receive at least no well-controlled studies in pregnant (10 mg/mL), and intravenous (IV) injec-
50 mg per day of brivaracetam compared women. However, in animal studies, there tion (50 mg/mL). If oral administration of
with 10% of patients receiving placebo. was evidence of developmental toxicity brivaracetam is not feasible, the injectable
The risk of gait disturbances is greatest at plasma exposures greater than clini- form may be administered at the same
early in treatment, but may occur at any cal exposures. Therefore, brivaracetam dosage and frequency as the tablets and
time throughout therapy.3 should only be used in pregnant patients oral solution. However, it is important to
Brivaracetam is also associated with if the potential benet outweighs the risk note that the clinical study experience
psychiatric adverse events, including to the fetus. In addition, pregnant patients with brivaracetam injection is limited to
nonpsychotic symptoms, such as irritabil- taking brivaracetam are advised to enroll four consecutive days of therapy.3
ity, anxiety, aggression, anger, agitation, in the North American Antiepileptic Drug The oral tablets and solution may be
and depression, and psychotic symptoms, Pregnancy Registry at 1-888-233-2334 or taken with or without food. Brivarace-
such as paranoia and acute psychosis. In www.aedpregnancyregistry.org. No data tam tablets should be swallowed whole
the phase 3 controlled, adjunctive epilepsy are available on the excretion of brivar- with liquid and not chewed or otherwise
trials, these adverse reactions were acetam in human milk. However, in rat crushed. The oral solution should be mea-
reported in 13% of patients randomized studies, it was found that brivaracetam is sured out and delivered with a calibrated
to receive at least 50 mg per day of bri- excreted in milk.3 measuring device in order to accurately
varacetam compared with 8% of patients deliver the prescribed dose. The oral solu-
receiving placebo.3 Pediatric and Geriatric Use tion does not need to be diluted and may
Brivaracetam is also associated with The safety and efcacy of brivarace- be administered using a nasogastric or
hypersensitivity reactions, namely tam has not been established in patients gastrostomy tube. Any unused brivar-
bronchospasm and angioedema. The younger than 16 years of age. However, in acetam oral solution should be discarded
medication should be discontinued in juvenile rats and dogs, potential adverse after ve months of opening the bottle.3
patients who develop hypersensitivity effects on postnatal growth and develop- Brivaracetam injection is for IV use
reactions after being treated with ment were observed. In addition, in the and is single-dose only. The injection
brivaracetam.3 double-blinded, placebo-controlled epi- does not need to be diluted, though it
lepsy trials, there were too few patients may be mixed with the following diluents:
DRUGDRUG INTERACTIONS ages 65 years or older to assess the medi- 0.9% sodium chloride injection USP, lac-
Due to the potential for CYP2C19 cations efcacy. However, dose selection tated Ringers injection, or 5% dextrose
induction, coadministration with rifampin for elderly patients should begin at the injection USP. The injection should be
decreases the plasma concentrations of lower end of the dosing range and should administered over two to 15 minutes. If
brivaracetam. The dose may need to be be made with careful consideration of the diluted, the solution may be stored in
doubled in patients receiving concomitant patients hepatic function, renal function, PVC bags, but must not be stored for
treatment with rifampin.3 and other drug therapy.3 more than four hours at room tempera-
Coadministration with carbamazepine ture. Generally, the medication may be
may increase exposure to its active metab- stored at 25C (77F), with excursions

Vol. 42 No. 2 February 2017 P&T


95
DRUG FORECAST

continued from page 85


permitted between 15C to 30C (59F Brivaracetam was well tolerated through-
to 86F). The injection and oral solution out all three phase 3 trials, which led to its the only insulin pump integrated with
formulations should not be frozen.3 FDA approval. The drug offers improved Dexcom G5 (Dexcom, Inc.) mobile CGM
seizure control with minimal safety risks technology, combining insulin dosing
COST for patients with epilepsy. technology from Animas with the CGM
Brivaracetam is supplied in three
REFERENCES sensing technology from Dexcom. The
formulations: 10-mg, 25-mg, 50-mg,
75-mg, and 100-mg tablets; 10-mg/mL 1. Lattanzi S, Cagnetti C, Foschi N, et al. system allows patients to see their glu-
oral solution; and 10-mg/mL injection Brivaracetam add-on for refractory focal cose reading at all times, either on their
epilepsy: a systematic review and meta-
for IV administration.3 The 10-mg tab- pumps or by using the Dexcom G5 app
analysis. Neurology 2016;86(14): 13441352.
lets are available for dose titration. The 2. Fisher RS, Acevedo C, Arzimanoglou on their smartphones, and to deliver the
average wholesale price (AWP) for a A, et al. ILAE ofcial report: a practical precise amounts of insulin they need from
60-tablet package of all dosages of the clinical denition of epilepsy. Epilepsia
tablet formulation or for the 300-mL bottle 2014;55(4):475482. the pumps.
3. Briviact (brivaracetam) prescribing infor- Source: Animas, December 20, 2016
of oral solution is $1,092.12 The AWP for a mation. Smyrna, Georgia: UCB, Inc.; 2016.
package of 10 single-dose 5-mL vials for 4. Synaptic vesicle glycoprotein 2A gene
IV administration is $468.12 (protein coding). GeneCards Human New MRSA Test
Gene Database. Available at: www.
The FDA has given the green light
P&T COMMITTEE genecards.org/cgi-bin/carddisp.
pl?gene=SV2A. Accessed May 16, 2016. to Xpert MRSA NxG (Cepheid Inter-
CONSIDERATIONS 5. Kaminski RM, Gillard M, Klitgaard H.
Brivaracetam is an FDA-approved Targeting SV2A for discovery of anti-
national), a new infection-control test
medication indicated as adjunctive ther- epileptic drugs. In: Noebels JL, Avoli M, for methicillin-resistant Staphylococcus
apy in patients with POS. Clinical studies Rogawski MA, et al., eds. Jaspers Basic aureus. The molecular assay provides
Mechanisms of the Epilepsies [Internet],
have evaluated the safety and efcacy of 4th ed. Bethesda, Maryland: National Cen- actionable results in approximately
brivaracetam in comparison with treat- ter for Biotechnology Information (US); one hour. From one to 80 Xpert assays
ment with placebo and found that bri- 2012. Available at: www.ncbi.nlm.nih.gov/
varacetam (dosed 50 mg per day, 100 mg books/NBK98183. Accessed May 16, 2016. can be performed at the same time. As a
6. Ryvlin P, Werhahn KJ, Blaszczyk B, et al. result, the test may be used by customers
per day, or 200 mg per day) demonstrates
Adjunctive brivaracetam in adults with
signicant reductions in POS frequency uncontrolled focal epilepsy: results from of all sizesfrom point-of-care settings
across all doses (P < 0.01 for all arms). a double-blind, randomized, placebo- to reference laboratories, according to
Brivaracetam is available in tablet, oral controlled trial. Epilepsia 2014;55(1):4756.
7. Biton V, Berkovic SF, Abou-Khalil B,
Cepheid.
solution, and injection formulations with
et al. Brivaracetam as adjunctive treat- Source: Cepheid International,
a price that is comparable to other FDA- ment for uncontrolled partial epilepsy in
approved therapies for adjunctive treat- December 19, 2016
adults: a phase III randomized, double-
ment of POS. The oral formulations are blind, placebo-controlled trial. Epilepsia
available with at pricing; therefore, all 2014;55(1):5766. Micro-Ultrasound System
8. Klein P, Schiemann J, Sperling MR,
strengths would likely need to be added For Prostate Imaging
et al. A randomized, double-blind, placebo-
to a drug formulary. controlled, multicenter, parallel-group The ExactVu micro-ultrasound system
Despite promising data from clinical study to evaluate the efcacy and safety of
studies, there is a lack of evidence sug- adjunctive brivaracetam in adult patients (Exact Imaging) has received 510(k)
gesting that brivaracetam offers any ben- with uncontrolled partial-onset seizures. clearance from the FDA for prostate
Epilepsia 2015;56(12):18901898. doi:
et over other AEDs, such as levetirace- 10.1111/epi.13212.
microimaging. With resolution down
tam. While the available data suggests 9. Kwan P, Trinka E, Van Paesschen W, et al. to 70 microns (0.07 of a millimeter), the
brivaracetam may provide some benet Adjunctive brivaracetam for uncontrolled system provides a 300% improvement
over placebo, this is not sufcient cause focal and generalized epilepsies: results
of a phase III, double-blind, randomized, in imaging resolution compared with
for it to be included on hospital formu-
placebo-controlled, exible-dose trial. traditional standard-of-care urologic
laries. Brivaracetam may have a role as Epilepsia 2014;55(1):3846.
an adjunctive therapy for patients whose 10. Tian X, Yuan M, Zhou Q, et al. The ef- ultrasound systems, according to the
epilepsy remains uncontrolled despite cacy and safety of brivaracetam at dif- manufacturer.
taking one to two concomitant AEDs. ferent doses for partial-onset epilepsy:
a meta-analysis of placebo-controlled Source: Exact Imaging, December 9,
studies. Expert Opin Pharmacother 2016 Q
CONCLUSION 2015;16(12):17551767.
Brivaracetam is a racetam derivative 11. Ma J, Huang S, You C, et al. Adjunctive
and SV2A ligand approved as adjunctive brivaracetam for patients with refrac-
tory partial seizures: A meta-analysis of
therapy for the treatment of POS in adults
randomized placebo-controlled trials.
and adolescents 16 years of age and older. Epilepsy Res 2015;114:5965.
This medication has shown promise in 12. Red Book Online. Ann Arbor, Michi-
patients with epilepsy whose seizures gan: Truven Health Analytics. Accessed
persist despite adequate treatment. December 19, 2016. Q

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


FDA Flags Inconsistent Hospital Reporting
Of Medical Device Problems
Hazy Reporting Rules Beget Confusion
Stephen Barlas

oncerns about medical devices going awry in hospitals issuance of guidance documents, many of which have included

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
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,
changes both directly and indirectly in the way hospitals collect such as Diane Wurzburger, Executive of Regulatory Affairs
and report incident information. Passive hard-copy for GE Healthcare, had asked the FDA to include
reports, dinosaurs in this electronic day and age, language committing the FDA to validate with the
will be out. The establishment of the new National manufacturer any signal the agency receives. The
Evaluation System for Health Technology (NEST) FDA declined to do so.
will usher in an era of active electronic reports
that include clinical data (the current hot term is The Current System ... and Its Limitations
real-world evidence or RWE) about patients hurt by Under federal rules, hospitals have 10 days to
medical devices. New software will appear. Although report serious device-related injuries to the devices
reporting to the NEST will be voluntary, hospitals, manufacturer and to notify both the manufacturer and
medical device manufacturers, disease registries, Stephen Barlas
the FDA about any deaths that may have resulted.
insurance companies, and others will be forced to Manufacturers are required to le reports with the
understand new industry software standards, such as the sud- FDA within 30 days of learning about an injury or death that
denly popular Fast Healthcare Interoperability Resources; may have been caused by a device. Manufacturers must also
purchase new inventory and claims software; and upgrade device report to the FDA when they become aware that their device
tracking to identify unique device identication (UDI) barcodes. has malfunctioned and would be likely to cause or contribute
Signicant capital expenditures will be involved. to a death or serious injury if the malfunction were to reoccur.
What portion of our health care dollars should we be spend- The above reports are sent in on a 3500A form. Although a
ing on reporting in this time when health care dollars are user facility is not required to report a device malfunction, it
shrinking? asks Janis Orlowski, MD, MACP, Chief Health can voluntarily inform the FDA of product problems through
Care Ofcer for the American Association of Medical Colleges MedWatch, the FDAs safety information and adverse event
in Washington, D.C. We have to be very cognizant of that. reporting program.
The FDAs recent push for medical device regulation has Hospitals cannot be blamed fully for failures to report. The
something to do with an investigation of 17 hospitals conducted reporting requirement states that reporting is necessary if a
in December 2015. It conrmed what the FDA probably already device may have caused death or serious illness or injury
knew: the medical device reports that hospitals are supposed or a malfunction. The qualier may throws confusion into
to submit to the FDA and, in some instances, to device manu- the denition. Isaac Chang, PhD, Director of the Division of
facturers are very often not submitted.1 The negative impact Postmarket Surveillance at the FDAs Center for Devices and
on patient safety can be signicant. Radiological Health (CDRH), says that a hospital does not have
The FDAs concern gave birth to a December 2016 workshop to provide causality before reporting. Almost every word
called The Role of Hospitals in Modernizing Evidence Generation of the reporting requirement can be parsed. Serious illness
for Device Evaluation: Harnessing the Digital Revolution for or injury means a life-threatening situation or permanent
Surveillance. At the meeting, Jeffrey Natterman, Risk Manager impairment, or damage to a body function or structure. Even
and Associate Senior Counsel for the Johns Hopkins Hospital, temporary impairment dictates a report when there was quick
said, One of the problems at hospitals is that no one knows medical or surgical intervention to prevent it from becoming
they are supposed to do it. The it was a reference to reporting permanent. And even if a life-threatening condition is a tem-
adverse effects from medical devices. The FDA is committed porary threat, it must be reported. The malfunction portion
to undertaking an education program with hospitals, but the of the requirement is equally ambiguous.
details have not been announced.
Over the past year, the FDA has focused on improving report- Controversial Guidance Documents
ing from medical device manufacturers, too, mostly through the The FDA tried to clarify some of these conundrums when
it published nal guidance called Medical Device Reporting for
Mr. Barlas is a freelance writer in Washington, D.C., who covers Manufacturers in November.3 Again, this guidance only covers
issues inside the Beltway. Send ideas for topics and your comments manufacturers, not hospitals, though health care facilities have
to sbarlas@verizon.net. 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- at some hospitals, Dr. Shuren wrote in an agency blog report.
tioned in the previous paragraph. The precipitating event is Hospital staff often were not aware of, nor trained to comply
when a manufacturer receives or otherwise becomes aware with, all of the FDAs medical device reporting requirements.
of information from any source that reasonably suggests that We feel certain there is a better way to work with hospitals to
one of its marketed devices caused injury or malfunctioned. get the real-world information we need, and we should work
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. in light of developments in the creation and evaluation of
One concern has to do with the use of trend analysis to electronic health information.1
determine whether a reportable event has occurred in the past. While those and other hospitals can make a case for the
That comes up in the guidances explication of when a company turgidity of reporting regulations, it is also true that hospitals
becomes aware of information, which includes trend analysis. that fail to report have very little to worry about in terms of
It is unclear from the nal guidance whether trend analysis is FDA remedial action. In the case of the 17 hospitals subject to
required or is something that, if done voluntarily, must be an the FDA inspections starting in December 2015, the agency
element in a decision as to whether the company becomes issued a Form FDA 483 to 15 of them, which noted observa-
aware that a reportable event under medical device reporting tions that the FDA investigators made during the inspections.
(MDR) necessitates remedial action to prevent an unreasonable Observations listed on a Form FDA 483 do not represent a
risk of substantial harm to public health. Jeffrey Secunda, MS, nal agency determination regarding a facilitys compliance.
MBA, Vice President of Technology and Regulatory Affairs for The violations noted during the inspections varied by facility but
the Advanced Medical Technology Association in Washington, included observations that written MDR procedures had not
D.C., the device manufacturers trade group, states, It is not been developed, maintained, and implemented. For some
clear when an event that was previously evaluated as not hospitals with signicant violations of the MDR regulation, FDA
reportable would become reportable based on a trend. received a response that we determined was not adequate to
address those violations, and we engaged with these facilities
Hospital Underreporting to facilitate an effective path to voluntary compliance, states
Over the past year, however, the high visibility issue has Deborah Kotz, an FDA spokeswoman. These hospitals indi-
been the FDAs concern about hospital underreporting of medi- cated their willingness to work with us and address the viola-
cal device problems. Throughout their workday, hospital staff tions, and at this time, we do not believe any additional action
members use a variety of medical devices: imaging machines, with regard to these hospitals is necessary. The FDA plans to
electrocardiographs, and in vitro tests to make diagnoses; infu- partner with hospitals to educate them on the agencys MDR
sion pumps, ventilators, and robotics to provide treatment; and requirements to improve their reporting of device-related
an array of implants to replace diseased joints and organs. The adverse events.
agency held a meeting at its suburban Maryland location on
December 5 and outlined some of its concerns about hospital Long-Standing Problems
reporting, its ongoing initiatives to encourage reporting, and its The FDA recognized about ve years ago, before the inves-
understanding of the barriers that either prevent or discourage tigation of the 17 hospitals reconrmed it, that a better sys-
hospitals from reporting instances in which a device may have tem for reporting was needed. In 2012, the agency issued a
caused death, serious illness, or injury or a malfunction. report, Strengthening Our National System for Medical Device
The agency has long guessed that reporting is sketchy at Postmarket Surveillance, that described the limitations of cur-
best. That assumption was born out in early 2016 when the rent authorities and approaches to medical device post-market
FDA announced the results of 17 hospital inspections it initiated surveillance and proposed a strategy for a national medical
in December 2015.1 The hospitals were chosen because there device post-market surveillance system.4
were reports of events at these facilities related to the spread There are issues, I am not going to lie, states Hopkins
of uterine cancer from the use of morcellators or the spread of Natterman, referring to the barriers hospitals face when com-
infections associated with contaminated duodenoscopes. While plying with the reporting requirement. Part of the problem is
these events appeared to be the kind that would have fallen lack of buy-in from hospital leadership. Concern about hos-
under current medical device reporting requirements, we did not pital liability also dampens reporting. It has happened that
see corresponding adverse event reports in our adverse event we send a report to the manufacturer, and then it goes into a
MAUDE [Manufacturer and User Facility Device Experience] black hole, Natterman continues. Then we get sued, and we
database, states Jeffrey Shuren, MD, JD, Director of the FDAs end up struggling with the manufacturer to get information.
CDRH. Some of the reporting lapses were found at Massachusetts Even if every hospital in the country reported adverse events
General Hospital in Boston, at NewYorkPresbyterian Hospital, correctly, the FDA would still have a MAUDE database lled
and at two hospitals in Los Angelesthe Ronald Reagan UCLA with passive information. Such passive surveillance has impor-
Medical Center and the CedarsSinai Medical Center. Among tant limitations because it relies on people to identify that harm
the 17 hospitals reviewed, the FDA said six didnt properly report occurred or risk is present, recognize that the harm or risk
both patient deaths and injuries linked to medical devices within is associated with the use of a particular device, and take the
10 days, as required. Five other hospitals didnt report serious time to report it. In the past few years, the FDA has initiated
injuries in a timely manner, according to the agency. efforts to make it easier for some hospitals to report and for
We believe that these hospitals are not unique in that there the agency to obtain adverse effect information beyond what
is limited to no reporting to the FDA or to the manufacturers a hospital reports on its 3500A.

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


FDA Flags Inconsistent Hospital Reporting of Medical Device Problems
The Medical Product Safety Network (MedSun) was created Early critical data partners include the National Patient-
in 2002. Composed of 300 hospitals, it allows them to submit Centered Clinical Research Network, Sentinel, coordinated
data electronically (not necessary in MAUDE) and gives the registry networks, payers, large health care systems, claims
FDA the ability to go into a hospital and tweeze out additional data systems, the device industry, the National Center for
information. But participation in MedSun is limited, in part Health Statistics, and patients, to name a few examples. Dawn
because the FDA requires 10 reports to be led every year. Bardot, PhD, Vice President of Technology Innovation for
Hopkins Natterman says that of the six hospitals in the Johns MDIC, did not reply to a request for information about the
Hopkins Health System, only hisJohns Hopkins Hospital NESTs progress.
les MedSun reports. The concept of the NEST is well and good. However, the
MedSun is an improvement over MAUDE because it collects problem with collecting RWE on medical devices is that the
more than just passive information. But the Holy Grail is the quality of clinical information is inconsistent. In July, the FDA
collection of more robust data. Obtaining clinical informa- issued draft guidance on what it would like to see from the
tion from hospitals, insurance companies, electronic health various sectors that could contribute medical device RWE.6
records (EHRs), medical registries, and other sources would The responses indicate the long road the FDA has ahead of it
be an even bigger boon. The Sentinel system does that. It was as it tries to wrestle various sectors into a unied approach to
authorized by Congress in 2008, but has taken more than half submission of RWE. The 510(k) Coalition, composed of device
a decade to progress beyond a pilot stage. It allows the FDA manufacturers, feels the draft guidance relies too heavily on
to weed through medical claims data submitted by insurers in registries. The nal guidance needs to be clear that RWE is not
an attempt to nd early-warning signs that a device is causing limited to situations where the data is derived from a registry,
problems. The Sentinel system apparently has access to claims states Ralph Hall, a partner at Leavitt Partners, a Washington
for nearly 200 million Americans.5 policy shop headlined by former Health and Human Services
The medical device surveillance program within Sentinel is (HHS) Secretary Mike Leavitt.
called BloodScan. It looks for problems with biologic products, The Coalition also believes that the draft guidance is not
such as vaccines, allergenic products, blood, blood components, clear enough on the usage of different types of RWE and real-
and blood derivatives, tissues, and cellular and gene therapies. world data (RWD). Most of the examples in the draft guidance
It has a lot of power, given those 200 million individuals, when seem to focus on clinical-type data, and do not consider data
it comes to looking for rare events for the purpose of analysis. from sources such as engineering analysis and bench testing,
However, 10% of the records in the Sentinel database are from Hall explains. Such information is often highly valuable in the
EHRs, and the rest are from claims data. That has a lot of device context. Hall declined to elaborate.
limitations for the kind of work we want to do, admits Steven RWD could be used in regulatory decision-making. But what
Anderson, PhD, MPP, Director of the Ofce of Biostatistics and about actions short of that, such as recalls or notications to
Epidemiology in the FDAs Center for Biologics Evaluation and physicians and consumers about devices on the market that
Research. Of the 24 data partners in the program, a major one have shown recent troublesome effects? It is that instance
is Hospital Corporation of America, which has 160 hospitals the agency attempted to clarify when it issued its nal guid-
and 20 million patient encounters a year. Dr. Anderson notes, ance document in December: Public Notication of Emerging
however, that there are signicant shortcomings to BloodScan, Postmarket Medical Device Signals.2 The objective was to
including medical chart validation, which can take from dene the emerging signals that raise an issue about a
six to eight months. That is, if the transfusion is even noted in device on the market that the agency has determined has the
the chart; 50% or more are not noted, he says. potential to impact patient management decisions and/or the
The ultimate bonanza is a system that leverages RWEdata known riskbenet prole of the device. An emerging signal
developed through routine clinical practice. These data would can arrive at the FDA from a variety of sources including, but
be captured in electronic health information (such as device not limited to, MDRs, MedSun reports, data from mandated
registries, EHRs, and payer claims forms) that incorporated post-market studies, clinical trials or data published in the
UDIs to quickly identify poorly performing devices; accurately scientic literature, epidemiologic research including evalu-
characterize and disseminate information about real-world ation of administrative databases, health care claims data or
device performance, including the clinical benets and risks registries, and inquiries or investigations from global, federal,
of marketed devices; and efciently generate data to support or state health agencies.
pre-market clearance or approval of new devices and new uses Mark B. Leahey, President and Chief Executive Ofcer of
of currently marketed devices. the Medical Device Manufacturers Association in Washington,
That evolution is moving forward with the creation of the D.C., worries that the FDAs guidance may have unintended
NEST. The FDA issued a $3 million grant in September to the consequences related to unvalidated information being relied
Medical Device Innovation Consortium (MDIC) to establish upon by patients, providers, and the public to make certain
the coordinating center, which would organize and run the clinical decisions that may not be in a patients best interest.
NEST. It is envisioned as a virtual network of data partners, But in the nal guidance, the FDA nowhere states the need
connected through reusable, standardized data use agreements, for any emerging signal to be validated before the agency
that permits access to data from multiple sources to optimize issues a communication of concern. Rather, it cites a standard
data standardization, expedite project-specic research agree- that the available evidence is of sufcient strength. It does
ments, and reduce the cost of evidence development through note, however, that the device manufacturer will be consulted
economies of scale. 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 PROGNOSTIC FACTORS AND


Chronic lymphocytic leukemia (CLL) is the most common TREATMENT STRATIFICATION
adult leukemia in the Western world. The American Cancer The initial diagnosis of CLL is based on the presence of at
Society predicted approximately 18,000 new cases in 2016, least 5 x 109 B lymphocytes per liter of peripheral blood with
with nearly 5,000 estimated deaths.1 CLL is characterized as a CLL phenotype and by ruling out other lymphoproliferative
a B-cell malignancy, marked by a progressive accumulation disorders.2,5 Lymphadenopathy and/or splenomegaly with less
of incompetent clonal B lymphocytes with a CLL phenotype. than 5 x 109 B lymphocytes per liter of peripheral blood is the
The main diagnostic criterion of CLL is the presence of at denition of small lymphocytic lymphoma (SLL), which some
least 5 x 109 B-cell lymphocytes per liter with a CLL pheno- experts consider to be a different manifestation of the same
type in peripheral blood.2 In comparison to normal peripheral disease.2,5 Once a diagnosis of CLL is established, the Rai and
blood B cells, CLL cells are CD5-positive.3 In addition, they Binet staging systems are used worldwide in the assessment
express B-cell surface antigens CD19, CD20, and CD23. The of prognosis.2,5 They are based on physical examination nd-
extent of expression of these surface markers is part of the ings and on hemoglobin and platelet concentrations. Both
process involved in distinguishing CLL from other hematologic systems dene lower-risk disease as the presence of lympho-
malignancies. cytosis in the absence of enlarged lymph nodes, splenomegaly,
The exact cause of CLL is unknown, and there are few known hepatomegaly, anemia, or thrombocytopenia. Individuals with
risk factors. However, it is more common in men, in people intermediate- and higher-risk CLL have multiple palpable
with a family history of the disease, and in people of European enlarged areas and cytopenias. Median survival times are
genetic ancestry.3 It is also more common in the elderly, with approximately 12.5 years, seven years, and one to two years for
an average age of 72 years at diagnosis, although up to 30% low-, intermediate-, and high-risk CLL, respectively.5 The Rai
of cases occur in individuals younger than 55 years of age.3 and Binet clinical staging systems do not identify which low-risk
Some studies have linked CLL to exposure to chemicals such patients will progress rapidly. Additional molecular markers
as Agent Orange.3 Farming and long-term exposure to some are used in risk stratication and treatment determination.
pesticides may potentially increase risk.3 Continued progress in understanding the pathology of CLL
Many individuals with CLL are asymptomatic at diagno- has led to the discovery of a large number of novel prognostic
sis, and the disease may be detected upon routine labora- markers.68 Establishing a prognostic score for patients with
tory examination. Others may present with constitutional CLL continues to be an area of research, and there are more
symptoms including fever, weight loss, fatigue, night sweats, than 20 such markers available.8,9 Immunoglobulin heavy-
and weakness, while a physical examination may demon- chain variable (IGHV) mutational status is a strong indepen-
strate lymphadenopathy, splenomegaly, and hepatomegaly.3 dent predictor of survival outcomes in CLL, with unmutated
Depending on prognostic factors and comorbidities, 82.6% of (2% or fewer cells mutated) or VH3-21 mutated IGHV indicating
CLL patients are expected to survive at least ve years, based a poor prognosis and shorter treatment-free period and overall
on data from the National Institutes of Healths Surveillance, survival (OS), regardless of stage.5,10 Treatment selection is
Epidemiology, and End Results or SEER program.4 Advances in determined by the presence of certain chromosomal abnormali-
molecular and cytogenetic analyses have allowed more precise ties. In particular, a deletion of chromosomes 11 (del[11q])
risk-stratication models that have dened current treatment and 17 (del[17p]) and/or mutation of the TP53 gene have been
algorithms composed of novel targeted agents. Novel treatment associated with worse prognosis.6,9 Therefore, evaluation for
options beyond conventional chemotherapy include monoclonal the presence of these three specic cytogenetic abnormalities,
antibodies and targeted small-molecule inhibitors impacting among others, has been incorporated into treatment guidelines,
B-cell signaling. Allogeneic stem cell transplant offers a cura- particularly before each anticipated treatment to account for
tive option but is reserved for select individuals: Few qualify mutations occurring over the course of the disease.5,9 Treatment
given its toxicities. This article describes clinical outcomes and options are stratied by cytogenetic abnormality (Table 1).
therapeutic application of newly approved pharmacotherapies
and highlights emerging investigational therapeutic options. TREATMENT PRINCIPLES
With the exception of allogeneic hematopoietic stem cell
transplantation (HSCT), CLL is not generally considered
Dr. Olin is a Professor of Pharmacy at Wingate University School curable. However, long-term disease-free survival has been
of Pharmacy in Wingate, North Carolina. Katherine Canupp is a demonstrated in some subsets of patients.11 Goals of chemo-
Doctor of Pharmacy Candidate, Class of 2019, at the same institution.
Dr. Smith is a Clinical SpecialistHematology/Oncology at Novant Disclosures: The authors report no commercial or nancial interests
Health Presbyterian Medical Center in Charlotte, North Carolina. in regard to this article.

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


New Pharmacotherapies in Chronic Lymphocytic Leukemia
group (P = 0.001.)16 However, patients with del(17p) did not
Table 1 Selected First-Line Treatment benet as much from FCR, and older patients with comorbidi-
Options for Chronic Lymphocytic Leukemia5,9 ties, including reduced renal function, may not tolerate FCR as
CLL Without del(17p) and/or TP53 Mutation well as other options.16 Data from a phase 2 FCR study showed
Physically Fit Patients Elderly or Frail Patients or that patients with a mutated IGHV gene achieved sustained
Those With Signicant remission after a median 12.8 years of follow-up, which was
Comorbidities the rst success of this type demonstrated in CLL.11 The com-
bination of bendamustine with rituximab (BR) was compared
Fludarabine + Obinutuzumab + chlorambucila with FCR in untreated physically t patients and did not meet
cyclophosphamide + rituximab Ibrutiniba the prespecied criteria for noninferiority.14 Because BR was
Pentostatin + Ofatumumab + chlorambucil associated with fewer infectious complications, it remains
cyclophosphamide + rituximab Rituximab + chlorambucil a consideration for older patients at risk for infections.5,9,17
Fludarabine + rituximab Bendamustine rituximabb Front-line chemotherapy options for CLL are stratied based
Bendamustine rituximab on del(17p)/TP53 mutations and the patients tness level or
CLL With del(17p) and/or TP53 Mutation ability to handle intensive chemotherapy (Table 1).5,9
A potentially curative modality is allogeneic HSCT, which
Ibrutinib
remains an option for patients with del(17p)/TP53 abnor-
Idelalisib rituximabc
malities and/or patients who have not responded to or have
High-dose methylprednisolone + rituximab
relapsed with rst-line therapy. While many CLL patients are
Allogeneic stem cell transplant
not candidates for HSCT due to age and comorbidities, the
CLL = chronic lymphocytic leukemia; del(17p) = chromosome 17 deletion; use of nonmyeloablative reduced-intensity conditioning (RIC)
NCCN = National Comprehensive Cancer Network. regimens has expanded accessibility. A summary of prospective
a
Category 1 recommendation as per NCCN guidelines studies using RIC HSCT in CLL patients with median follow-
b
Not guideline-recommended for patients categorized as frail up of up to six years demonstrated approximately 40% median
c
Not endorsed by NCCN PFS and 50% to 60% median OS, with the most signicant
complication of chronic graft-versus-host disease (cGVHD)
therapy include inducing remission and prolonging life while in almost 50% of patients.18 The novel B-cell-receptor signal-
minimizing treatment-related adverse effects. No survival ing inhibitors ibrutinib (Imbruvica, Pharmacyclics, Inc.) and
advantage was demonstrated when comparing immediate idelalisib (Zydelig, Gilead Sciences, Inc.) have prolonged PFS
with deferred initiation of treatment in older trials of alkylat- in higher-risk patients in whom transplant was previously the
ing agents.12 Therefore, chemotherapy is not offered in earlier only option; these therapies are discussed below. An overview
stages where presentation is often asymptomatic; patients are of the newly available pharmacotherapies for CLL rst-line
managed with periodic follow-up until the development of signs therapy, including place in therapy, pharmacotherapeutic
and symptoms, including progressive lymphadenopathies, considerations, and cost implications, can be found in Table 2.
splenomegaly, or cytopenias.2,5,9 The current availability of
more targeted therapies and molecular markers points to BIOLOGIC THERAPIES
the need for continued research into the impact of earlier Anti-CD20 Antibody Therapies
treatment options. Because the addition of rituximab to udarabine and cyclo-
Historically, chlorambucil (Leukeran, Aspen Global) was the phosphamide demonstrated improved activity and was well
standard therapy for initial treatment, and it is still an option tolerated, FCR became a rst-line therapy. Further research
today, now most often given in combination with an anti-CD20 into the biological activity of the CD20 receptor led to the
monoclonal antibody.5 A phase 3 trial comparing udarabine development of ofatumumab (Arzerra, Novartis) and obinutu-
to chlorambucil in patients with a median age of 70 years zumab (Gazyva, Genentech), which have distinct CD20-binding
showed improved complete response (CR) with udarabine, characteristics. Ofatumumab, a fully human monoclonal CD20
but no difference in OS.13 Thus, chlorambucil monotherapy antibody, and rituximab have been classied as type-1 anti-CD20
remains a rst-line option for older patients with comorbidi- antibodies because they lead to binding with C1q, which acti-
ties.5,9 Introduction of the biologic agent rituximab, an anti- vates complement-dependent cytotoxicity (CDC).25,26 However,
CD20 monoclonal antibody, revolutionized the management ofatumumab binds at distinct, discontinuous regions of CD20,
of B-cell malignancies, including CLL, with the combination of which differentiates it from rituximab.26,27 Obinutuzumab,
udarabine, cyclophosphamide, and rituximab (FCR) becom- a type-2 anti-CD20 antibody, binds to CD20 with less inten-
ing the recognized gold standard in patients able to tolerate sity, resulting in lower CDC but more lysosomal cell death
intensive therapy.14,15 (antibody-dependent cellular cytotoxicity).25,26 Continued
In the CLL8 trial, untreated physically t patients were studies of ofatumumab and obinutuzumab will help further
randomized to receive six courses of FCR or udarabine and dene the clinical impact of their molecular differences.
cyclophosphamide (FC). Progression-free survival (PFS)
was higher in the FCR group after three years (65% versus Obinutuzumab
45%; hazard ratio [HR], 0.56; 95% condence interval [CI], Obinutuzumab was approved by the Food and Drug
0.460.69]).16 With 5.9 years of follow-up, median OS was Administration (FDA) in combination with chlorambucil for
86 months for the FC group and not yet reached for the FCR 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 16.3 months, and 11.1 months in the obinutuzumab plus
in the majority of individuals with CLL, the CLL11 trial evalu- chlorambucil, rituximab plus chlorambucil, and chlorambucil
ated participants with coexisting conditions. Treatment-nave groups, respectively; HR for progression or death, 0.18; 95%
patients with comorbidities (N = 781), as indicated by either a CI, 0.130.24; P < 0.001 for obinutuzumab plus chlorambucil
cumulative illness rating scale score greater than 6 or moder- compared with chlorambucil). Direct comparison of obinutu-
ate renal impairment, were randomized to one of three arms: zumab plus chlorambucil with rituximab plus chlorambucil
chlorambucil alone, obinutuzumab plus chlorambucil, or ritux- demonstrated prolonged PFS (HR, 0.39; 95% CI, 0.310.49;
imab plus chlorambucil. Patients median age was 73 years, P < 0.001.) The PFS benet with obinutuzumab did not extend
and 82% had at least three comorbidities. Median PFS was to those patients with del(17p).28 Grade 3 or 4 infusion reactions
signicantly improved in both combination arms (26.7 months, 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 an antihistamine 30120 minutes prior to infusion and should
during subsequent infusions.25 be closely monitored during the infusion for blood
Obinutuzumab demonstrated activity in heavily pretreated pressure changes, flushing, pyrexia, chills, and other
patients in a phase 1/2 study, but it is not approved by the infusion reactions.19
FDA for this indication.29 Patients administered obinutu-
zumab should receive acetaminophen, a corticosteroid, and

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New Pharmacotherapies in Chronic Lymphocytic Leukemia
Ofatumumab major hemorrhages in ve patients. Grade 23 atrial bril-
Ofatumumab plus chlorambucil was evaluated in the lation occurred in six patients with drug discontinuation in
COMPLEMENT-1 trial, a phase 3 study in treatment-nave CLL two patients, and grade 3 hypertension occurred in six patients,
patients deemed to be ineligible for udarabine based on age none requiring dose modication. In a follow-up analysis of this
or comorbidities.20,30 Participants were randomized to receive trial and other studies of ibrutinib in previously treated patients,
ofatumumab with chlorambucil (n = 221) or chlorambucil alone median PFS and OS still hadnt been reached, with more than
(n = 226) with continued treatment until best response or a 89% PFS at two years.38 Outcomes were favorable with ibru-
maximum of 12 cycles, with the primary endpoint of median tinib in previously treated patients as well.39 Patients taking
PFS. Participants median age was 69 years, and 72% had at least ibrutinib should be educated about and monitored for signs
two comorbidities, which included cardiovascular, metabolic, and symptoms of bleeding, infection, and atrial brillation.21
respiratory, renal, or other conditions. After 28.9 months of
follow-up, PFS was improved in the combination therapy arm Idelalisib
with median PFS of 22.4 months versus 13.1 months (HR, 0.57; Idelalisib is another small molecule that affects B-cell
95% CI, 0.450.72; P < 0.001). In patients with del(17p), PFS signaling pathways. Phosphatidylinositol-3 kinases (PI3Ks) in
was unchanged with the addition of ofatumumab (HR, 0.46; lymphocytes and other cells regulate processes such as prolif-
95% CI, 0.181.19). Patients receiving combination therapy were eration and migration and have been shown to be expressed
more likely to experience neutropenia, but rates of infection in isolated B-CLL cells.40,41 Inhibition of the PI3K-delta isoform
were similar between groups. Grade 3 and 4 infusion reactions pathway leads to enhanced apoptosis.41 Idelalisib is an inhibi-
were experienced in 10% of patients. As with obinutuzumab, tor of PI3K-delta that affects signaling through B-cell receptor
patients receiving ofatumumab should receive premedication pathways by inducing apoptosis.22 It is approved in combina-
and should be closely monitored for infusion reactions. The tion with rituximab for treatment of relapsed or refractory
ndings of this trial led to FDA approval of ofatumumab with CLL based on ndings of the Study 116 trial.22,42 The combi-
chlorambucil in untreated patients ineligible for udarabine.20,30 nation of idelalisib and rituximab was compared with ritux-
Ofatumumab is also FDA-approved with udarabine and imab alone in CLL patients who had progressed on previous
cyclophosphamide for relapsed disease, as extended treatment regimens with a median of at least three drugs; PFS was the
in patients who responded to at least two lines of therapy, and primary endpoint. Patients (N = 220) had a median age of
for patients failing udarabine or alemtuzumab.20 Its activity 71 years with median estimated creatinine clearance of
in the setting of relapsed disease was demonstrated in the 6267 mL per minute. Median PFS was 5.5 months in the
COMPLEMENT-2 study with improved PFS of ofatumumab rituximab-only arm and had not yet been reached with combi-
with FC compared with FC alone (HR, 0.67; 95% CI, 0.510.88; nation therapy when the study was halted at the prespecied
P = 0.0032).31 The PROLONG investigators evaluated ofatu- stopping point for efcacy (P = 0.001). OS at one year was
mumab as a maintenance therapy in 238 patients for up to improved with combination therapy (92% versus 80%; HR, 0.28;
two years compared with observation, and improved PFS was P = 0.02). Of note, the PFS benet of idelalisib was extended to
observed with therapy (HR, 0.50; 95% CI, 0.380.66; P < 0.001).32 those patients with del(17p).42 Given the activity of idelalisib
Activity of ofatumumab has been observed in patients failing and the limited options for patients with del(17p), idelalisib was
udarabine or alemtuzumab.20,33 approved in Europe for treatment-nave patients with del(17p)
and is recommended by the German CLL study group as an
Small-Molecule Therapies option for rst-line therapy in this subgroup.9
Ibrutinib Of concern with idelalisib are fatal or severe hepatotoxicity,
Ibrutinib is a small-molecule therapy and Brutons tyrosine severe diarrhea or colitis, and serious or fatal infections, which
kinase (BTK) inhibitor approved for several hematologic occurred in 18%, 14%, and 21% of patients in monotherapy trials
malignancies.21 BTK has a well-characterized role in the B-cell and 11%, 19%, and 36% of patients in combination trials, respec-
receptor signaling pathway that leads to proliferation and cell tively.22 In a phase 2 study of idelalisib as rst-line therapy,
survival.34,35 Specically, it promotes homing and adhesion 54% experienced grade 3 or higher transaminitis.43 A safety
of CLL cells to the microenvironment, an activity that is analysis was conducted with patients receiving idelalisib for
chemokine-mediated.36,37 Ibrutinib forms covalent bonds with multiple indications. Of 1,073 evaluated patients, 51% experi-
a cysteine residue in the active site of the BTK.21 This leads enced transaminitis of any grade with median onset of 39 days.
to an inhibition of enzymatic activity of the BTK and thus Rechallenge of some participants with at least grade 3 transam-
inhibits malignant B-cell proliferation and survival, resulting initis resulted in no further recurrence.44 Patient counseling
in cell death.21 for idelalisib should include monitoring and awareness to alert
Ibrutinib was compared with chlorambucil in an international, the provider about severe skin reactions, diarrhea, or new or
open-label, randomized phase 3 trial of 269 previously untreated worsening coughing or shortness of breath.22
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 Venetoclax
at baseline, and a third had a cumulative illness rating score While improved CLL outcomes have been demonstrated
greater than 6. Treatment with ibrutinib resulted in longer with ibrutinib and idelalisib, there is still the potential for
rates of PFS and OS. The relative risk of progression or death relapse and resistance, particularly in patients with del(17p).
was 84% lower with ibrutinib (HR, 0.16; 95% CI, 0.090.28; The B-cell lymphoma-2 (BCL-2) family of proteins regulates
P = 0.001).37 Adverse effects with ibrutinib included grade 34 cellular apoptosis and oncogenic functions. Selective inhibi-

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


New Pharmacotherapies in Chronic Lymphocytic Leukemia
tion of BCL-2 has resulted in tumor lysis within 24 hours.45 with high levels of toxicity, drug resistance due to incomplete
Venetoclax (Venclexta, AbbVie/Genentech) is thought to bind BTK receptor blockade, and Richters transformation (evolution
BCL-2 and restore apoptosis.23 This small-molecule therapy is of CLL into large-cell lymphoma).53,54 Acalabrutinib (ACP-196,
approved specically for patients with del(17p) CLL who have Acerta Pharma) is a second-generation irreversible inhibitor
received at least one prior therapy.23 of BTK that offers several pharmacological improvements
Venetoclax was studied in a phase 1 dose-escalation study compared with its rst-generation counterpart. This agent
(1501,200 mg per day) of 116 participants with relapsed or represents a more selectively targeted BTK inhibitor that does
refractory CLL or SLL.23,38 Patients median age was 66 years, not bind to alternative kinases, such as epidermal growth factor
they had received from one to 11 previous therapies, and 30% receptor, TEC family, and insulin receptor kinase, thereby
had the del(17p) mutation. The overall response rate (ORR) providing improved tolerability. In addition, acalabrutinib
across all doses was 79%, with a 71% response rate among those has more rapid oral absorption (peak plasma values occur
with del(17p). Clinically signicant tumor lysis syndrome (TLS) between 0.6 and 1.1 hours versus one and two hours) and a
occurred in three patients, with one requiring dialysis and one shorter half-life (one hour versus four to 13 hours) compared
sudden death after a dose increase. In the study expansion with ibrutinib, allowing for twice-daily dosing. This method
with revised dose-escalation adjustments and administration of administration has been shown to provide better plasma
of TLS prophylactic medications in higher-risk participants, exposure (continuous, greater-than-95% blockade of BTK) than
no clinically signicant TLS occurred. Other adverse effects ibrutinib. As a result, rates of drug resistance and Richters
included diarrhea (52%), upper respiratory infection (48%), transformation may be effectively reduced.55
and grade 34 neutropenia (41%).46 At 24 months, the subset Acalabrutinib was initially shown to be safe and effective in
of participants maintained on the 400-mg daily dose had esti- an uncontrolled, multicenter, phase 1/2 trial of 60 relapsed/
mated PFS of 62% (95% CI, 4575). Grade 3 or higher adverse refractory CLL patients in which the ORR with 100-mg twice-
events occurred in 86%, with neutropenia as the most common. daily dosing was 95% (partial response [PR], 85%; PR with
Most were treated with granulocyte-colony stimulating factor, lymphocytosis, 10%) with a median follow-up period of
and all responded.47 14.3 months. Stable disease (SD) occurred in 5% of patients.
A phase 2 study of 107 participants with relapsed or refractory ORR in patients with del(17p) was 100%. No cases of Richters
CLL demonstrated 79.4% ORR (95% CI, 70.586.6) at one year. transformation were reported, and only a single case of disease
Some participants had failed ibrutinib or idelalisib, which progression occurred. Patients had a median of three prior
provides further support for venetoclax in higher-risk popula- therapies, and a majority had poor prognostic features. Most
tions.48 Several studies are under way evaluating venetoclax toxicities were grade 12, with the most common being
in previously untreated CLL, including various combinations headache (43%), diarrhea (39%), increased weight (26%),
with ibrutinib, obinutuzumab, and rituximab (NCT02758665, pyrexia (23%), and upper respiratory infection (23%). Therapy
NCT02756897, and NCT02950051).4951 discontinuation due to toxicity occurred in three patients
Patients receiving venetoclax should be instructed to drink at (5%).55 Preliminary ndings in an ongoing phase 1/2 study
least six glasses of water daily, should be educated about symp- (NCT02029443) of acalabrutinib in 74 patients with treatment-
toms of TLS, and should receive appropriate TLS prophylaxis as nave CLL reected similar results (ORR, 96%; PR, 86%; PR plus
indicated. Inpatient dose initiation and escalation is recommended lymphocytosis, 10%; SD, 4%). The median time to response
for high-risk patients, such as those with any lymph nodes 10 cm was two months, with a rapid reduction in lymphadenopathy.
or larger or with an absolute lymphocyte count of 25 x 109 per Treatment was highly tolerable, with 97% of patients continu-
liter or greater and any lymph nodes 5 cm or larger.23 ing on the study drug.56 A phase 3 trial is under way based on
these results (NCT02475681).57
HSCT
Prior to the availability of the small-molecule therapies, Lenalidomide
allogeneic HSCT was the only treatment option for relapsed/ Lenalidomide (Revlimid, Celgene), an FDA-approved
refractory high-risk patients, such as those with del(17p). Use immunomodulatory agent for multiple myeloma, mantle cell
of RIC regimens has expanded accessibility and produced lymphoma, and myelodysplastic syndrome,58 is being explored
curative potential, but cGVHD has been a limitation. While as a treatment option for CLL. Although well known for its
small-molecule therapies provide alternatives for managing antiangiogenic, antineoplastic mechanisms, lenalidomide is
high-risk patients, their long-term efcacy remains unknown. classied as an immunomodulatory agent due to its ability to
HSCT may still be a viable option for some patients. A suggested enhance the immune system. It counters T-cell dysfunction
sequencing of modalities is the use of the novel agents until, known to exist in patients with CLL and also inhibits the sup-
ideally, an achievement of a maximum response (or even if no pressive effects that malignant CLL clones have on the immune
response) and then HSCT, especially in younger patients with system.5961 Among the mechanisms of cancer-induced immune-
a well-matched donor available.52 system suppression discovered to date, checkpoint inhibition
has been identied as a potential target in CLL. Malignancies
EMERGING THERAPIES of many types, including CLL, use the programmed death
Acalabrutinib (ACP-196) receptor-1 (PD-1) pathway to diminish the growth and activ-
BTK inhibition has become an important advance in the treat- ity of T cells that would normally be malignant cell lysis.59,62,63
ment of CLL because this target has been shown to be highly Lenalidomide blocks the inhibitory interaction that occurs
active in the malignancy.3436 However, ibrutinib is associated between the programmed death receptor ligand-1 (PD-L1)

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New Pharmacotherapies in Chronic Lymphocytic Leukemia
found on malignant cells and the PD-1 found on CD4+ and CD8+ assurance assays are conducted on the product prior to release
T cells, thereby increasing T-cell cytotoxicity and enhancing for clinical use. After approximately 1014 days, these cells
immune system function.60 are ready to be transfused back into the patient following a
Existing data suggest a potential role for lenalidomide in the round of preparatory lymphosuppressive chemotherapy. Once
management of CLL. Trials to date have demonstrated an ORR infused, they work to destroy malignant cells expressing the
of 56% and 58% when lenalidomide is given as monotherapy at antigen targeted by the CAR, with the lymphosuppression
1025 mg orally daily on days 121 of a 28-day schedule in both being needed to make room for these targeted cells to mul-
the untreated and relapsed/refractory settings.64,65 Toxicities tiply. This autologous T-cell procedure can provide targeted
unusual to lenalidomide but found in studies with CLL patients antitumor activity without the morbidities associated with
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 Data from 29 patients who received CAR T cells targeted to
is characterized by symptoms associated with immune-system the CD19 (B lymphocyte) receptor for CLL have been published
activation, specically increased B-cell antigen presentation. in the literature through small clinical trials.7376 The results
These symptoms include acute lymphadenopathy with inam- have shown promise for second-generation CD19 CAR T cells
mation in the overlying skin, fever, and rash.66 Titrating CLL in the relapsed/refractory setting, with both durable complete
patients from lower doses (510 mg daily) by 5 mg every remissions and ORRs ranging from 38% to 86%. However,
28 days to 25 mg daily may provide noninferior response rates much variability exists between them in both the use and type
and reduce the incidence of the are reaction.66 of conditioning regimen and the dose of CD19 CAR T cells
Although combinations of lenalidomide with traditional infused. Patients received conditioning regimens composed
chemotherapy agents were found to be prohibitively toxic, of cyclophosphamide with or without pentostatin/udarabine
lenalidomide has been combined with anti-CD20 monoclonal and CD19 CAR T-cell doses of 0.4 to 3 x 107 cells/kg.7376
antibodies to provide synergy and added efcacy without Optimization of these parameters is needed to establish the
excessive toxicities.67,68 Addition of rituximab to lenalidomide clinical benet that this therapeutic option may provide.
is associated with ORR approaching 83% in the rst-line setting The largest and most recently documented study to be com-
and 61% in the relapsed/refractory setting, with or without the pleted is a phase 1 trial that demonstrated a 57% ORR among
presence of poor prognostic features.69,70 Lenalidomide has 14 patients with relapsed/refractory CLL.76 Lymphodepleting
been included in the National Comprehensive Cancer Network preparatory regimens consisted of cyclophosphamide plus
guidelines as a treatment option both alone and in combination either udarabine (n = 3), pentostatin (n = 5), or bendamus-
with rituximab in the relapsed/refractory setting, regardless tine (n = 6). Doses of CD19 CAR T cells infused ranged from
of mutation status.4 However, it is still not recommended in 0.14 x 108 to 11 x 108 (median, 1.6 x 108). Four patients achieved
the rst-line setting, nor has the FDA granted approval for a CR and four achieved a PR. The CD19 CAR T cells persisted
lenalidomide use in CLL. The combination of lenalidomide and for four years in the rst two patients who achieved CR. No
the second-generation anti-CD20 monoclonal ofatumumab may patients who achieved a CR had progressed or shown evidence
provide even better results, with phase 2 data suggesting an of minimal residual disease, suggesting this treatment may
ORR of 71% with 24% CR in the relapsed/refractory setting.71 be a possible cure for CLL. All patients achieving a response
Further studies with anti-CD20 monoclonal antibodies are in experienced cytokine release syndrome, which was correlat-
development and should help elucidate the role of lenalido- ing both with T-cell expansion in vivo and clinical response.
mide in CLL. CD19 CAR T-cell infusions were well tolerated, with only mild
infusion-related, low-grade fevers and chills noted. Two patients
CAR T-Cell Therapy developed TLS.76
Antineoplastic treatment strategies that harness the immune
system have become the mainstay of cancer research today. Other Agents
In particular, therapies meant to amplify T cells in the adaptive Outside of the emerging therapies previously discussed,
immune system have been shown to provide durable treatment many other pharmacotherapeutic mechanisms are being
outcomes in a wide range of malignancies. Chimeric antigen researched for the management of CLL. Phase 2 studies are
receptor (CAR) technology involves the genetic reprogram- under way for novel antibodies targeting the B-cell lineage-
ming of a patients own T cells to recognize and target specic specic CD37 (NCT02538614) and CD19 (NCT01466153,
surface antigens, thereby increasing their specicity toward NCT02005289) surface antigens.7779 In addition, checkpoint
particular malignant clones. This emerging therapeutic option inhibitors, specically those that target PD-1 and PD-L1, are
has been studied thus far in the management of B-cell malignan- being researched as part of combination regimens in both the
cies including non-Hodgkins lymphoma, acute lymphoblastic untreated and relapsed/refractory settings. However, given
leukemia, and CLL. However, a major limitation exists with the dysfunctional T-cell state found in CLL, the malignancy is
regard to CAR technology use in CLL given the well-known relatively resistant to PD-1 inhibition alone, and development of
dysfunctional or exhausted state of T cells in patients with the agents as monotherapy is unlikely to occur.59,62,63 Preclinical
this malignancy.59 For CAR T-cell development, T-cell lympho- data suggest PD-1 inhibitors act in a synergistic manner with
cytes are collected through leukapheresis, transduced with BTK inhibitors,80 and a phase 2 study of combination therapy
a chimeric T-cell receptor/immunoglobulin transgene, and with nivolumab (Opdivo, Bristol-Myers Squibb) and ibrutinib
expanded using CD3 and CD28 T-cellactivating antibodies.72 is ongoing in patients with relapsed/refractory or high-risk
Once the desired CAR T dose is attained, quality control and untreated CLL (NCT02420912).81

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New Pharmacotherapies in Chronic Lymphocytic Leukemia
ECONOMIC CONSIDERATIONS 8. Claus R, Lucas DM, Stilgenbauer S, et al. Quantitative DNA
Given that CLL is the most common leukemia in the United methylation analysis identies a single CpG dinucleotide important
for ZAP-70 expression and predictive of prognosis in chronic lym-
States and primarily affects older individuals, most treatment phocytic leukemia. J Clin Oncol 2012;30(20):24832491.
costs are borne by Medicare. Average wholesale prices per 9. Cramer P, Langerbeins P, Eichhorst B, Hallek M. Advances in
unit of the newer treatments appear in Table 2. The economic rst-line treatment of chronic lymphocytic leukemia: current recom-
burden for CLL has to be considered in the context that patients mendations on management and rst-line treatment by the German
CLL study group (GCLLSG). Eur J Haematol 2016;96(1):918.
may require multiple lines of therapy and possibly HSCT. The
10. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes
cost of ibrutinib at standard dose could be expected to be are associated with a more aggressive form of chronic lymphocytic
higher than $100,000 per year, which can exceed the cost of leukemia. Blood 1999;94(6):18481854.
some HSCT scenarios.52 A systematic review of the literature 11. Thompson PA, Tam CS, OBrien SM, et al. Fludarabine, cyclo-
identifying costs in CLL reported annual direct costs per person phosphamide, and rituximab treatment achieves long-term disease-
free survival in IGHV-mutated chronic lymphocytic leukemia. Blood
of $43,913 in the United States, with 26.2% to 79% potentially 2016;127(3):303309.
attributable to drug therapy.82 In comparison, the median 12. CLL Trialists Collaborative Group. Chemotherapeutic options in
100-day total cost for an allogeneic SCT was estimated at chronic lymphocytic leukemia: a meta-analysis of the randomized
$203,026.83 However, if patients receive multiple lines of drug trials. J Natl Cancer Inst 1999;91(10):861868.
13. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with
therapy, the potential estimated costs are in the millions of
udarabine compared with chlorambucil does not result in a major
dollars.84 While intravenous therapies are covered by Medicare benet for elderly patients with advanced chronic lymphocytic
Part B, the newer oral agents will be covered by Medicare leukemia. Blood 2009;114(16):33823391.
Part D, which will shift more cost burden to patients.84 The 14. Byrd JC, Rai K, Peterson BL, et al. Addition of rituximab to udara-
shift of cost responsibility to the patient may impact adherence, bine may prolong progression-free survival and overall survival in
patients with previously untreated chronic lymphocytic leukemia:
which may in turn, affect the degree of response to therapy.84 an updated retrospective comparative analysis of CALGB 9712 and
CALGB 9011. Blood 2005;105(1):4953.
CONCLUSION 15. Hallek PM, Fischer K, Fingerle-Rowson G, et al. Addition of ritux-
New therapeutic advances have changed the treatment land- imab to udarabine and cyclophosphamide in patients with chronic
lymphocytic leukaemia: a randomized, open-label, phase 3 trial.
scape for patients with CLL. New biological therapies, including
Lancet 2010;376(9747):11641174.
ofatumumab and obinutuzumab, and small-molecule inhibitors, 16. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after
including ibrutinib, idelalisib, and venetoclax, provide innova- FCR chemoimmunotherapy in previously untreated patients with
tive mechanisms in both the rst-line and relapsed/refractory CLL: updated results of the CLL8 trial. Blood 2016;127(2):208215.
treatment settings. Some of these therapies have demonstrated 17. Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmuno-
therapy with bendamustine and rituximab versus udarabine, cyclo-
activity against highly resistant, harder-to-treat CLL and offer phosphamide, and rituximab in patients with advanced chronic lym-
alternatives or additions to HSCT. Key emerging therapies, phocytic leukaemia (CLL10): an international, open-label, random-
including strategies that target the immune system, have ized, phase 3, noninferiority trial. Lancet Oncol 2016;17(7):928942.
shown some great potential. The cost of treatment, especially 18. McClanahan F, Gribben J. New insights into hematopoietic stem
cell transplantation for chronic lymphocytic leukemia: a 2015
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in participants with chronic lymphocytic leukemia. NCT02538614. 2. Food and Drug Administration. Public notication of emerging
November 15, 2016. Available at: http://clinicaltrials.gov/show/ postmarket medical device signals (emerging signals): guidance
NCT02538614. Accessed November 13, 2016. for industry and Food and Drug Administration staff. December
78. ClinicalTrials.gov. A phase 2, multicenter, open-label study of 14, 2016. Available at: www.fda.gov/downloads/medicaldevices/
MEDI-551 in adults with relapsed or refractory chronic lympho- deviceregulationandguidance/guidancedocuments/ucm479248.
cytic leukemia (CLL). NCT01466153. March 1, 2016. Available pdf. Accessed December 29, 2016.
at: http://clinicaltrials.gov/show/NCT01466153. Accessed 3. Food and Drug Administration. Medical device reporting for
November 13, 2016. manufacturers: guidance for industry and Food and Drug
79. ClinicalTrials.gov. Phase II MOR00208 in combination with lenalid- Administration staff. November 8, 2016. Available at: www.fda.
omide for patients with relapsed or refractory CLL, SLL, or PLL gov/ucm/groups/fdagov-public/@fdagov-meddev-gen/docu-
or older patients with untreated CLL, SLL, or PLL. NCT02005289. ments/document/ucm359566.pdf. Accessed December 29, 2016.
October 11, 2016. Available at: http://clinicaltrials.gov/show/ 4. Food and Drug Administration. Strengthening our national system
NCT02005289. Accessed November 13, 2016. for medical device postmarket surveillance. September 2012.
80. Sagiv-Bar I, Kohrt HE, Czerwinski DK, et al. Therapeutic anti- Available at: www.fda.gov/downloads/AboutFDA/Center-
tumor immunity by checkpoint blockade is enhanced by ibruti- sOfces/CDRH/CDRHReports/UCM301924.pdf. Accessed
nib, an inhibitor of both BTK and ITK. Proc Natl Acad Sci U S A December 29, 2016.
2015;112(9):E966E972. 5. Sentinel Coordinating Center. Background. Available at:
81. ClinicalTrials.gov. Nivolumab with ibrutinib for relapsed, refrac- www.sentinelinitiative.org/background. Accessed December
tory, or high-risk untreated patients with chronic lymphocytic 29, 2016.
leukemia (CLL). NCT02420912. October 24, 2016. Available 6. Food and Drug Administration. Use of real-world evidence to
at: http://clinicaltrials.gov/show/NCT02420912. Accessed support regulatory decision-making for medical devices: draft
November 13, 2016. guidance for industry and Food and Drug Administration staff.
82. Frey S, Blankart CR, Stargardt T. Economic burden and quality-of- September 16, 2016. Available at: www.fda.gov/ucm/groups/
life effects of chronic lymphocytic leukemia: a systematic review fdagov-public/@fdagov-meddev-gen/documents/document/
of the literature. Pharmacoeconomics 2016;34(5):479498. ucm513027.pdf. Accessed January 3, 2017. Q
83. Majhail NS, Mau LW, Denzen EM, Arneson TJ. Costs of autolo-
gous and allogeneic hematopoietic cell transplantation in the
United States: a study using a large national private claims data-
base. Bone Marrow Transplant 2013;48(2):294300.

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.

Although there was a low rate of arterial *The following randomized, double-masked
thromboembolic events (ATEs) observed pivotal trials were conducted for the 2 LUCENTIS
indications: wAMD: MARINAPhase III, multicenter,
in the LUCENTIS clinical trials, there is a 2-year, sham injectioncontrolled study; primary
potential risk of ATEs following intravitreal end point at 1 year. ANCHORPhase III, multicenter,
use of VEGF inhibitors. ATEs are dened 2-year, active treatmentcontrolled study; primary
as nonfatal stroke, nonfatal myocardial end point at 1 year. PIERPhase IIIb, 2-year, sham
INDICATION injectioncontrolled study; primary end point at
infarction, or vascular death (including 1 year. HARBORPhase III, multicenter, 2-year,
LUCENTIS (ranibizumab injection) 0.5 mg is
deaths of unknown cause). active treatmentcontrolled dose-response study;
indicated for the treatment of patients with: primary end point at 1 year. RVO: BRAVOPhase III,
Fatal events occurred more frequently in multicenter, 1-year, sham injectioncontrolled study;
Neovascular (wet) age-related macular
patients with DME and DR at baseline treated primary end point at 6 months. CRUISEPhase III,
degeneration (wAMD) multicenter, 1-year, sham injectioncontrolled study;
monthly with LUCENTIS compared with
Macular edema following retinal vein primary end point at 6 months.1-7
control. Although the rate of fatal events
occlusion (RVO) was low and included causes of death References: 1. Rosenfeld PJ, et al; MARINA Study
typical of patients with advanced diabetic Group. N Engl J Med. 2006;355:1419-1431. 2. Brown
IMPORTANT SAFETY INFORMATION complications, a potential relationship DM, et al; ANCHOR Study Group. Ophthalmology.
LUCENTIS is contraindicated in patients between these events and intravitreal use 2009;116:57-65. 3. Regillo CD, et al; PIER Study Group.
with ocular or periocular infections or Am J Ophthalmol. 2008;145:239-248. 4. Busbee
of VEGF inhibitors cannot be excluded. BG, et al; HARBOR Study Group. Ophthalmology.
hypersensitivity to ranibizumab or
2013;120:1046-1056. 5. Campochiaro PA, et al;
any of the excipients in LUCENTIS. ADVERSE EVENTS BRAVO Investigators. Ophthalmology. 2010;117:1102-
Serious adverse events related to the 1112. 6. Brown DM, et al; CRUISE Investigators.
WARNINGS AND PRECAUTIONS injection procedure that occurred in Ophthalmology. 2010;117:1124-1133. 7. LUCENTIS
Intravitreal injections, including those <0.1% of intravitreal injections included [package insert]. South San Francisco, CA:
with LUCENTIS, have been associated Genentech, Inc; January 2017.
endophthalmitis, rhegmatogenous retinal
with endophthalmitis, retinal detachment, detachment, and iatrogenic traumatic
and iatrogenic traumatic cataract. Proper cataract.
aseptic injection technique should always
be utilized when administering LUCENTIS. In the LUCENTIS Phase III clinical trials, the
Patients should be monitored during the most common ocular side effects included
week following the injection to permit early conjunctival hemorrhage, eye pain, vitreous
treatment, should an infection occur. oaters, and increased intraocular pressure.
The most common non-ocular side effects
Increases in intraocular pressure (IOP) have included nasopharyngitis, headache,
been noted both pre-injection and post- inuenza, sinusitis, cough, and nausea.
injection (at 60 minutes) with LUCENTIS. IOP
and perfusion of the optic nerve head should Please see Brief Summary of LUCENTIS full 2017 Genentech, Inc. South San Francisco, CA
be monitored and managed appropriately. prescribing information on adjacent page. LUC/120616/0149 1/17
6.2 Clinical Studies Experience 6.3 Immunogenicity
Because clinical trials are conducted under widely varying conditions, adverse As with all therapeutic proteins, there is the potential for an immune response
reaction rates observed in one clinical trial of a drug cannot be directly in patients treated with LUCENTIS. The immunogenicity data reflect the
compared with rates in the clinical trials of the same or another drug and may percentage of patients whose test results were considered positive for
not reflect the rates observed in practice. antibodies to LUCENTIS in immunoassays and are highly dependent on the
The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with sensitivity and specificity of the assays.
neovascular AMD in Studies AMD-1, AMD-2, and AMD-3; in 259 patients The pre-treatment incidence of immunoreactivity to LUCENTIS was 0%-5%
with macular edema following RVO. The data also reflect exposure to 0.3 mg across treatment groups. After monthly dosing with LUCENTIS for 6 to 24
Brief summaryplease see the LUCENTIS package LUCENTIS in 250 patients with DME and DR at baseline [see Clinical Studies (14 months, antibodies to LUCENTIS were detected in approximately 1%-9% of
insert for full prescribing information. in the full prescribing information)]. patients.
Safety data observed in Study AMD-4 and in 224 patients with mCNV were The clinical significance of immunoreactivity to LUCENTIS is unclear at this time.
1 INDICATIONS AND USAGE consistent with these results. On average, the rates and types of adverse Among neovascular AMD patients with the highest levels of immunoreactivity,
LUCENTIS is indicated for the treatment of patients with: reactions in patients were not significantly affected by dosing regimen. some were noted to have iritis or vitritis. Intraocular inflammation was not
1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD) Ocular Reactions observed in patients with DME and DR at baseline, or RVO patients with the
Table 1 shows frequently reported ocular adverse reactions in LUCENTIS- highest levels of immunoreactivity.
1.2 Macular Edema Following Retinal Vein Occlusion (RVO)
treated patients compared with the control group. 6.4 Postmarketing Experience
1.3 Diabetic Macular Edema (DME) The following adverse reaction has been identified during post-approval use
1.4 Diabetic Retinopathy (Non Proliferative Diabetic Retinopathy (NPDR), Table 1 Ocular Reactions in the DME and DR, AMD, and RVO Studies of LUCENTIS. Because this reaction was reported voluntarily from a population
Proliferative Diabetic Retinopathy (PDR)) in patients with Diabetic Macular DME and DR AMD AMD RVO of uncertain size, it is not always possible to reliably estimate the frequency or
Edema (DME) 2-year 2-year 1-year 6-month establish a causal relationship to drug exposure.
1.5 Myopic Choroidal Neovascularization (mCNV) 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- unexpected clinical trials results have added to the uncertainty.
tension, one of the leading causes of death and disability For instance, the landmark Action to Control Cardiovascular
throughout the world,1 are scheduled to be released in 2017 Risk (ACCORD) trial, published in 2010, found that intensive
by several internationally recognized organizations. In the blood pressurelowering (to less than 120 mm Hg versus
U.S., these guidelines, jointly prepared for the rst time by less than 140 mm Hg) did not reduce overall cardiovascular
the American College of Cardiology and the American Heart events among patients with type-2 diabetes, although there
Association (AHA), will serve as an update to the hypertension was a reduction in strokes in the intensively treated group.6
management guidelines prepared by the Eighth Joint National Still, to those outside the eld who have long been accus-
Committee (JNC 8) and published in 2014.2 tomed to the standard denition of hypertension
Findings from several recent clinical trials (readings of 140/90 mm Hg and higher), it
and analysesmost notably from the Systolic may seem puzzling that a target systolic blood
Blood Pressure Intervention Trial (SPRINT)3 pressure (SBP) of less than 150 mm Hg, rather
are expected to form the basis of these new than below 140 mm Hg, was recommended
guidelines, which should feature new hyper- by JNC 8 for people 60 years of age and older
tension treatment targets and new approaches in guidelines published less than three years
to the treatment of the elderly, among other ago.2 Perhaps more puzzling is that this target
recommendations. represented an increase in SBP compared with
For the rst time in decades, the primary the treatment goal of 130 mm Hg that appears
focus in the eld has moved from pharma- in 2003 guidelines7 for individuals with CKD
ceuticals to the meticulous analysis and inter- or diabetes. But Raymond R. Townsend, MD,
pretation of cumulative research data and the Director of the Hypertension Program and
translation of key ndings to best clinical prac- Professor of Medicine at the Perelman School
Raymond R. Townsend, MD
tices and directions for public health policy.4 of Medicine at the University of Pennsylvania,
While antihypertensive drug therapy has evolved to such a who served as a member of the JNC 8 panel, says the recom-
degree that a range of relatively inexpensive and well-tolerated mended SBP target of less than 150 mm Hg for people older
medications (Table 1)3 can be used alone or in combination than 60 years can be explained by the panels unyielding
to provide satisfactory control of hypertension in a majority of commitment to evidence-based medicine.
individuals requiring treatment,5 questions surrounding the When our panel convened in 2008, our directives were to
intricacies of hypertension management remain. The herculean establish guidelines based not on our professional opinions, but
task of sifting through available data for clinical pearlsinclud- rather on evidence from clinical trials, explains Dr. Townsend,
ing optimal ways to achieve more intensive treatment goals, who in 2016 was named Physician of the Year by the AHA.
the best methods for monitoring and assessing hypertensive After extensive research, we found that there simply was no
patients, and the magic keys to ensuring adherence to treat- solid evidence to support a systolic blood pressure target of
mentswill occupy researchers long after the release of new below 140.
guidelines. Yet just one year after the publication of SPRINT The panel was able to conrm only that positive outcomes
ndings, leading experts have already begun to distill informa- in a range of clinical trials were consistently reported for
tion from that landmark trial that is meaningful for clinicians older patients whose SBP was lowered to a target of below
and their patients. 150 mm Hg. Panel members were not able to consider nd-
ings from SPRINT, which was launched in 2010, two years
In Search of Treatment Targets after the panel convened.
Sufcient evidence to suggest that a reduction in elevated To more clearly determine the potential benet of inten-
blood pressure can lead to a reduction in the incidence of sive treatment, SPRINT randomly assigned 9,361 individuals
heart disease, including congestive heart failure and coronary (50 years of age or older) with an SBP of 130 mm Hg or higher
artery disease, as well as stroke and chronic kidney disease and an increased risk of cardiovascular disease to intensive
(CKD), across a range of patient populations has been available treatment (SBP target of less than 120 mm Hg) or standard
for nearly two decades. However, experts have long had dif- treatment (SBP target of less than 140 mm Hg).3 In 2015,
culty reaching a consensus with regard to appropriate blood the trial was stopped early after participants in the intensive
pressure targets during treatment. This uncertainty can be group were found to have a 25% lower risk of major cardio-
attributed in part to concerns about risks associated with blood vascular events and a 27% lower relative risk of death from
pressurelowering in some individuals and in part to a lack of any cause compared with those in the standard treatment
clear evidence to support intensive treatment. Inconclusive or group. In addition, although noteworthy patient populations
were excluded from the trial (including those under the age
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


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

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Experts Provide a Glimpse of the New Post-SPRINT Era of Hypertension
I am more likely to have patients referred to me when their medications among the most important unmet needs in his eld.
blood pressure cannot be adequately controlled on four or more Instead, he would prefer to see the development of a foolproof
medications. Very recently a patient was referred to me with method for ensuring that patients take their medications.
a blood pressure of 180/110 while taking seven medications. We know that the drugs we are currently using work. They
That patient, of course, would not have qualied for SPRINT, provide benet to the people who take them. So its essential
Dr. Townsend says. that we develop new methods or strategies, perhaps using
The method by which blood pressure was measured in mobile technologies, for encouraging adherence. Finding ways
the trial also may have led to results that would be difcult to foster greater persistencethat is, strategies for ensuring
to duplicate in clinical practice. To eliminate confounding that people continue to take their medications after they already
circumstances associated with ofce-based blood pressure have responded to treatmentalso is critical.
measurementparticularly elevated readings that can occur
in the presence of an observer (known as white coat hyper- Shaping Public Policy
tension)9an automated approach called automated ofce Findings from SPRINT already have begun to inuence
blood pressure (AOBP)10,11 was used in SPRINT. not only clinical practice but also research and health care
SPRINT investigators were able to obtain much more policy throughout the U.S. and around the world.4 Not long
accurate blood pressure readings, which on average were before the trials ndings were published, the World Health
likely 7 to 10 mm Hg lower than they would have been had Organization (WHO) formally recognized hypertension as the
those readings been obtained in an ofce with a standard rst noncommunicable disease to rank among primary global
sphygmomanometer, Dr. Townsend says. That limits the causes of major illness and premature mortality.13 At roughly
generalizability of the trials ndings as things stand right the same time, the World Hypertension League (WHL) for-
nowthat is, until we have a cultural paradigm shift in terms mally designated the U.S. Journal of Clinical Hypertension as
of how we measure blood pressure in U.S. clinical practices. the primary forum for its policy statements and position papers
Meanwhile, Dr. Townsend and other hypertension experts regarding the management of hypertensiona partnership
anticipate that 2017 guidelines will account for the difference that should help coordinate global efforts to optimize the care
between the automated readings obtained in SPRINT and of hypertensive individuals and accelerate the standardization
standard readings, most likely by recommending an SBP of information reporting.
treatment target of below 130 mm Hg. If more patients can be In a eld that attaches such importance to even minor
encouraged to obtain semiautomated readings at home, which changes in millimeters of mercury, the standardization of
may lead to more accurate and consistent readings than those blood pressure measurement is particularly importantan
traditionally obtained with a sphygmomanometer,12 future issue that was underscored by ndings from SPRINT. Yet
guidelines may eventually recommend SBP targets closer to for many decades, says Michael A. Weber, MD, Professor of
120 mm Hg. However, patients currently face an important Medicine at SUNY Downstate College of Medicine in New
barrier to regular home monitoring. York and Editor-in-Chief of the Journal of Clinical Hypertension,
Home blood pressure monitors, as valuable as they are, there were few if any discussions about the best method for
are currently not covered by many health insurance policies, measuring blood pressure.
Dr. Townsend says. Yet insurance will cover the cost of a Until about 10 years ago, Dr. Weber says, everyone knew,
glucose monitor for patients who need oneeven though when or thought they knew, that using the standard sphygmoma-
it comes to outcomes, there are far more data supporting the nometer with a mercury column and listening with a stetho-
value of lowering blood pressure compared with the value of scope to the sounds over the brachial artery in the upper arm
lowering blood sugar. represented the gold standard of blood pressure measure-
Ideally, home blood pressure monitoring should be used ment. Now that method has come under question for several
to conrm high readings obtained during in-ofce screening important reasons.
and to track a patients response to treatment. It also may be The high degree of inter- and intraobserver variability in read-
used to conrm the presence of a white coat effect, when home ings that rely so strongly on human performance, particularly
readings are lower, although whether minor differences due hearing, is a primary concern shared by experts in the eld,
to this effect can be considered an important risk factor for says Dr. Weber, who also serves on the executive committee for
sustained hypertension and related target organ damage is the International Society of Hypertension (ISH) and the board
still a matter of debate.9 of directors for the Center for Medicine in the Public Interest.
However, Dr. Townsend says, when a patient has a reading The potential for inaccuracies caused by simple carelessness
of 160/110 in the ofce and readings of 110/70 at home, that or bias also have been a concern. A growing uneasiness with
patients likelihood of developing real hypertension, both at this standard method of measurement has inspired experts to
home and in the ofce, will be greaterin part because of his take a closer look at relatively inexpensive automated devices,
or her tendency to signicantly overshoot normal regulatory which have been available in drug stores and department
mechanisms while in a medical environment. That tendency stores for more than a decade. Testing in recent years has
will eventually lead to an accumulation of microfractures and shown that compared with traditional measurement by
other types of damage to blood vessels that will increase the sphygmomanometer these devices are more reliable and
probability of eventual target organ damage. consistent.14
Like many hypertension experts in the U.S., Dr. Townsend A few years ago, Dr. Weber says, my ofce switched to
does not rank the development of new antihypertensive using only automated devices, which we have found to be more

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Experts Provide a Glimpse of the New Post-SPRINT Era of Hypertension
accurate and free from bias. Another benet of this method pressure and in turn a reduction in cardiovascular events has
is that our patients can use the same devices at home that we led the WHO to recommend a 30% reduction in dietary salt
are using in the ofce. by 2025. However, leading international entities, including the
The process of validating semiautomated and automated WHO, the WHL, and the ISH, have expressed concern over
methods of measuring blood pressure involves a comparison conicting and controversial ndings regarding salt intake
of readings from these devices with direct measurements of and have uniformly urged greater rigor in salt studies.4 Future
arterial pressure obtained from patients undergoing cardiac studies will be expected to demonstrate, among other things,
catheterization. The latter procedure, which measures blood more accurate methods for quantifying salt intake in individuals,
pressure in the aorta (central blood pressure) rather than in better statistical methodology, improved techniques for 24-hour
the arm, represents what many experts believe is the true gold urine collection, and better assessment of clinical endpoints.
standard of blood pressure measurement. However, because Effective approaches to treatment-resistant hypertension are
the invasive use of a catheter is not practical for regular use, among the greatest unmet needs in the eld, although both
noninvasive methods for obtaining central blood pressure are the prevalence and cause of this phenomenon have been dif-
under investigation. Pulse-wave velocity, a noninvasive measure cult to discern. With the use of just three classes of currently
of arterial stiffness that has been shown to be predictive of available antihypertensive medications, most leading hyper-
coronary disease and its severity,15 is being used increasingly in tension experts agree that it is possible to control hypertension
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- relatively few side effects.
invasive methodsa technique that Dr. Weber and his col- Right now most of us work primarily with three types of
leagues, among others, helped pioneer in the late 1970shas drugsthose that block the renin-angiotensin system, which
long been used for home monitoring and still is recommended include the ACE [angiotensin-converting enzyme] inhibitors
by the U.S. Preventive Services Task Force as a and ARBs [angiotensin-receptor blockers]; the
routine method for conrming the diagnosis of calcium-channel blockers; and the thiazide-
hypertension.16 ABPM also remains an important like diuretics. Those are the big three, the holy
method of identifying individuals at greater risk trinity of hypertension medications, and using
for adverse outcomes due to a lack of normal these it is possible to develop effective, well-
drop in blood pressure during the night. In tolerated regimens for most patients. When
normal healthy people, blood pressures should we do encounter individuals with so-called
fall at night by at least 10%, says Dr. Weber, but treatment-resistant hypertension, most of the
approximately 20% to 30% of people do not have time it turns out that these patients are not taking
that fall in values and may even have values that their medications reliably, Dr. Weber says.
are higher at night. Although there is broad For some patients who are truly resistant to
agreement that such nighttime patterns are these three classes of medications, Dr. Weber
strongly predictive of stroke and cardiovascular adds, spironolactone17 has proven to be effec-
events, the best approach to preventing events tive. Further research investigating treatment
Michael A. Weber, MD
in this population has yet to be determined. combinations18 and pharamcogenomics19 may
A growing trend toward nighttime dosing of blood pressure result in effective tools for addressing true treatment-resistant
medications, however, may provide at least a partial solution. hypertension, as well as strategies for eliminating some of the
We worry most about the early morning hours after people trial and error involved in selecting medications for all patients.
wake up, Dr. Weber says. Those rst few hours are the most Early research focused on renal denervation, a procedure
dangerous times of the day, when a disproportionate number involving the ablation of renal nerves, also has shown promise.20
of strokes and heart attacks occur. To offer patients greater It may turn out that this procedure is helpful in individuals
protection during those hours, I prefer to prescribe blood pres- who are not responding to drugs, Dr. Weber says, or perhaps
sure medications at night, and a few major clinical trials have more importantly for patients who are unable or unwilling to
reported very strong results and good protection for patients take their medications reliably.
with nighttime dosing of medications. When this approach is
used regularly with all patients, it may be less important to The Elderly, Women, and Groups Excluded From SPRINT
identify patients who dont have the appropriate fall in blood As the U.S. population continues to age, there will likely be a
pressure at night. growing focus on the treatment of hypertension in the elderly.
Nighttime dosing, adds Dr. Weber, also may help to limit the Results of the SPRINT trial have for the rst time shown that
faintness and dizziness that some patients experience during targeting a systolic blood pressure of less than 120 mm Hg,
the rst few hours after taking their medications. a normal blood pressure level, is safe and effective for prevent-
ing deaths and major cardiovascular events like heart failure
Salt and Treatment-Resistant Hypertension and myocardial infarctions in individuals 75 years of age and
Important current research that will continue to inuence public older with hypertension.21 Earlier notable studies, such as
health policy in the coming years includes studies focused on salt Hypertension in the Very Elderly (HYVET) and the Systolic
intake and on approaches to treatment-resistant hypertension. Hypertension in the Elderly Program (SHEP), which were not
A consensus among public health scholars that a reduction designed to address questions regarding appropriate targets,
in salt intake would lead to a population-wide reduction in blood 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 women randomized to receive chlorthalidone, a thiazide-type
poses some special risks. diuretic, had signicantly fewer fractures than those random-
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 important because signicant fractures, such as hip and pelvic
pressure actually tends to be lower than in younger people, fractures, require hospitalization and sometimes surgery and
says Suzanne Oparil, MD, Professor of Medicine and Director can lead to life-ending complications.
of the Vascular Biology and Hypertension Program at the Dr. Oparil adds that, compared with men, research also
University of Alabama at Birmingham, who in 2016 received has indicated that women tend to have a larger number of
the Excellence Award for Hypertension Research from the adverse events while taking ACE inhibitors, such as cough
AHA Council on Hypertension. Electrolyte abnormalities, or and angioedema. Future research is needed to detect other
low sodium and low potassium, also are a particular concern gender-related differences and identify treatment strategies
in the elderly. Postural hypotension, which can lead to falls that will offer greater protection to women. Basic science
and serious fractures, is another major concern in individuals research is also called for to further investigate the effect that
who are already frail and unsteady. sex hormones, particularly estrogen, have on blood vessels
With targeted supplementary funding, SPRINT investigators in women as they age.
were able to address some of these concerns by recruiting Im particularly interested in examining why the benecial
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 be that there is a reduction in the number of estrogen receptors,
older than 75 years of age. or it may be that with age receptor proteins are modied in
The very frail elderly, such as those in assisted living or in such a way that they dont signal properly. Perhaps estrogen
nursing homes, were excluded from the trial, Dr. Oparil says, is metabolized differently with agewe dont yet know the
as were individuals with signs of cognitive answers to these questions.
dysfunction or dementia. So we still lack infor- Questions also remain for a fairly wide range
mation about treatment in those individuals. But of patients who were excluded from SPRINT,
SPRINT very clearly demonstrated that for the including patients with diabetes, those with pre-
reasonably high-functioning elderly, aggressive vious stroke, and those younger than 50 years
treatment to targets as low as 120 mm Hg is safe of age. Patients with diabetes were excluded
and effective, and that adverse events in this from SPRINT largely because of the ACCORD
population were comparable to those seen in trial; however, experts continue to be uncertain
younger groups, which was quite surprising. about appropriate blood pressure targets in
Consequently, many experts anticipate less these patients because of a number of factors
age stratication with regard to recommended that served to confound ACCORD data.24
treatment targets in future hypertension SPRINT excluded patients with prior stroke
guidelines. These experts agree that follow- largely because of the Secondary Prevention
up research examining further stratication of Suzanne Oparil, MD of Small Subcortical Strokes (SP3) trial, which
this population by functional status, rather than examined whether an SBP target of less than
by age, would likely be of value. Currently, Dr. Oparil says, it 130 mm Hg would reduce recurrent stroke in patients who
makes sense to avoid aggressive treatment of hypertension had experienced recent lacunar stroke.25 Consequently, the
in frail elderly patients who are already experiencing frequent impact of intensive blood pressurelowering on patients with
dizziness and falls. recent stroke was left unanswered by SPRINT.
Meanwhile, a component of the SPRINT trial called SPRINT- The literature clearly indicates that stroke is the outcome
MIND is addressing yet another important question regarding that is generally most sensitive to blood pressurelowering
elderly patients: the effects of intensive treatment of systolic more so than heart attack and heart failure. And yet, largely
blood pressure on cognitive function. SPRINT-MIND investi- because of its inclusion and exclusion criteria, we didnt nd
gators will aim to discover whether intensive blood pressure that in SPRINT. We found that heart failure was reduced more
lowering to the 120 mm Hg target reduces cognitive decline than any other single outcome, Dr. Oparil says.
and the incidence of all-cause dementia.22 In patients at high risk for stroke and in those with previous
To date, hypertension guidelines have not offered specic stroke, further research is needed to identify best treatment
guidelines for women, even though women have several kinds approaches and the extent to which other variables, including
of high blood pressureincluding oral contraceptive- and the lowering of cholesterol, play a relevant role in the risk for
pregnancy-related hypertensionnot found in men. Likewise future stroke.
SPRINT, which had a somewhat larger male population, was A need also exists for smaller studies that more closely
not specically designed to detect gender-related differences examine the effects of hypertension treatment on other high-
in response to hypertension treatment. However, recent meta- risk patient populations, including individuals with a wide
analyses have shown that some antihypertensive medications range of chronic diseases who were excluded from SPRINT.
might be more benecial for women. Research has shown, for example, that individuals with
We know that thiazide diuretics more than other drug HIV [human immunodeciency virus infection] tend to have
classes are better for bone health in women, says Dr. Oparil, accelerated vascular disease and also tend to have increased
coauthor of a recent analysis of ALLHAT,23 which indicated that nocturnal hypertension. We dont yet know why such

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


Experts Provide a Glimpse of the New Post-SPRINT Era of Hypertension
differences exist in these patients. Are they related to choles- 11. Myers MG, Kaczorowski J, Dolovich L, et al. Cardiovascular risk in
terol? Or perhaps to inammation? We also dont yet know relation to achieved automated blood pressure in clinical practice.
Hypertension 2016;68(4):866872.
whether these individuals will respond as well to aggressive 12. Myers MG. The great myth of ofce blood pressure measurement.
blood pressurelowering. J Hypertens 2012;30(10):18941898.
Two other important groups excluded from SPRINT, which 13. World Health Organization. NCD Global Monitoring Framework:
many hypertension experts feel have been unduly neglected in ensuring progress on noncommunicable diseases in countries.
Available at: www.who.int/nmh/global_monitoring_framework/
hypertension literature, are children and young adults at high
en. Accessed January 5, 2017.
risk for hypertension, as well as low-risk individuals of all ages. 14. Ruzicka M, Akbari A, Bruketa E, et al. How accurate are home
Although the incidence of hypertension in children is increasing, blood pressure devices in use? A cross-sectional study. PLoS One
Dr. Oparil says that research designed to determine the best 2016;11(6):e0155677.
treatment for these patients has yet to be conducted. A closer 15. Hofmann B, Riemer M, Erbs C, et al. Carotid to femoral pulse
wave velocity reects the extent of coronary artery disease. J Clin
examination of low-risk individuals also will be increasingly impor- Hypertens (Greenwich) 2014;16(9):629633.
tant, in part to gain a better understanding of the mechanisms 16. Siu AL; U.S. Preventive Services Task Force. Screening for high
of hypertension. Answers to all of these questions will almost blood pressure in adults: U.S. Preventive Services Task Force
certainly require the development of new research methods. recommendation statement. Ann Intern Med 2015;163(10):778786.
17. Williams B, MacDonald TM, Morant S, et al. Spironolactone versus
Its unlikely that we will able to answer these questions with
placebo, bisoprolol, and doxazosin to determine the optimal treat-
other large-scale trials such as SPRINT because such trials are ment for drug-resistant hypertension (PATHWAY-2): a randomised,
prohibitively expensive, Dr. Oparil says. As we move into the double-blind, crossover trial. Lancet 2015;386(10008):20592068.
future, questions will more likely be addressed using big data- 18. Taddei S. Combination therapy in hypertension: what are the
bases, such as those drawn from electronic medical records. best options according to clinical pharmacology principles
and controlled clinical trial evidence? Am J Cardiovasc Drugs
The American Heart Association, for example, is using large 2015;15(3):185194.
databases in a study designed to answer some larger questions 19. Fontana V, Luizon MR, Sandrim VC. An update on the pharmaco-
about cardiovascular diseasea study that will likely provide genetics of treating hypertension. J Hum Hypertens 2015;29(5):
some valuable information about hypertension.26 283291.
20. Mahfoud F, Brilakis N, Bhm M, et al. Long-term (3-year) safety
Observational trials, and studies that rely on telemonitoring
and effectiveness from the Global SYMPLICITY Registry of renal
perhaps making use of the growing trend toward home blood denervation in a real-world patient population with uncontrolled
pressure monitoringwill likely play a role in study designs that hypertension. J Am Coll Cardiol 2016;68(18S):B308.
may replace traditional randomized clinical trials in the guidance 21. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs.
of antihypertensive treatment in the future, Dr. Oparil adds. standard blood pressure control and cardiovascular disease out-
comes in adults aged 75 years: a randomized clinical trial. JAMA
2016;315(24):26732682.
REFERENCES 22. National Institute on Aging. Systolic blood pressure intervention
1. Campbell NR, Khalsa T, Lackland DT, et al. High blood pres- trial: memory and cognition in decreased hypertension (SPRINT-
sure 2016: why prevention and control are urgent and impor- MIND). Available at: www.nia.nih.gov/alzheimers/clinical-trials/
tant. The World Hypertension League, International Society of systolic-blood-pressure-intervention-trial-memory-and-cognition-
Hypertension, World Stroke Organization, International Diabetes decreased. Accessed January 5, 2017.
Foundation, International Council of Cardiovascular Prevention 23. Puttnam R, Davis BR, Pressel SL, et al. Association of three
and Rehabilitation, International Society of Nephrology. J Clin different antihypertensive medications with hip and pelvic fracture
Hypertens (Greenwich) 2016;18(8):714717. risk in older adults: secondary analysis of a randomized clinical
2. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guide- trial. JAMA Intern Med 2017;177(1):6776.
line for the management of high blood pressure in adults: report 24. Brunstrm M, Carlberg B. Effect of antihypertensive treatment at
from the panel members appointed to the Eighth Joint National different blood pressure levels in patients with diabetes mellitus:
Committee (JNC 8). JAMA 2014;311:507520. systematic review and meta-analyses. BMJ 2016;352:i717.
3. The SPRINT Research Group. A randomized trial of intensive 25. Benavente OR, White CL, Pearce L, et al. The Secondary
versus standard blood-pressure control. N Engl J Med Prevention of Small Subcortical Strokes (SPS3) study. Int J Stroke
2015;373:21032116. 2011;6(2):164175.
4. Weber MA, Lackland DT. Contributions to hypertension public 26. Benjamin I, Brown N, Burke G, et al. American Heart Association
policy and clinical practice: a review of recent reports. J Clin Cardiovascular Genome-Phenome Study: foundational basis and
Hypertens (Greenwich) 2016;18(10):10631070. program. Circulation 2015;131(1):100112. Q
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 P&T TV
the Joint National Committee on prevention, detection, evaluation, P&T is accepting video clips from our readers, and
and treatment of high blood pressure: the JNC 7 Report. JAMA
2003;289:25602572. we might post yours on our PTCommunity website
8. Sica DA, Phillips RA, White WB, et al. Translational medicine: (www.PTCommunity.com). Please feel free to send in
transforming SPRINT ndings into clinical practice. J Am Soc a short video about the activities of your P&T commit-
Hypertens 2016;10(5):382386. tee. All entries will be considered for posting to our
9. Myers M, Stergiou G. White coat phenomenon: removing the website.
stigma of hypertension. Hypertension 2016;67(6):11111113.
10. Armstrong D, Matangi M, Brouillard D, Myers MG. Automated You can contact the Editor, J. Stephen McIver, at
ofce blood pressurebeing alone and not location is what 267-685-3713 or smciver@medimedia.com.
matters most. Blood Press Monit 2015;20(4):204208.

Vol. 42 No. 2 February 2017 P&T


123
A Peer-Reviewed Journal for Managed Care
and Formulary Management Decision-Makers

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


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 INTRODUCTION
Objectives: The primary objective was to assess whether Most surgeries today are conducted in the outpatient setting.1
the use of intravenous acetaminophen (APAP) in the ambula- From 1992 to 2012, the proportion of surgeries performed at
tory surgery setting is associated with a decreased length of ambulatory centers in the United States increased from 54%
stay in the post-anesthesia care unit (PACU). The secondary to 65%.2 Historically, opioids have been the primary analge-
outcomes evaluated were pain scores, opioid consumption, sics used for postoperative pain control in these patients.
and total cost of analgesics used in the PACU. However, opioids have adverse effects, such as central nervous
Methods: This was a retrospective cohort study conducted system and respiratory depression, which limit their use. Thus,
in adult patients (18 years of age or older) who received an eye, guidelines suggest that multimodal analgesia should be used
ear, nose, or throat (EENT) procedure at an outpatient surgery to minimize opioid consumption, increase effectiveness of
center between January 2014 and January 2015. Patients were postoperative analgesic therapy, and decrease drug-induced
consecutively included until the desired sample was reached adverse effects.3 The concept of multimodal analgesia is the
during two six-month time periods: 1) intravenous APAP simultaneous provision of different classes of analgesics with
available on the formulary (APAP group) and 2) intravenous different mechanisms to produce an additive or synergistic
APAP not available on the formulary (non-APAP group). analgesic effect.4 Intravenous acetaminophen (APAP) is one
Results: The cohort included 174 patients who received an treatment option for postoperative pain that can be used as part
EENT procedure (87 patients in the APAP group and 87 patients of a multimodal treatment regimen. Intravenous APAP does
in the non-APAP group). The median PACU length of stay was not have central nervous system or respiratory depressant
66 minutes (interquartile range [IQR], 4892) in the APAP properties and may reduce postoperative opioid requirements
group and 71 minutes (IQR, 5289) in the non-APAP group because of its analgesic effect. This has the potential to improve
(P = 0.269). Mean pain score categories in the APAP versus patient recovery after surgery.
non-APAP group were mild (85% versus 53%, respectively; In the ambulatory surgery setting, intravenous APAP has
P < 0.001), moderate (13% versus 33%, respectively; P = 0.002), unique properties that make it an appealing adjunctive agent. It
and severe (2% versus 14%, respectively; P = 0.005). The is relatively safe with few adverse effects, and the intravenous
median opioid consumption in morphine equivalents was 9 mg formulation as opposed to the oral formulation allows for drug
(IQR, 513) in the APAP group and 8 mg (IQR, 512) in the administration soon after surgery to control postoperative pain
non-APAP group (P = 0.081). The total cost of analgesics used when patients are unable to take tablets.5 Intravenous APAP
in the PACU was signicantly greater in the APAP group has a half-life of 2.4 hours and a dosing interval of six hours.
($15 versus $1; P < 0.001). It is theorized that the use of a single postoperative dose of
Conclusions: Intravenous APAP use in EENT ambulatory intravenous APAP would enable earlier patient recovery, which
surgery is not associated with decreased PACU length of stay. would facilitate an earlier discharge from the post-anesthesia
However, it may decrease postoperative pain following EENT care unit (PACU).
procedures. Although previous studies have evaluated postoperative
pain control and opioid consumption, none have evaluated
Keywords: acetaminophen, pain, ambulatory surgical the effect on earlier discharge from the PACU. In one trial,
procedures, analgesics 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
Dr. Khobrani is a Postdoctoral Pharmacy Fellow in the Department group and only 25% of patients in the intravenous APAP group.
of Pharmacy Practice and Science at the College of Pharmacy of However, the effect on length of stay was not evaluated. Most
the University of Arizona in Tucson, Arizona, and a Lecturer in other trials have been performed in patients undergoing
the Department of Pharmacy Practice and Science of the College of major surgery during hospitalization.713 In hospitalized post-
Pharmacy at King Khalid University in Abha, Saudi Arabia. operative patients, some studies have shown that the use of
Dr. Camamo is a Pharmacist in the Department of Pharmacy Services intravenous APAP decreased pain, reduced opioid consumption,
at Banner University Medical Center in Tucson. Dr. Patanwala is
an Associate Professor in the Department of Pharmacy Practice and Disclosures: Dr. Patanwala has received grant funding from Mallinckrodt
Science at the College of Pharmacy of the University of Arizona in Pharmaceuticals, the makers of intravenous acetaminophen. The other
Tucson. authors report no commercial or nancial interests in regard to this article.

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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 Study Variables and Data Collection
literature pertaining to ambulatory surgery. Data were collected from electronic medical records by one
Our primary objective was to assess whether intravenous of the investigators and entered into an online data capture
APAP use in the ambulatory surgery setting is associated with a system using a standardized form. Research Electronic Data
decreased length of stay in the PACU. The usual length of stay Capture (REDCap) was used for data collection. Data col-
can vary but is typically less than three hours in the ambulatory lected included demographics, comorbidities, surgery type,
surgery setting. We hypothesized that there would be a reduced pain scores, analgesic consumption (opioid and nonopioid),
length of stay with the use of intravenous APAP. The secondary adverse effects, and PACU length of stay. Pain was measured
objectives were to evaluate the effect of intravenous APAP on on a numerical rating scale of 0 to 10 (0 = no pain, 10 = worst
pain scores, opioid consumption, and analgesic drug costs. possible pain). We collected all pain scores documented in the
PACU after administration of intravenous APAP, which was
METHODS given immediately after surgery. The mean pain score was
Study Design and Setting then calculated and used for analysis. Three or more scores
This was a retrospective cohort study conducted at an were documented for most patients. The only nonsteroidal
ambulatory surgery center afliated with a university hospi- anti-inammatory agent used in these patients was intravenous
tal in the United States. The surgery center did not have any ketorolac. All opioids were converted to intravenous morphine
written protocol in place for postoperative pain management, so equivalents for our outcome of opioid consumption in the PACU.
analgesic provision was based on provider preference. Providers The institutions average acquisition cost was used to derive
had access to opioids, ketamine, intravenous and oral APAP, total analgesic cost in the PACU, with all costs represented
lidocaine, and ketorolac. None of the patients in the study in 2014 U.S. dollars.
used patient-controlled analgesia in the PACU. Intravenous
APAP was routinely used in all eye, ear, nose, or throat Data Analysis
(EENT) procedures because this set of providers considered Continuous data were reported as means with standard
that this drug would improve recovery and decrease PACU deviations if normally distributed. Data that were not nor-
length of stay. This was the primary rationale that EENT physi- mally distributed were reported as medians with interquartile
cians used to justify the medications costs and its retention ranges (IQRs). The distribution of data for each variable was
on the formulary. No providers other than EENT physicians evaluated visually via histograms. Because length of stay is
utilized intravenous APAP at the facility. In addition to intra- typically skewed, this variable was also reported as medians.
venous APAP, pain in the PACU was primarily managed using An unpaired Students t-test or the Wilcoxon rank-sum test
intermittent intravenous boluses of opioids. was used to compare continuous data between groups as
In July 2014, the institution removed intravenous APAP from appropriate. Categorical data were reported as percentages
the formulary due to a cost increase from the manufacturer. and compared between groups using the Fishers exact test
After this, all EENT procedures were performed without the or chi-square test as appropriate. The mean pain scores were
use of intravenous APAP for postoperative pain. At the time highly skewed, thus this variable was categorized as mild
of removal from the formulary, the EENT providers were pain (score 03), moderate pain (score 46), and severe pain
notied that other analgesics, such as ketamine, lidocaine, (score 710). An a priori alpha of 0.05 was used for all analyses.
and ketorolac, could be used instead of intravenous APAP. All data analyses were conducted in Stata 13 (StataCorp LP,
In addition, oral APAP could be used when possible. The College Station, Texas).
universitys institutional review board approved the study prior Based on previous studies conducted in outpatient surgery
to data collection. settings, we considered a mean PACU length of stay of approxi-
mately 120 minutes for the APAP group and 150 minutes for
Patient Selection the non-APAP group with a common standard deviation of
Consecutive adult patients (at least 18 years of age) who 70 minutes.14 This reduction of 30 minutes was based on what
received an EENT procedure in the ambulatory surgery center we considered to be clinically meaningful and on estimates
were included until the desired sample of 87 patients was reached of the EENT providers at our institution to justify the use of
in each group. A list of all patients who underwent a procedure was intravenous APAP. Using an alpha of 0.05 and power of 80%,
generated, and EENT procedures were identied. We selected we established a sample size of 87 patients in each group.
a population of patients who received only EENT procedures
to provide a relatively homogenous population. This was also RESULTS
the only population of patients for whom intravenous APAP was The overall cohort included 87 patients who received intra-
routinely used. Patients in the APAP group were included during venous APAP in the PACU and 87 patients who did not receive
the period when the medication was available on the formulary intravenous APAP. Because the initial list we obtained included
(January 2014 to June 2014). Patients in the non-APAP group only EENT ambulatory surgeries, no patients were excluded.
were included during the period when it was not available on The mean age was 49 19 years, 94 patients (54%) were men,
formulary (July 2014 to January 2015). Patients were included and mean weight was 81 19 kg. Comparisons between groups
chronologically until the desired sample size was reached for with regard to demographic and clinical variables appear in
each period. In other words, the rst 87 patients in each period Table 1 along with the types of EENT surgeries performed. The
were included consecutively. There were no exclusion criteria two groups were similar with respect to demographic catego-
other than the age limits and procedure type listed above. ries and most comorbid conditions. There were more patients

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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.

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Effect of IV Acetaminophen on PACU Length of Stay, Opioid Consumption, Pain, and Costs
PACU and thus decrease recovery time, enabling patients to tion of these results. There was an imbalance between groups
be discharged home sooner.1 However, our ndings suggest with regard to a few comorbidities, such as coronary artery
that opioid consumption was not reduced, and PACU length of disease, COPD, and anxiety disorder. Patients in the non-APAP
stay was similar between groups. A signicant nding is that group were more likely to have anxiety disorder, which has the
the use of intravenous APAP was associated with better pain potential to inuence pain and opioid consumption.17 However,
control in the PACU. There were also greater analgesic drug the comorbidities we considered to be most important per-
costs associated with the use of intravenous APAP ($15 versus tained to the presence of chronic pain conditions, which were
$1). This was primarily attributed to the cost of intravenous similar between groups. There were also differences between
APAP. The drugs cost doubled at our institution, which led groups with regard to the use of adjunctive analgesic agents.
to its removal from the formulary. Thus, this disparity in drug For instance, the intravenous APAP group was less likely to
costs is expected to be greater today than reported in our study. receive oral APAP. This is intuitive because after removal of
In a previous randomized controlled study (N = 74) conducted intravenous APAP from the formulary, the staff was provided
in patients undergoing endoscopic sinus surgery, patients with information regarding available alternatives, such as oral
received a single dose of 1 g intravenous APAP or placebo.6 APAP. A few patients in the intravenous APAP group also were
Within four hours after surgery, fewer patients in the APAP more likely to receive intravenous ketamine, and patients in
group required rescue opioid analgesia (25% versus 71%; the non-APAP group were more likely to receive intravenous
P = 0.001). There were also fewer patients in the APAP group lidocaine. Although the increased use of lidocaine was expected,
who reported signicant pain (31% versus 58%; P = 0.018). The the decrease in the use of ketamine was surprising. However, it
authors dened this as a score greater than 3 on 010 numeri- should be noted that there were very few patients overall who
cal rating scale at any time during the study. In our study, we received ketamine, and this difference could be attributed to
showed a reduction in pain, but opioid consumption was not random variation. This occurred because the staff decided to
reduced. This could result from differences in the types of use other intravenous options instead of APAP. We can only
EENT procedures in our population or differences in the use speculate regarding how these differences affected pain scores
of other adjunctive analgesics. and opioid consumption. It is possible that the use of these
The use of intravenous APAP has been studied after a variety other adjunctive agents instead of intravenous APAP resulted
of surgeries, such as abdominal, cardiac, orthopedic, dental, in minimizing potential differences in length of stay. We did not
otolaryngologic, and others.15 However, the evidence is greatest collect information regarding the timing of pain scores in the
for major surgeries, such as those involving the abdomen. In one PACU. Thus we could not plot the time course of pain to gain a
systematic review involving seven randomized controlled trials, better understanding for this measure in the PACU. However,
intravenous APAP was associated with an opioid-sparing effect, because the stay in the PACU is only for a few hours, we did
involving a 20% reduction in morphine use via patient-controlled not consider this to be necessary. At the time of the study
analgesia.10 However, it did not reduce morphine-related adverse there was no protocol in place for postoperative pain, and this
effects. Some studies have shown a decrease in hospital length management was at the discretion of the physician. As a result,
of stay with the use of intravenous APAP.8,16 In patients under- there could have been variation among patients with regard
going abdominal hysterectomy, the mean hospital length of stay to their analgesic provision. However, we have no reason to
was decreased from 6.4 days to 5.2 days (P < 0.05).8 Similarly, believe that this variation would be any different between the
in patients undergoing laparoscopic colorectal resection, mean two study phases. We did not collect data regarding provid-
hospital length of stay decreased from ve days to three days ers, which would have inuenced the selection of analgesics.
(P < 0.05). However, these trials have been conducted in Finally, we considered PACU length of stay to be more mean-
European countries, limiting extrapolation to the United States ingful as an outcome than discharge from the surgical center.
because of different processes and conditions that determine This is because PACU length of stay inuences throughput in
eligibility for discharge. Our study is unique because it was in the surgical center. Discharge from the surgical center itself
a population that has not been studied as extensively. Given the can be attributed to nonmedical issues, such as availability of
increasing trend toward ambulatory surgery, this study helps transport, so it was not used as our outcome.
evaluate the use of intravenous APAP in a population where
there is increasing interest in its utilization. When the decision CONCLUSION
was made to remove intravenous APAP from the formulary Intravenous APAP use in ambulatory surgery patients under-
due to budgetary implications, proponents for its use argued going EENT procedures is not associated with decreased PACU
that the increase in cost was justied because the medication length of stay. However, intravenous APAP may decrease
decreased resource use by reducing PACU length of stay. We postoperative pain in this setting. Analgesic drug costs are
did not see an increased length of stay after intravenous APAPs signicantly greater when intravenous APAP is used.
removal from the formulary. This suggests that other adjunctive
agents (e.g., oral APAP, lidocaine, ketorolac, ketamine) may REFERENCES
be adequate as part of multimodal regimens in this setting. 1. Crews JC. Multimodal pain management strategies for ofce-based
However, the increase in pain scores that occurred after removal and ambulatory procedures. JAMA 2002;288:629632.
of intravenous APAP from the formulary is concerning. 2. Wier LW, Steiner CA, Owens PL. Surgeries in hospital-owned
outpatient facilities. Healthcare Cost and Utilization Project. AHRQ
The study has a few important limitations inherent in the Statistical Brief #188. 2015. Available at: www.hcup-us.ahrq.gov/
retrospective design. The study was conducted in a single reports/statbriefs/sb188-Surgeries-Hospital-Outpatient-Facili-
institution in the United States, which may limit the generaliza- 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- ments include the use of electroconvul- Based on these positive ndings,
order primarily characterized by sive therapy or repetitive transcranial Alkermes has moved ALKS 3831 into a
delusions, hallucinations, difculty magnetic stimulation.18,19 phase 3 clinical development program
with thinking and concentration, and Table 1 lists the leading schizophrenia consisting of two trials: ENLIGHTEN-1
lack of motivation. The disorder affects treatments in the United States.6 and ENLIGHTEN-2. In the rst study,
approximately 1% of the U.S. population.1 Analysts have identied ve unmet ALKS 3831 is being compared with olan-
The precise cause of schizophrenia is needs in the schizophrenia marketplace. zapine alone and placebo in an estimated
unknown, but some investigators have They include:6 390 patients with schizophrenia. The
suggested that it may begin in utero.2,3 primary endpoint is the change in the
Genetic, environmental, and social factors Drugs that enhance cognition PANSS score after four weeks of treat-
have also been implicated.4,5 Drugs that treat negative symptoms ment. The study began in December 2015
Although there is no cure for schizo- (such as lethargy, apathy, and social and has an anticipated completion date of
phrenia,1 numerous drugs are available withdrawal) April 2018.21 The second trial is evaluat-
for initial and maintenance therapy, Drugs that provide improved options ing weight gain during treatment with
with the goal of controlling symptoms.6 for treatment-resistant patients ALKS 3831 compared with olanzapine
According to the American Psychiatric Drugs with enhanced safety proles in adults with schizophrenia. The study
Association, second-generation (atypical) Drugs that increase compliance has two primary endpoints: the percent
antipsychoticswith the exception of clo- change from baseline in body weight at
zapineare the agents of choice for the With these needs in mind, pharmaceu- 24 weeks and the proportion of patients
rst-line treatment of schizophrenia.7 Clo- tical companies are working to develop with 10% or greater weight gain at the
zapine is not recommended because of several novel schizophrenia drugs same time point. The study was initi-
its risk for causing agranulocytosis or sei- (Table 2). These investigational thera- ated in February 2016, with a projected
zures.2,8 All of the atypical antipsychotic pies are discussed below. completion date of March 2018.22
drugs offer comparable efcacy.9,10 After ALKS 3831 (Alkermes) is a xed-dose If ALKS 3831 is approved by the Food
patients have recovered from their acute combination of samidorphan, a mu-opioid and Drug Administration (FDA), it is
psychotic episode, maintenance therapy receptor antagonist, and the atypical expected to be launched in the U.S. in
is initiated.11 antipsychotic drug olanzapine (generic the third quarter of 2019.6
Most schizophrenia patients (approxi- Zyprexa).6 The combination treatment AVN-211 (Avineuro Pharmaceuticals)
mately 80% to 90%) experience a relapse uses the action of samidorphan to reduce is an oral, small-molecule antagonist of
during the course of their illness.12 the weight gain and metabolic adverse the 5-hydroxytryptamine 6 (5-HT6) family
Breakthrough psychotic episodes may events associated with olanzapine while of serotonin receptors that has received
result from nonadherence to mainte- maintaining olanzapines antipsychotic attention as a potential adjunctive treat-
nance therapy, persistent substance use, efcacy.6 ment for the cognitive impairments asso-
poorer premorbid adjustment, or stressful ALKS 3831 was evaluated in a 12-week, ciated with schizophrenia. There are no
life events.13 Long-acting injectable anti- phase 2, randomized, double-blind, active- marketed drugs with this indication.6
psychotics are commonly used to prevent controlled, dose-ranging study involving In 2015, however, AVN-211 failed
relapse.14 In addition, adjunctive psycho- 300 adults with schizophrenia. Alkermes to demonstrate statistically signicant
social interventionsincluding family reported top-line results from this trial in results in a phase 2 pilot study, which
psychosocial education, social skills train- January 2015. ALKS 3831 achieved the evaluated the efcacy of AVN-211 in
ing, and cognitive behavioral therapy studys primary efcacy endpoint, demon- amplifying the effects of antipsychotic
have been shown to prevent relapse and strating equivalence to olanzapine in the drugs in 80 patients with schizophrenia
to improve medication adherence.7,15 reduction from baseline in Positive and in incomplete remission receiving stable
Approximately 10% to 30% of schizo- Negative Syndrome Scale (PANSS) total antipsychotic therapy. AVN-211 was not
phrenic patients are treatment resis- scores. ALKS 3831 also met the studys signicantly different from placebo on
tant.7 The optimal management of these principal secondary endpoints, demon- the studys primary efcacy endpoint.23
patients may require switching to the strating a 37% lower mean weight gain Moreover, as a drug discovery and
atypical antipsychotic clozapine or aug- compared with olanzapine at week 12 in development company, Avineuro may
menting current therapy with other the full study population (P = 0.006) and lack the sales and marketing expertise
approaches.16,17 Augmentation treat- a 51% lower mean weight gain compared required for a successful launch of AVN-
with olanzapine at week 12 in a subset of 211. Therefore, the company may need
Chris Fellner is a medical writer and the patients who gained weight in the one- to attract a partner or forge a licensing
Editor of PTCommunity.com. week olanzapine lead-in (P < 0.001).20 agreement to maximize the drugs com-

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


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

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

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treatment period. RBP-7000 also met the Rovi submitted the PRISMA-2 data, along In summary, several products are
key secondary endpoint with signicant with ndings from previous studies, to being developed to address the signi-
improvements in the Clinical Global the FDA in order to request guidance cant unmet needs that exist in the schizo-
ImpressionSeverity scale compared with on the design of a phase 3 trial of risperi- phrenia marketplace. For example, three
placebo during the eight-week treatment done ISM. The company predicted that potential treatmentsITI-007 (Intra-
period, as indicated by the change from recruitment for such a study would be Cellular Therapies), MIN-101 (Minerva
baseline to the end of treatment.33 under way by the third quarter of 2016.40 Neurosciences), and NaBen (SyneuRx)
Indivior subsequently announced If approved, risperidone ISM is are aimed at managing the negative symp-
that it was weighing the options for the expected to be launched in the U.S. in toms of the disease. In addition, AVN-211
nal stages of clinical development and the fourth quarter of 2019 for the treat- (Avineuro Pharmaceuticals) is in late-
commercialization of RBP-7000. These ment of patients with schizophrenia or stage development as a treatment for the
options included potential partnerships, schizoaffective disorder.6 cognition impairments associated with
outlicensing or outright sale of the NaBen (sodium benzoate, SyneuRx schizophrenia, and Lu AF35700 (Lund-
product, and maintaining ownership of International [Taiwan] Corp.) is a beck) addresses treatment resistance
the product.34,35 D-amino acid oxidase inhibitor under in schizophrenia patients. Finally, three
Analysts anticipate that RBP-7000 clinical development as a schizophrenia formulations of risperidonerisperidone
will be launched in the U.S. in the treatment.6 It was granted orphan drug implant (Braeburn Pharmaceuticals), ris-
fourth quarter of 2017, with an indica- status for the treatment of schizophre- peridone ISM (Rovi), and RBP-7000 (Indi-
tion for acute and maintenance treat- nia patients with refractory disease in vior)are expected to offer improved
ment of patients with schizophrenia. It combination with clozapine in December safety proles.6
is expected, however, to meet strong 2011 and for the treatment of schizophre-
competition from generic risperidone.6 nia in pediatric patients in July 2012.41 REFERENCES
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Accessed November 29, 2016. able at: http://ir.minervaneurosciences. news/10December2014.html. Accessed
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Accessed November 2, 2016. able at: www.indivior.com/wp-content/

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MEETING HIGHLIGHTS

American Society of Hematology


Annual Meeting and Exposition
Walter Alexander

sustained remission with durations of more than one year,


Billed as the worlds premier event in malignant and six months, and three months.
nonmalignant hematology, this years American Society Relapses were associated with changes in CD22 expression
of Hematology (ASH) meeting hosted more than 27,000 level. Weve been able to show that you can give a second
hematology professionals December 36 in San Diego. CAR therapy that is directed against a different antigen and
We review below key sessions on pharmacotherapy have it be safe and effective, Dr. Fry said, noting that a single
clinical trials across a wide span of disease states, antigen-directed CAR immunotherapy probably wont be suf-
including leukemia, graft-versus-host disease, myelobrosis, cient for long-term durable remissions in many patients. The
multiple myeloma, and sickle cell disease. 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
Minimal Residual Disease Negative Complete CD19-negative B-ALL, he concluded.
Remissions Following Anti-CD22 Chimeric
Antigen Receptor Therapy in Children and Chronic Myeloid Leukemia Patients With
Young Adults with Relapsed/Refractory Stable Molecular Responses May Safely
Acute Lymphoblastic Leukemia Decrease the Dose of Their Tyrosine Kinase
Terry J. Fry, MD, National Cancer Institute, Bethesda, Inhibitor: Data from the British DESTINY Study
Maryland
Mhairi Copland, MD, PhD, University of Glasgow, Glasgow,
United Kingdom
A National Cancer Institute (NCI) phase 1 study of anti-
CD22 chimeric antigen receptor (CAR) therapy in children Like patients with deep molecular responses, most chronic
and young adults with relapsed/refractory acute lymphoblastic myeloid leukemia (CML) patients with stable responses
leukemia (ALL) revealed complete remissions without severe (molecular response with a 3.0 log reduction [MR3]; BCRABL
or irreversible neurotoxicity. protein level less than 0.1%) can safely cut their tyrosine kinase
Not all relapsed/refractory ALL patients respond to anti-CD19 inhibitor (TKI) dose in half. The consequence, according to
CAR therapy, and CD19-negative escape has been observed, Dr. Copland, is fewer side effects and reduced cost.
Dr. Fry said at an ASH press brieng. He noted that CD22, Reporting ndings from the DESTINY study at an ASH press
which is widely expressed in ALL, represents an ideal target. brieng, Dr. Copland noted that several studies report 50% to
The NCI trial tested anti-CD22 CAR therapy to determine the 60% of CML patients with enduring good responses can stop
feasibility of producing anti-CD22 CAR cells and the safety TKI therapy. All of these studies, however, are restricted to
of administering escalating doses of anti-CD22 CAR T cells. patients with very deep responses (less than MR4; BCRABL
Preliminary assessment of antileukemia effects, a secondary less than 0.01%). Dr. Copland asked, What about patients with
endpoint, was also conducted. less deep responses? Could they manage on reduced-dose
Anti-CD22 CAR T-cell therapy, in which a patients own treatment? This might improve side effects and save money.
genetically altered T cells track down and kill cancer cells One of the challenges in CML, she added, is how to manage
expressing CD22, plus udarabine 25 mg/m2 was given to patients with side effects.
16 patients 1 to 30 years of age with relapsed/refractory CD22- DESTINY included CML patients in MR4 or better and in
positive hematologic malignancies. All patients had CD22 MR3. They were assigned half-dose therapy with imatinib
expression on more than 99% of their malignancy, with a median (Gleevec, Novartis) 200 mg once daily (n = 148), nilotinib
site density of 2,589 molecules per cell (range, 84613,452). (Tasigna, Novartis) 200 mg twice daily (n = 16), or dasatinib
All had previously undergone at least one allogeneic stem (Sprycel, Bristol-Myers Squibb) 50 mg once daily (n = 10).
cell transplant, and a majority of participants (11 of 16) had Individual TKI side effects such as lethargy, diarrhea, rash,
relapsed after receiving anti-CD19 CAR T-cell therapy before nausea, periorbital edema, and hair thinning improved in the
entering the trial. rst one to two months of de-escalation, but plateaued there-
Among the 10 participants treated at a higher dose after. Quality-of-life measures were optimal at the trial outset,
(comparable to that used by current CD19 CAR programs), however, and were not impacted.
eight attained a complete remission without evidence of residual Molecular relapses, dened as loss of MR3 on two consecutive
disease after one month of their infusion. Two patients had samples, were reported for 12 patients between study months 2
mild cytokine release syndrome. Three patients are in ongoing and 12. The molecular relapse rate was higher in patients with
less deep molecular responses at the outset (MR4 in three of
The author is a freelance writer living in New York City. 125 patients [2.4%]; MR3 in nine of 49 patients [18.4%]).

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MEETING HIGHLIGHTS: American Society of Hematology

According to Dr. Copland, halving treatment led to a 46.7% Dr. Mahon concluded, With inclusion and relapse criteria less
cost savings of 1,943,364 (US $1,530,204) from an expected TKI strict than in many previous trials, and with decentralized but
budget (without de-escalation) of 4,156,969 (US $3,273,197). standardized PCR [polymerase chain reaction] monitoring,
In CML patients with stable MR3 or better, decreasing stopping of TKI therapy in a large cohort of CML patients
TKI treatment to half the standard dose appears safe and appears feasible and safe.
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
Multicenter, Open-Label, Phase 2 Study
ambitious de-escalation are warranted. Of Ibrutinib in Chronic Graft-Versus-Host
Disease After Failure of Corticosteroids
Cessation of Tyrosine Kinase Inhibitor David Miklos, MD, Stanford University, Palo Alto, California
Treatment in Chronic Myeloid Leukemia Data from a multicenter, open-label, phase 2 study of
Patients with Deep Molecular Response: ibrutinib (Imbruvica, Pharmacyclics/Janssen) support the
Results of the EURO-SKI Trial kinase inhibitors use in patients with steroid-refractory
chronic graft-versus-host disease (GVHD), Dr. Miklos said in a
Francois-Xavier Mahon, MD, PhD, University of Bordeaux,
late-breaking clinical trials session.
Bordeaux, France
He described GVHD as a complication of allogeneic stem cell
In a clinical trial with a large cohort of chronic myeloid transplantation that affects approximately 4,000 of the 10,000
leukemia (CML) patients, stopping tyrosine kinase inhibitor individuals in the United States who undergo allogeneic stem
(TKI) therapy was feasible and safe, according to ndings from cell transplantation each year. Immune-suppressing cortico-
the EURO-SKI trial, which were discussed by Dr. Mahon in steroids, the standard treatment, do not benet all patients. The
an ASH press brieng. kinase inhibitor ibrutinib, which was recently granted break-
The feasibility of stopping TKI treatment has been dem- through therapy status by the Food and Drug Administration,
onstrated previously,13 and the concept of treatment-free reduces the severity of chronic GVHD through its inhibition
remission was validated in the STIM study.1 While it has of Bruton tyrosine kinase and interleukin-2inducible T-cell
been established that a sustained deep molecular remission kinase.4 Both B and T cells play a role in the pathophysiology
on long-term TKI therapy is necessary prior to an attempt at of chronic GVHD, Dr. Miklos said.
treatment-free remission, the exact preconditions for stopping All 42 patients (median age, 56 years; range, 1974 years)
CML treatments are not dened. with chronic GVHD in Dr. Miklos study needed additional
The EURO-SKI trial included 821 patients treated at 61 sites therapy. Included patients had received prior regimens for
in 11 countries. All were chronic-phase CML patients who chronic GVHD and had erythematous rash over more than 25%
had received imatinib (Gleevec, Novartis), nilotinib (Tasigna, of their body surface or National Institutes of Health mouth
Novartis), or dasatinib (Sprycel, Bristol-Myers Squibb) for scores of greater than 4. All were treated daily with 420 mg
three years or more without treatment failure. All were in ibrutinib until unacceptable toxicity or disease progression.
deep molecular response (molecular response with a 4.0 log The study evaluated the efcacy and safety of ibrutinib, with
reduction [MR4]; BCRABL protein level less than 0.01% on changes in corticosteroid use among the secondary endpoints.
the international scale) for at least one year. Median duration of chronic GVHD was 13.7 months at study
Molecular recurrence in the EURO-SKI study was dened entry. The median number of prior regimens was two (range,
by the loss of the major molecular response (BCRABL less one to three). The overall response rate, after a median follow-up
than 0.1% on the international scale) at any point. Loss of of 13.9 months, was 67%. Complete responses were observed
major molecular response among the 755 evaluable patients in 45% of patients, with sustained responses of 20 weeks or
occurred in 373 patients. That loss occurred within the rst greater in 71% and 32 weeks or greater in 48%.
six months in 78.3% of patients (n = 292). Median follow-up Curtailed or reduced corticosteroid use was facilitated
was 14.9 months for the entire group and 26.0 months among with ibrutinib, with low corticosteroid doses (less than
the 383 patients who did not experience loss of response. 0.14 mg/kg per day) given in 75% of patients and complete
Molecular recurrence-free survival was 61% at six months, cessation of corticosteroid use while in response in
52% at 18 months, and 47% at 36 months. ve patients (12%). Clinician-assessed chronic GVHD median
While gender, age, or any other variable did not predict the severity scores decreased from 7 at baseline to 4 at week 49.
probability of successful therapy cessation, longer duration Score improvements using the Lee chronic GVHD symptom
of imatinib therapy (optimally 5.8 years or longer) prior to scale were reported overall in 61% of the 28 responders versus
TKI cessation correlated with a higher probability of relapse- 11% in nine nonresponders.
free survival. In addition, each additional year of TKI therapy Adverse events, consistent with those previously observed
increased a patients chances of successful TKI discontinuation for ibrutinib in B-cell malignancies and chronic GVHD,
by about 16%. Resumption of TKI therapy for patients with were experienced in 45% of patients. The most common
molecular recurrence led to regaining prior remission levels adverse events were fatigue (57%), diarrhea (36%), muscle
in most patients, and none progressed to advanced disease. spasms (29%), nausea (26%), and bruising (24%). Two fatal
With about half of the enrolled patients remaining in events (multilobular pneumonia and bronchopulmonary
remission two years after stopping their TKI therapy, aspergillosis) were reported.

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


MEETING HIGHLIGHTS: American Society of Hematology
Dr. Miklos underscored the importance of active monitoring time of the clinical hold, there had been 15 deaths in the QD
to manage ibrutinib-related adverse events. He commented arm (14%), 10 deaths in the BID arm (9%), and 14 deaths
that analysis of biomarker changes shows that ibrutinib has a (14%) in the BAT arm. The rates for the primary endpoint
positive effect on immune cell subsets. of spleen volume reduction at 24 weeks were signicantly
I think clinicians will nd these data support the use of improved for both pacritinib arms versus BAT (QD, 14.7%,
ibrutinib in patients with steroid-refractory chronic GVHD, P = 0.017; BID, 21.6%, P = 0.001). Percentages of patients with
Dr. Miklos concluded. 50% or greater total symptom score reductions were signi-
cantly higher only for the pacritinib BID arm versus BAT (32.4%
Results of the PERSIST-2 Phase 3 versus 13.9%; P = 0.011).
Overall survival was censored at the clinical hold date. It was
Study of Pacritinib Versus Best slightly higher with pacritinib versus BAT in the QD group
Available Therapy, Including Ruxolitinib, (hazard ratio [HR] = 1.18) but was lower in the BID group
In Patients With Myelobrosis and Platelet (HR = 0.68). The need for red blood cell transfusions at
Counts Less Than 100,000 per mcL week 24 was reduced in the pacritinib arms, especially the
BID arm (0.67 units per month versus 1.33 in the BAT arm).
John Mascarenhas, MD, Tisch Cancer Institute, Icahn School Serious cardiac events and bleeding events were comparable
of Medicine at Mount Sinai, New York, New York among all groups and were relatively rare. The most common
adverse events with pacritinib were diarrhea, vomiting, nausea,
Among patients with myelobrosis (MF) and platelet counts anemia, and low platelet count.
of less than 100,000 per mcL, pacritinib was signicantly more Despite study truncation due to the clinical hold, pacri-
effective than best available therapy (BAT)(including ruxoli- tinib QD and BID was signicantly more effective than best
tinib [Jaka, Incyte]) for spleen volume reduction. A trend available therapy, including ruxolitinib, for spleen volume
toward improved total symptom score was also observed, reduction with a trend toward improved total symptom score,
according to an ASH late-breaking clinical trial presentation Dr. Mascarenhas said. He also noted that the pacritinib BID
by Dr. Mascarenhas. benetrisk prole appeared to be better than that of BAT,
A life-threatening hematologic malignancy characterized by including ruxolitinib.
splenomegaly and debilitating constitutional symptoms, MF The FDA recommended that the manufacturer conduct
presents with thrombocytopenia, platelet counts of less than dose-exploration studies for pacritinib in patients with MF and
50,000 per mcL (associated with reduced quality of life), heavier should submit nal study reports and datasets for PERSIST-1
symptom burden, and likelihood of shortened overall survival and PERSIST-2.
in 25% of patients. The Janus kinase 1 (JAK1)/JAK2 inhibi-
tor ruxolitinib has been shown to reduce splenomegaly and SUSTAIN: A Multicenter, Randomized,
related symptoms. However, it is associated with dose-limiting
cytopenias and is not indicated for patients with platelet counts
Placebo-Controlled, Double-Blind, 12-Month
of less than 50,000 per mcL. Pacritinib is an oral kinase inhibitor Study to Assess Safety and Efficacy of
with specicity for JAK2, FMS-like tyrosine kinase-3, inter- SEG101 With or Without Hydroxyurea
leukin-1 receptor-associated kinase 1, and colony-stimulating Therapy in Sickle Cell Disease Patients
factor 1 receptors. With Sickle CellRelated Pain Crises
In the PERSIST-1 trial, which compared pacritinib to BAT
(excluding JAK2 inhibitors), pacritinib demonstrated sus- Kenneth I. Ataga, MD, University of North Carolina at Chapel
tained spleen volume reduction and symptom control in MF Hill, Chapel Hill, North Carolina
patients regardless of baseline platelet counts. The PERSIST-2
phase 3 trial tested two doses of pacritinib (400 mg once daily High-dose SEG101 (crizanlizumab, formerly SelG1, Novartis)
[QD] and 200 mg twice daily [BID]) versus BAT (including resulted in a statistically signicant and clinically meaning-
ruxolitinib). The coprimary endpoints were the number of ful reduction in the frequency of sickle cellrelated pain
patients achieving spleen volume reductions of 35% or greater crises (SCPCs) in patients with sickle cell disease, according
and reductions in total symptom score of 50% or greater at to SUSTAIN clinical trial results presented at an ASH press
week 24. The 1:1:1 randomization included 75 patients receiving brieng. SEG101 is a rst-in-class humanized anti-P-selectin
pacritinib QD, 74 receiving pacritinib BID, and 72 receiving antibody given as an intravenous infusion over 30 minutes.
BAT. Mean age was approximately 68 years, and 57% of the Upregulation of P-selectin, an adhesion molecule expressed
patients were men. Median spleen length was approximately on activated vascular endothelial cells and platelets, plays a key
14 cm. Approximately 44% of patients had received prior treat- role in the pathogenesis of SCPC, Dr. Ataga said.
ment with ruxolitinib. BAT most commonly consisted of rux- In sickle cell disease, pain is caused by tissue ischemia
olitinib (45%) and hydroxyurea (19%). The safety and overall created when sickled red blood cells and leukocytes adhere
survival analysis included approximately 100 patients per arm. to the endothelium and lead to vaso-occlusion. SCPCs occur
The PERSIST-2 study was truncated by a Food and Drug unpredictably and often require hospitalization, Dr. Ataga
Administration (FDA)-mandated full clinical hold ordered explained. While hydroxyurea is known to decrease SCPC
after interim analysis revealed patient deaths related to intra- frequency in sickle cell anemia, many patients receiving
cranial hemorrhage, cardiac arrest, and heart failure. At the 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 intermediate (50%) or adverse (36%) cytogenetic risk, and 17%
double-blind to placebo (n = 65), SEG101 2.5 mg/kg (n = 66), of patients have secondary AML.
or SEG101 5.0 mg/kg (n = 67). Patients received an initial dose, Adverse event rates with VDT are acceptable, according to
one dose 14 days later, and then one dose every four weeks Dr. Erba. Among hematologic treatment-related adverse events,
through week 50 for a total of 14 doses. The primary efcacy grade 3 febrile neutropenia has been reported in approximately
endpoint was the annual rate of SCPC in the 5.0-mg/kg SEG101 65% of patients, and grade 4 thrombocytopenia, as expected, was
group versus placebo. An SCPC was dened as acute sickle reported in all patients. Nonhematologic toxicities were similar
cellrelated pain that resulted in a visit to a medical facility and to those seen with 7+3 alone and most commonly included
required a parenteral or oral narcotic or parenteral nonsteroidal grades 1 and 2 nausea (60%), diarrhea (36%), and constipation
anti-inammatory drug. The primary endpoint was the median (33%). No grade 3 or higher nonhematologic events have been
rate of SCPC per year. observed in 15% or more of patients. The 30-day mortality
Median patient age was 28 years, 45% of patients were male, rate is 2%. No veno-occlusive disease, sinusoidal obstruction
and approximately 93% were African-American. Concomitant syndrome, or signicant hepatotoxicity has been observed.
hydroxyurea was being taken by 62% of patients. Dr. Erba reported that complete remissions (CRs) have
For patients receiving the higher SEG101 dose, the median been achieved in 60% of patients, with 30 of 32 (94%) achiev-
rate of SCPC per year was 1.63. For those receiving the lower ing CR within one cycle of therapy. Among these, 25 of
dose, it was 2.01, and for patients receiving placebo, it was 2.98. 32 patients (78%) are MRD-negative. An additional 17% have
In the high-dose group, 24 patients were SCPC-free. Twelve in CRs with incomplete platelet recovery. Dr. Erba observed that
the low-dose SEG101 group were SCPC-free over the course CRs tracked closely with cytogenic risk (favorable = 100%;
of the study, as were 12 in the low-dose group and 11 in the intermediate = 67%; adverse = 40%).
placebo group. Median time to the rst and second SCPC Vadastuximab talirine can be safely combined with 7+3,
events was signicantly longer in the high-dose SEG101 group Dr. Erba concluded, adding that the recommended dose is
(4.07 months and 10.32 months, respectively; P = 0.001) than 20+10 mcg/kg on days 1 and 4. An alternate schedule of single-
in the placebo group (1.38 months and 5.09 months, respec- day dosing on day 1 is under investigation, and a randomized
tively; P = 0.022). Differences between the low-dose SEG101 phase 2 trial of vadastuximab talirine plus 7+3 versus 7+3
group and placebo group were not signicant. Adverse event alone is planned.
incidence with SEG101 was low.
Treatment with high-dose SelG1 [SEG101] resulted in a Survival Following Allogeneic Hematopoietic
statistically signicant and clinically meaningful reduction in
the frequency of SCPC in patients with sickle cell disease,
Cell Transplantation in Older High-Risk Acute
Dr. Ataga concluded. Myeloid Leukemia Patients Initially Treated
With CPX-351 Liposome Injection Versus
A Phase 1b Study of Vadastuximab Talirine Standard Cytarabine and Daunorubicin:
In Combination With 7+3 Induction Therapy Subgroup Analysis of a Large Phase 3 Trial
For Patients With Newly Diagnosed Jeffrey E. Lancet, MD, Moftt Cancer Center and Research
Acute Myeloid Leukemia Institute, Tampa, Florida
Harry P. Erba, MD, PhD, University of Alabama at
Treatment with CPX-351 for older patients with high-risk
Birmingham, Birmingham, Alabama
acute myeloid leukemia (AML) leads to better outcomes after
Vadastuximab talirine (VDT) can be safely combined with allogeneic hematopoietic cell transplantation (HCT), according
standard 7+3 chemotherapy in patients with newly diagnosed to an exploratory analysis of an open-label, parallel-arm study.
acute myeloid leukemia (AML), according to preliminary This liposomal formulation of cytarabine and daunorubicin may
results of an ongoing phase 1b trial. Standard induction treat- also provide a bridge to successful transplant in poor-risk older
ment for this population has been 7+3 (cytarabine for 7 days AML patients, Dr. Lancet said in an ASH press conference.
with an anthracycline for 3 days) for 30 years, Dr. Erba said Remission rates in patients older than 60 years of age are
in an ASH press brieng. lower and induction mortality is higher compared with younger
VDT is an antibody that targets the cell surface antigen patients. CPX-351s 5:1 molar ratio is said to maximize the
CD33. CD33 is expressed in about 90% of AML and leads to synergy between cytarabine and daunorubicin, leading to
cell death. Remissions brought about by adding VDT to 7+3 preferential drug uptake into leukemic cells. In earlier phase 3
chemotherapy could be enhanced and deeper than those with trial reporting, survival was superior in newly diagnosed older
standard chemotherapy alone, leading to minimal residual patients with secondary AML versus standard 7+3 cytarabine
disease (MRD) status. Achieving MRD-negative remission and daunorubicin.
postinduction correlates with improved survival, Dr. Erba said. Among older patients, Dr. Lancet observed, few can be
The safety and antileukemic activity of VDT added to cured with chemotherapy alone. He conducted an explor-
the 7+3 regimen with induction on days 1 and 4 of a 28-day atory analysis among those patients who received allogeneic
treatment cycle are being evaluated in Dr. Erbas trial. The HCT after induction treatment. The study included patients
study includes 42 patients (36% male; mean age, 45.5 years) 60 to 75 years of age with newly diagnosed secondary
with previously untreated AML. Most patients have AML. Patients with complete responses (CRs) or CRs

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


MEETING HIGHLIGHTS: IV Acetaminophen in the PACU
American Society of Hematology
continued from page 128
with incomplete platelet or neutrophil recovery (CPX-351, 3. American Society of Anesthesiologists Task Force on Acute
n = 73; 7+3, n = 52) were considered for allogeneic HCT based Pain Management. Practice guidelines for acute pain manage-
ment in the perioperative setting: an updated report by the
on institutional criteria.
American Society of Anesthesiologists Task Force on Acute Pain
CRs (with and without platelet/neutrophil recovery) were Management. Anesthesiology 2012;116:248273.
more frequent with CPX-351 than with 7+3 (47.7% versus 33.3%). 4. Kehlet H, Dahl JB. The value of multimodal or balanced
Also, median survival landmarked from time of transplant analgesia in postoperative pain treatment. Anesth Analg
was not reached in the CPX-351 patients (n = 52) and was 1993;77:10481056.
5. Jones VM. Acetaminophen injection: a review of clinical informa-
10.25 months for the 7+3 patients (n = 39) (hazard ratio, 0.46, tion. J Pain Palliat Care Pharmacother 2011;25:340349.
favoring CPX-351; P = 0.0046). 6. Kemppainen T, Kokki H, Tuomilehto H, et al. Acetaminophen is
While cautioning that the analysis is exploratory, Dr. Lancet highly effective in pain treatment after endoscopic sinus surgery.
underscored that the reduction in deaths was 53%, with all-cause Laryngoscope 2006;116:21252128.
7. Alhashemi JA, Alotaibi QA, Mashaat MS, et al. Intravenous aceta-
mortality by day 100 after transplant at 9.6% in the CPX-351
minophen vs. oral ibuprofen in combination with morphine PCIA
group and 20.5% in the 7+3 group. after cesarean delivery. Can J Anaesth 2006;53:12001206.
Outcomes after allogeneic transplant in older patients with 8. Arici S, Gurbet A, Turker G, et al. Preemptive analgesic effects of
high-risk AML appear superior in patients treated with CPX- intravenous paracetamol in total abdominal hysterectomy. Agri
351, he concluded. The ndings of lower-inductionrelated 2009;21:5461.
9. Memis D, Inal MT, Kavalci G, et al. Intravenous paracetamol
morbidity and more patients in CR suggest that patients are reduced the use of opioids, extubation time, and opioid-related
transplanted in better condition, he commented. adverse effects after major surgery in intensive care unit. J Crit
Care 2010;25:458462.
REFERENCES 10. Remy C, Marret E, Bonnet F. Effects of acetaminophen on
morphine side effects and consumption after major surgery:
1. Mahon FX, Ra D, Guilhot J, et al. Discontinuation of imatinib meta-analysis of randomized controlled trials. Br J Anaesth
in patients with chronic myeloid leukaemia who have main- 2005;94:505513.
tained complete molecular remission for at least 2 years: the 11. Salihoglu Z, Yildirim M, Demiroluk S, et al. Evaluation of intra-
prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol venous paracetamol administration on postoperative pain and
2010;11(11):10291035. doi: 10.1016/S1470-2045(10)70233-3. Epub recovery characteristics in patients undergoing laparoscopic chole-
2010 Oct 19. cystectomy. Surg Laparosc Endosc Percutan Tech 2009;19:321323.
2. Ross DM, Branford S, Seymour JF, et al. Safety and efcacy of 12. Unal C, Cakan T, Baltaci B, Basar H. Comparison of analgesic
imatinib cessation for CML patients with stable undetectable efcacy of intravenous Paracetamol and intravenous dexketoprofen
minimal residual disease: results from the TWISTER study. Blood trometamol in multimodal analgesia after hysterectomy. J Res Med
2013;122(4):515522. doi: 10.1182/blood-2013-02-483750. Sc 2013;18:897903.
3. Rousselot P, Charbonnier A, Cony-Makhoul P, et al. Loss of 13. Wininger SJ, Miller H, Minkowitz HS, et al. A randomized,
major molecular response as a trigger for restarting tyrosine double-blind, placebo-controlled, multicenter, repeat-dose study
kinase inhibitor therapy in patients with chronic-phase chronic of two intravenous acetaminophen dosing regimens for the treat-
myelogenous leukemia who have stopped imatinib after durable ment of pain after abdominal laparoscopic surgery. Clin Ther
undetectable disease. J Clin Oncol 2014;32(5):424430. doi: 2010;32:23482369.
10.1200/JCO.2012.48.5797. Epub 2013 Dec 9. 14. Chung F, Mezei G. Factors contributing to a prolonged stay after
4. Dubovsky JA, Flynn R, Du J, et al. Ibrutinib treatment amelio- ambulatory surgery. Anesth Analg 1999;89:13521359.
rates murine chronic graft-versus-host disease. J Clin Invest 15. Yeh YC, Reddy P. Clinical and economic evidence for intravenous
2014;124(11):48674876. doi: 10.1172/JCI75328. Epub 2014 Oct 1. Q acetaminophen. Pharmacotherapy 2012;32:559579.
16. Zafar N, Davies R, Greenslade GL, Dixon AR. The evolution of
analgesia in an accelerated recovery programme for resectional
laparoscopic colorectal surgery with anastomosis. Colorectal Dis
For the Latest News 2010;12:119124.
17. de Heer EW, Gerrits MM, Beekman AT, et al. The association of
... Visit PTcommunity.com. At this online resource for depression and anxiety with pain: a study from NESDA. PLoS One
P&T decision-makers, youll nd breaking-news cover- 2014;9:e106907. doi: 10.1371/journal.pone.0106907. Q
age of all of these topics:
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Vol. 42 No. 2 February 2017 P&T


139
RESEARCH BRIEFS
Prevention Efforts Have Mixed Even Just A Few Cigarettes
Results for Injection-Drug Users Have Long-Term Consequences
More people who need them are using syringe services There is no safe level of smokingthats the conclusion
programs (SSPs), but they still arent always using sterile needles, of National Cancer Institute researchers, based on data from
according to a Centers for Disease Control and Prevention 290,215 adults in the 20042005 NIH-AARP Diet and Health
(CDC) Vital Signs report. Thus, theyre still at risk for human Study. Smoking even a small number of cigarettes per day
immunodeciency virus (HIV), hepatitis B, and hepatitis C has substantial negative health effects, said lead author Maki
(HCV) infection. Inoue-Choi, PhD.
Researchers conducted a study of people who inject drugs in The participants responded to a questionnaire that assessed
22 U.S. cities with a high number of HIV cases. In 2015, more lifetime smoking intensity. Those who smoked between one and
than half of people who inject drugs said they used an SSP in 10 cigarettes a day had an 87% higher risk of earlier death. But
the previous year, compared with about one-third in 2005. But even people who smoked an average of less than one cigarette
the percentage of people who received at least one syringe from per day over their lifetimes still had a 64% higher risk of earlier
an SSP and shared syringes was about the same as those who death compared with never-smokers.
had not received any syringes from SSPs (31% versus 38%). The researchers also looked at specic causes of death.
The good news is that annual acquired immunodeciency Not surprisingly, they found a particularly strong associa-
syndrome (AIDS) diagnoses among people who inject drugs tion for lung cancer mortality. But again, even people who
have dropped by a stunning 90%. Nonetheless, about 9% of consistently averaged less than one cigarette per day over their
HIV infections diagnosed each year are due to injecting drugs. lifetimes had nine times the risk of dying from lung cancer
Injection drug use has also contributed to a 150% rise in acute than never-smokers. Among those who smoked between one
cases of HCV infections. and 10 cigarettes a day, the risk of dying from lung cancer was
But prevention efforts are paying off in the African-American nearly 12 times higher.
and Latino communities, says Eugene McCray, MD, Director People who smoked between one and 10 cigarettes a day
of the CDCs Division of HIV/AIDS Prevention. The number also had more than six times the risk of dying from respiratory
of African-Americans getting all syringes from SSPs was up by disease and about one and a half times the risk of dying of
48%, and the number sharing syringes was down 34% from 2005. cardiovascular disease compared with never-smokers.
The number of HIV diagnoses among African-Americans who The younger people were when they quit smoking, the lower
inject drugs declined by 60% from 2008 to 2014. their risk of early death.
Syringe sharing was also down 12% among Latinos, and HIV Source: National Institutes of Health, December 2016
diagnoses dropped by 50% from 2008 to 2014 in that population.
In contrast, whites who inject drugs continue to share at Multiple Myeloma and Stroke: Whats the Risk?
similar levels45% in 2005 versus 43% in 2015. The number Some 20% to 40% of patients with multiple myeloma have
receiving all syringes from sterile sources remained unchanged renal impairment and may also be taking drugs that raise the
at 22%, and HIV diagnoses remained stable from 2012 to 2014. risk of venous thromboembolism (VTE). Are those the factors
Recent trends indicate that heroin use and injection drug use responsible for the higher risk of arterial thrombosis in this
among whites are on the rise; that, coupled with high rates of patient group? Researchers from the University of Arkansas
syringe sharing, might challenge the decades of progress in HIV and Ohio State University conducted a large retrospective,
prevention, the researchers say. They also point to obstacles comparative case-control study to nd out.
such as a potential lack of sufcient sterile equipment, too few The patients were all enrolled in total therapy protocols
SSPs in rural areas, and absence of legal support in many states. that tested varying combinations of thalidomide, bortezomib,
Decisions about SSPs are made at state and local levels, the lenalidomide, and dexamethasone. Of 1,148 patients, 46 (4%)
report notes. In 2015, Congress gave states and local commu- had strokes, usually ischemic stroke (33 patients or 72%).
nities the opportunity to use federal funds to support certain Hypercoagulability, atrial brillation, and small-vessel occlusion
components of comprehensive SSPs, which also offer or refer were common mechanisms. While other research has found a
people to prevention, care, and treatment. higher risk of arterial thrombosis from activated prothrombotic
Until now, the nation has made substantial progress in pre- factors, especially during the early period of chemotherapy, in
venting HIV among people who inject drugs, but this success this study, vascular events occurred even months later.
is threatened, says Jonathan Mermin, MD, MPH, Director of Seven patients died in the hospital (15% compared with a
the CDCs National Center for HIV/AIDS, Viral Hepatitis, STD, national average of 5%). Although six of those deaths were
and TB Prevention. Syringe services programs work, and their stroke-related, most patients (78%similar to the national
expansion is pivotal for progress in the coming decades. average) were discharged home or to a rehabilitation facility;
Source: CDC, December 2016 two were discharged to a long-term nursing facility. During a

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


RESEARCH BRIEFS
median follow-up of 10 years, six patients had another stroke. proven method, HHS says, that combines improvement in safety
The cumulative risk of recurrent stroke was 15% compared culture, teamwork, and communications with evidence-based
with 5% for the general population. practices to protect patients. AHRQ has worked hand-in-hand
Stage I and II cancer and renal insufciency independently with front-line clinicians to help them use CUSP in a series of
predicted stroke. Also noteworthy, the researchers said, is highly effective nationwide projects.
that patients with multiple myeloma who developed renal AHRQ has been building a foundation of patient safety
insufciency had worse clinical outcomes despite improve- research for the last decade and a half at the request
ment in their renal function or lack of signicant difference of Congress, said AHRQ Director Andy Bindman, MD.
in their baseline renal functions between various treatment Now were seeing these investments continue to pay off in
protocols. Thus, the increased risk of stroke, recurrent stroke, terms of lives saved, harm avoided, and safer care delivery
and mortality could partly be due to renal disease, which might overall.
or might not have resulted from myeloma. Source: HHS, December 2016
Use of combination chemotherapy has markedly improved
clinical outcomes for multiple myeloma patients, the research- When Work Puts Employees at Risk for Asthma
ers said, but those drugs have also been associated with an As many as 2.7 million American workers might have asthma
increased risk of VTE, especially during the rst months of that their work has caused or worsened, say Centers for Disease
chemotherapy. Thalidomide alone did not increase the risk of Control and Prevention (CDC) researchers. Data from the
VTE, nor did lenalinomide on its own. However, thalidomide 20062007 Behavioral Risk Factor Surveillance System Asthma
combined with multiagent chemotherapy increased VTE risk Call-back Survey of 208,788 adults in 33 states revealed that
as much as 34% in newly diagnosed patients, and lenalinomide nearly half of adult asthma might be related to work, and thus
with dexamethasone boosted risk as high as 75%. potentially preventable.
The researchers found no signicant relationship between Of the respondents employed in the previous year, 7.7% had
mortality and use of thalidomide. Median survival was asthma, ranging from 5% in Mississippi to 10% in Michigan.
103 months for a thalidomide-based regimen and 78 months Among the 21 states that collected information on industry and
for a regimen without thalidomide. occupation, prevalence was highest among workers in health
Interestingly, the researchers noted, the patients developed care support occupations in Michigan (21.5%). In fact, health
strokes despite a trend toward coagulopathy, to the extent that care ranked rst among the ve industries with the highest
half were ineligible for immediate use of antiplatelet agents. asthma prevalence, and health care practitioners ranked second
The study ndings heightened our awareness, the research- among the ve occupational groups with the highest asthma
ers said, that aggressive preventive measures can help reduce prevalence.
the incidence of stroke in patients with renal insufciency. Different industries and occupations have different irritants.
Source: PLoS One, November 2016 In health care, for instance, cleaning and disinfection products,
powdered latex gloves, and aerosolized medications have
Hospital-Acquired Conditions on the Decline doubled the likelihood of new-onset asthma, the report notes.
Hospital-acquired conditions (HACs) are still trending down- But its possible to make a big dent in the illness prevalence
ward, with 3 million fewer adverse eventsa 21% dropover with evidence-based changes. The researchers say powder-
a ve-year period, according to the recently released National free natural rubber latex or nonlatex gloves, for instance,
Scorecard on Rates of Hospital-Acquired Conditions. Thanks in considerably reduced workplace asthma in the health care
part to provisions of the Patient Protection and Affordable Care industry.
Act, the Department of Health and Human Services (HHS) The researchers say their ndings might help physicians
says, about 125,000 fewer patients died due to HACs, and more and state public health ofcials identify workers who should
than $28 billion in health care costs were saved. be evaluated for work-related asthma in order to plan and
Agency for Healthcare Research and Quality (AHRQ) target interventions.
researchers used national data systems to analyze the Source: CDC, December 2016 Q
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

Vol. 42 No. 2 February 2017 P&T


141
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