The medical letter on drugs and therapeutics february 3 2014

The Medical Letter

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On Drugs and Therapeutics
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IN THIS ISSUE (starts on next page)

Perampanel (Fycompa) for Epilepsy .......................................................,,,,,,....p 9
Certolizumab Pegol (Cimzia) and Ustekinumab (Stelara)
for Psoriatic Arthritis ...................................................................................... p 10
In Brief: Rosiglitazone (Avandia) Unbound .................................................... p 12
Addendum: Renal Sympathetic Denervation for Hypertension ................... p 12

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The Medical Letter

®

On Drugs and Therapeutics
Published by The Medical Letter, Inc. • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication
Volume 56 (Issue 1435)
February 3, 2014

ALSO IN THIS ISSUE

Certolizumab Pegol (Cimzia) and Ustekinumab
(Stelara) for Psoriatic Arthritis ................. p 10
In Brief: Rosiglitazone Unbound ................ p 12
Addendum: Renal Sympathetic Denervation
for Hypertension ......................................... p 12

Perampanel (Fycompa) for Epilepsy
Perampanel (per am’ pa nel; Fycompa – Eisai), a firstin-class noncompetitive AMPA receptor antagonist, has
been approved by the FDA for adjunctive treatment of
partial-onset seizures in patients >12 years old. New
drugs for epilepsy are often initially approved by the
FDA as adjunctive treatment for partial seizures.1
MECHANISM OF ACTION — AMPA (-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors
are a subtype of glutamate receptors. Perampanel is a
noncompetitive antagonist of AMPA receptors on postsynaptic neurons. In vitro, it inhibits AMPA-dependent
increases in intracellular calcium, but the mechanism by
which it reduces seizure activity is unclear.2
Table 1. Pharmacology
Drug class

Noncompetitive AMPA receptor antagonist

Route

Oral

Formulation

2, 4, 6, 8, 10, 12 mg film-coated tablets

Tmax

0.5-2.5 h fasting (2-3 h later with food)

Time to steady state

2-3 wks (5-7 days with enzyme-inducing AEDs)

Metabolism

Primary oxidation (mediated by CYP3A and
possibly other CYP enzymes) and sequential
glucuronidation

Half-life
(terminal)

53-136 h (25 h with the enzyme-inducing
AED carbamazepine)

Elimination

Feces (48%); urine (22%)

CLINICAL STUDIES — Approval of perampanel was
based on the results of 3 randomized, double-blind,
placebo-controlled trials in a total of about 1500 pa-

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tients >12 years old with refractory partial-onset seizures. Each trial was divided into 3 periods: baseline
(6 weeks), titration (6 weeks), and maintenance (13
weeks). The patients in these trials generally were taking 2-3 antiepileptic drugs (AEDs) before entering the
study, had a mean duration of epilepsy of 21 years,
and had a median baseline seizure frequency of about
9-14 seizures per 28 days. About 50% were taking an
enzyme-inducing AED (carbamazepine, phenytoin, or
oxcarbazepine) that significantly lowered serum concentrations of perampanel.3-5
A pooled analysis of all 3 studies found that addition of perampanel 4, 8, or 12 mg/day reduced median 28-day seizure frequency from baseline during
19 weeks of treatment (the primary endpoint) by 2329% compared to 13% with placebo. The responder
rate (>50% reduction in seizure frequency during the
maintenance period compared to baseline) was 2935% with perampanel 4-12 mg/day compared to 19%
with placebo. The differences from placebo were statistically significant for all 3 doses of perampanel, but
increasing the dose from 8 to 12 mg/day often did not
improve efficacy. A 2-mg/day dose used in one of the
trials did not show a statistically significant difference
compared to placebo.6
In an open-label extension of the 3 double-blind clinical
trials, decreases in seizure frequency were maintained
after a median duration of 51 weeks.7

ADVERSE EFFECTS — In clinical trials, the percentages of patients who discontinued perampanel as a
result of an adverse reaction were 3%, 8%, and 19%
with doses of 4 mg, 8 mg, and 12 mg/day, respectively,
compared to 5% of those taking placebo. Dizziness,
somnolence, vertigo, ataxia, anger, irritability, aggression, blurred vision, and dysarthria were the adverse
reactions most commonly leading to discontinuation
and appeared to be dose-dependent. Other adverse effects included fatigue, falls in the elderly, nausea, and
weight gain. A boxed warning recommends monitoring
patients for serious or life-threatening psychiatric and

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9


behavioral adverse reactions including homicidal ideation and threats. Perampanel can cause euphoria; it is
classified as a schedule III controlled substance.
Pregnancy – Perampanel is classified as category C
(developmental toxicity in animals; no adequate and
well-controlled studies in pregnant women) for use
during pregnancy.
DRUG INTERACTIONS — Perampanel clearance can
be significantly affected by enzyme-inducing AEDs.
Serum concentrations of perampanel were reduced
by 67% with coadministration of carbamazepine, 50%
with phenytoin or oxcarbazepine, and 20% with topiramate. Strong CYP3A inducers other than AEDs should
be avoided in patients taking perampanel.8 Strong
CYP3A4 inhibitors may increase perampanel serum
concentrations and extend its half-life. In clinical trials,
perampanel decreased oxcarbazepine clearance by

26%. In patients taking oral contraceptives, perampanel
12 mg/day decreased levonorgestrel levels by 40%;
nonhormonal forms of contraception are recommended
for patients taking perampanel.
DOSAGE AND COST — The recommended starting
dose of perampanel is 2 mg once daily at bedtime
(4 mg in patients taking enzyme-inducing AEDs). The
dose can be increased by no more than 2 mg weekly
to a maximum of 12 mg once daily. Dose increases
should be made more slowly in elderly patients and
those with hepatic impairment. Maximum daily doses
should be lower in patients with mild (6 mg) or moderate (4 mg) hepatic impairment. Perampanel is not
recommended for patients with severe hepatic or renal
impairment.
Patients taking enzyme-inducing AEDs concomitantly
may need higher doses of the drug, but no data are
available; close monitoring is recommended when
enzyme-inducing AEDs are introduced or withdrawn.
The cost for 30 days’ treatment with perampanel 4,
6, or 8 mg/day is $568.80.9 According to the manufacturer, the 10- and 12-mg tablets are not currently
available.
CONCLUSION — Perampanel (Fycompa) appears to
be effective for once-daily adjunctive treatment of partial-onset seizures in patients >12 years old, but it can
cause serious psychiatric adverse effects.
1. Drugs for epilepsy. Treat Guidel Med Lett 2013; 11:9.
2. T Hanada et al. Perampanel: a novel, orally active, noncompetitive
AMPA-receptor antagonist that reduces seizure activity in rodent
models of epilepsy. Epilepsia 2011; 52:1331.
3. JA French et al. Adjunctive perampanel for refractory partial-onset
seizures: randomized phase III study 304. Neurology 2012; 79:589.

10

4. JA French et al. Evaluation of adjunctive perampanel in patients
with refractory partial-onset seizures: results of randomized global
phase III study 305. Epilepsia 2013; 54:117.
5. GL Krauss et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012; 78:
1408.
6. BJ Steinhoff et al. Efficacy and safety of adjunctive perampanel for
the treatment of refractory partial seizures: a pooled analysis of
three phase III studies. Epilepsia 2013; 54:1481.
7. GL Krauss et al. Perampanel, a selective, noncompetitive -amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist,
as adjunctive therapy for refractory partial-onset seizures: interim
results from phase III, extension study 307. Epilepsia 2013; 54:126.
8. Inhibitors and inducers of CYP enzymes and P-glycoprotein. Med
Lett Drugs Ther 2013; 55:e44.
9. Approximate wholesale acquisition cost (WAC). Source:
Analy$ource® Monthly (Selected from FDB MedKnowledge™)
January 5, 2014. Reprinted with permission by FDB, Inc. All rights
reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy.
Actual retail price may be higher.

Certolizumab Pegol (Cimzia) and
Ustekinumab (Stelara) for Psoriatic
Arthritis
Certolizumab pegol (Cimzia – UCB), a tumor necrosis
factor (TNF) inhibitor previously approved for treatment of Crohn’s disease1 and rheumatoid arthritis2,
and ustekinumab (Stelara – Janssen), a human interleukin-12 and -23 antagonist previously approved for
treatment of moderate-to-severe plaque psoriasis3,
have now been approved by the FDA for treatment of

active psoriatic arthritis.
STANDARD TREATMENT — NSAIDs may be tried
first for treatment of psoriatic arthritis, particularly
for mild disease. Methotrexate is generally used for
treatment of moderate-to-severe disease. If there is
minimal improvement or toxicity after 12-16 weeks
of methotrexate treatment, a TNF inhibitor is often
added or substituted.
TNF inhibitors appear to be the most effective treatment available to date for psoriatic arthritis.4 Certolizumab pegol is the fifth TNF inhibitor to be approved
by the FDA for this indication (see Table 1). They
have been effective in reducing disease activity, preventing structural damage, and improving function,
and some patients who have not responded to one
TNF inhibitor have responded to another.5
Ustekinumab plus methotrexate has generally been
used only for patients with psoriasis (not psoriatic arthritis) who do not respond to or cannot tolerate a TNF
inhibitor.6
CLINICAL STUDIES — A randomized, double-blind,
24-week trial (RAPID-PsA) in 409 patients with active psoriatic arthritis found that significantly more

The Medical Letter • Volume 56 • Issue 1435 • February 3, 2014


Table 1. Biologic Agents FDA-Approved for Psoriatic Arthritis
Drug

Source

Some Available
Formulations

Usual Adult Dosage
for Psoriatic Arthritis

Cost1

$2526.50

TNF Inhibitors
Etanercept (Enbrel – Amgen)

Human

25 mg vial; 25 mg/0.5 mL,
50 mg/mL syringe

50 mg SC once/wk

Infliximab (Remicade – Janssen)

Mouse and human

100 mg vial

5 mg/kg IV at 0, 2, and 6 wks,
then 5 mg/kg q8wks

1687.102

Adalimumab (Humira – Abbvie)

Human

40 mg vial; 20 mg/0.4 mL,
40 mg/0.8mL syringe

40 mg SC q2wks

2502.60

Golimumab (Simponi – Janssen)

Human

50 mg/0.5 mL, 100 mg/mL
syringe

50 mg SC once/month

2535.60

Certolizumab pegol (Cimzia – UCB)

Humanized

200 mg vial; 200 mg/mL
syringe

400 mg SC at 0, 2, and
4 wks, then 200 mg
q2wks or 400 mg q4wks

2769.20

Human

45 mg/0.5 mL, 90 mg/mL
syringe

45 mg SC at 0 and 4 wks,
then 45 mg q12wks3

2299.20

Interleukin-12/23 Antagonist
Ustekinumab (Stelara – Janssen)

1. Approximate wholesale acquisition cost (WAC) for 4 weeks’ treatment with the maintenance dosage. Source: Analy$ource® Monthly (Selected from FDB
MedKnowledge™) January 5, 2014. Reprinted with permission by FDB, Inc. All rights reserved. ©2014. www.fdbhealth.com/policies/drug-pricing-policy. Actual retail prices
may be higher.
2. Cost of the drug alone for a 70-kg patient.
3. For patients who also have moderate-to-severe plaque psoriasis and weigh >100 kg, the dosage is 90 mg SC at 0 and 4 weeks, followed by 90 mg every 12 weeks.

patients taking certolizumab pegol had an ACR20
response (20% improvement on the American College of Rheumatology scale) than those treated with
placebo. At week 12, 58% and 52% of patients treated with certolizumab pegol 200 mg q2 weeks and
400 mg q4 weeks, respectively, and 24% of those
treated with placebo had an ACR20 response.7

Exacerbations and new onset of heart failure have occurred with TNF inhibitor treatment. TNF inhibitors have
been associated with development of auto-antibodies,

including anti-nuclear antibodies and anti-dsDNA antibodies, and, rarely, with induction of a lupus-like syndrome. Pancytopenia and demyelinating disorders such
as multiple sclerosis have also been reported.

A trial in 615 patients with active psoriatic arthritis (PSUMMIT 1) found that patients treated with
ustekinumab 45 mg or 90 mg were significantly more
likely to have achieved an ACR20 response at week 24
than those receiving placebo (42% with 45 mg, 50%
with 90 mg, and 23% with placebo). With continued
treatment, responses were maintained at week 52.8

Ustekinumab – Ustekinumab can cause serious infections (especially tuberculosis), malignancies, hypersensitivity reactions, and reversible posterior leukoencephalopathy. Screening for tuberculosis is recommended
before treatment.

ADVERSE EFFECTS — Neither of the clinical trials
for the 2 new indications detected any new safety
issues.
Certolizumab Pegol – Serious infections, including
bacterial sepsis and reactivation of tuberculosis and
hepatitis B virus, have been reported with all TNF
inhibitors, especially during the first 2-7 months of
treatment. These drugs should not be given to patients with active localized or chronic infections. Tuberculin skin testing and chest radiography are recommended before starting anti-TNF therapy.
Lymphoma and other malignancies have been reported
with use of TNF inhibitors in patients with rheumatoid
arthritis, but a cause-and-effect relationship has not
been established. TNF inhibitors generally should not
be used in patients with a recent malignancy.

Pregnancy – All of the TNF inhibitors and ustekinumab
are classified as category B (no evidence of risk in animals; no adequate human studies) for use during pregnancy.
CONCLUSION — Certolizumab pegol (Cimzia) is the

fifth tumor necrosis factor (TNF) inhibitor to be approved
by the FDA for treatment of psoriatic arthritis. There is
no evidence that it offers any advantage over any of
the other drugs in this class. Ustekinumab (Stelara) is
the first interleukin-12/23 antagonist to be approved for
psoriatic arthritis. How it compares to the TNF inhibitors
for this indication remains to be determined.
1. Drugs for inflammatory bowel disease. Treat Guidel Med Lett 2012;
10:19.
2. Drugs for rheumatoid arthritis. Treat Guidel Med Lett 2012; 10:37.
3. Drugs for acne, rosacea and psoriasis. Treat Guidel Med Lett 2013;
11:1.
4. L Eder et al. Tumour necrosis factor  blockers are more effective
than methotrexate in the inhibition of radiographic joint damage
progression among patients with psoriatic arthritis. Ann Rheum
Dis 2013 April 25 (epub).

The Medical Letter • Volume 56 • Issue 1435 • February 3, 2014

11


5. PJ Mease. Psoriatic arthritis – treatment update. Bull NYU Hosp Jt
Dis 2011; 69:243.
6. American Academy of Dermatology Work Group. Guidelines of
care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol 2011; 65:137.
7. PJ Mease et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a phase
3 double-blind randomised placebo-controlled study (RAPID-PsA).
Ann Rheum Dis 2014; 73:48.
8. IB McInnes et al. Efficacy and safety of ustekinumab in patients

with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet
2013; 382:780.

Coming Soon in The Medical Letter:
Afatinib (Gilotrif) for Metastatic Non-Small Cell Lung Cancer
Tbo-Filgrastim (Granix) for Prevention of Febrile Neutropenia
Tobramycin Inhalation Solution (Bethkis) for Cystic Fibrosis
Coming Soon in Treatment Guidelines:
Drugs for Diabetes
Drugs for Hypertension

The Medical Letter

®

On Drugs and Therapeutics
EDITOR IN CHIEF: Mark Abramowicz, M.D.
EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School
EDITOR: Jean-Marie Pflomm, Pharm.D.
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D.,
Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.
CONSULTING EDITORS: Brinda M. Shah, Pharm.D., F. Peter Swanson, M.D.

IN BRIEF

Rosiglitazone (Avandia) Unbound
The FDA has removed prescribing and dispensing
restrictions placed on rosiglitazone (Avandia, and
others) in 2010 because of concerns about its
cardiovascular safety.1 The removal of restrictions was

based on the results of an independent reevaluation
of the RECORD trial, which found no significant
difference between rosiglitazone and metformin/
sulfonylurea in the risk of cardiovascular (or unknown
cause) death, myocardial infarction, or stroke.2
1. FDA Drug Safety Communication: FDA requires removal of some
prescribing and dispensing restrictions for rosiglitazone-containing diabetes medicines. Available at www.fda.gov/drugs/drugsafety/ucm376389.htm. Accessed January 27, 2014.
2. KW Mahaffey et al. Results of a reevaluation of cardiovascular
outcomes in the RECORD trial. Am Heart J 2013; 166:240.

Addendum:
Renal Sympathetic Denervation for Hypertension (Med Lett Drugs Ther 2012; 54:55)
Our July 9, 2012 article on renal sympathetic denervation for multiple-drug resistant hypertension concluded
that the catheter-based procedure (Symplicity Catheter
System – Medtronic) can lower blood pressure in most
patients with hypertension resistant to >3 antihypertensive drugs. That conclusion was based on the results of
2 studies. SYMPLICITY HTN-1 compared outcomes to
baseline blood pressures. SYMPLICITY HTN-2 randomized patients to renal denervation or usual care.
Medtronic has issued a press release (January 9,
2014) announcing that SYMPLICITY HTN-3, a doubleblind trial with sham controls, failed to meet its primary
efficacy endpoint, the change in office blood pressure
from baseline to 6 months (www.medtronic.com).

CONTRIBUTING EDITORS:
Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons
Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical School
Eric J. Epstein, M.D., Albert Einstein College of Medicine
Jane P. Gagliardi, M.D., M.H.S., F.A.C.P Duke University School of Medicine
Jules Hirsch, M.D., Rockefeller University
David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre

Richard B. Kim, M.D., University of Western Ontario
Hans Meinertz, M.D., University Hospital, Copenhagen
Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine
Dan M. Roden, M.D., Vanderbilt University School of Medicine
Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School
F. Estelle R. Simons, M.D., University of Manitoba
Neal H. Steigbigel, M.D., New York University School of Medicine
Arthur M. F. Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University
SENIOR ASSOCIATE EDITOR: Amy Faucard
MANAGING EDITOR: Susie Wong
ASSISTANT MANAGING EDITOR: Liz Donohue
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No quantitative results have been published to date. In
all 3 trials, there were no serious complications of the
procedure.

12

The Medical Letter • Volume 56 • Issue 1435 • February 3, 2014


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®

Online Continuing Medical Education
To take CME exams and earn credit, go to:
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Issue 1435 Questions
(Correspond to questions #13-18 in
Comprehensive Exam #70, available July 2014)

Perampanel (Fycompa) for Epilepsy
1.

In clinical trials, addition of perampanel to other antiepileptic
drugs reduced median 28-day seizure frequency by about:
a. 10-20%
b. 20-30%
c. 40-50%
d. >50%

2.

Adverse effects of perampanel have included:

a. rash
b. reversible posterior leukoencephalopathy
c. homicidal ideation
d. all of the above

3.

Strong enzyme-inducing antiepileptic drugs that can lower serum
concentrations of perampanel include:
a. carbamazepine
b. oxcarbazepine
c. phenytoin
d. all of the above

Certolizumab Pegol (Cimzia) and Ustekinumab (Stelara) for
Psoriatic Arthritis
4.

For treatment of psoriatic arthritis, TNF inhibitors are:
a. often added to or substituted for methotrexate
b. effective in reducing disease activity
c. effective in preventing structural damage
d. all of the above

5.

Both certolizumab pegol and ustekinumab can cause:
a. serious infections
b. closed-angle glaucoma
c. exacerbation of psoriatic skin plaques

d. all of the above

6.

A 31-year-old woman has recently developed mild psoriatic
arthritis. Assuming no contraindications exist, the drug of
choice for this patient would be:
a. an NSAID
b. methotrexate
c. certolizumab pegol
d. ustekinumab

ACPE UPN: Per Issue Exam: 0379-0000-14-435-H01-P; Release: February 3, 2014, Expire: February 3, 2015
Comprehensive Exam 70: 0379-0000-14-070-H01-P; Release: July 2014, Expire: July 2015

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