The medical letter on drugs and therapeutics february 3 2014

• 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofi t Publication IN THIS ISSUE starts on next page Perampanel Fycompa for Epilepsy ...,,,,,,....p 9 Certolizumab Pegol Cimzia and

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On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofi t Publication

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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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

Table 1 Pharmacology

Drug class Noncompetitive AMPA receptor antagonist

Formulation 2, 4, 6, 8, 10, 12 mg fi lm-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 53-136 h (25 h with the enzyme-inducing

(terminal) AED carbamazepine)

Elimination Feces (48%); urine (22%)

Perampanel (per am’ pa nel; Fycompa – Eisai), a fi

rst-in-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-hy-droxy-5-methyl-4-isoxazolepropionic acid) receptors

are a subtype of glutamate receptors Perampanel is a

noncompetitive antagonist of AMPA receptors on

post-synaptic neurons In vitro, it inhibits AMPA-dependent

increases in intracellular calcium, but the mechanism by

which it reduces seizure activity is unclear.2

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-tients >12 years old with refractory partial-onset sei-zures Each trial was divided into 3 periods: baseline (6 weeks), titration (6 weeks), and maintenance (13 weeks).The patients in these trials generally were tak-ing 2-3 antiepileptic drugs (AEDs) before entertak-ing 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 signifi cantly lowered serum con-centrations of perampanel.3-5

A pooled analysis of all 3 studies found that addi-tion of perampanel 4, 8, or 12 mg/day reduced me-dian 28-day seizure frequency from baseline during

19 weeks of treatment (the primary endpoint) by 23-29% compared to 13% with placebo The responder rate (>50% reduction in seizure frequency during the maintenance period compared to baseline) was 29-35% with perampanel 4-12 mg/day compared to 19% with placebo The differences from placebo were sta-tistically signifi cant for all 3 doses of perampanel, but increasing the dose from 8 to 12 mg/day often did not improve effi cacy A 2-mg/day dose used in one of the trials did not show a statistically signifi cant 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

percent-ages 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, aggres-sion, blurred viaggres-sion, and dysarthria were the adverse reactions most commonly leading to discontinuation and appeared to be dose-dependent Other adverse ef-fects included fatigue, falls in the elderly, nausea, and weight gain A boxed warning recommends monitoring patients for serious or life-threatening psychiatric and

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

Certolizumab Pegol (Cimzia) and Ustekinumab (Stelara) for Psoriatic

Arthritis

Certolizumab pegol (Cimzia – UCB), a tumor necrosis

factor (TNF) inhibitor previously approved for treat-ment of Crohn’s disease1 and rheumatoid arthritis2,

and ustekinumab (Stelara – Janssen), a human

inter-leukin-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 treat-ment available to date for psoriatic arthritis.4 Certoli-zumab 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, pre-venting 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 ar-thritis) 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 ac-tive psoriatic arthritis found that significantly more

behavioral adverse reactions including homicidal

ide-ation and threats Perampanel can cause euphoria; it is

classifi ed as a schedule III controlled substance

Pregnancy – Perampanel is classifi ed 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 signifi cantly 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

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

mod-erate (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

manu-facturer, the 10- and 12-mg tablets are not currently

available

CONCLUSION — Perampanel (Fycompa) appears to

be effective for once-daily adjunctive treatment of

par-tial-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

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 per-ampanel for refractory partial-onset seizures Neurology 2012; 78: 1408.

6 BJ Steinhoff et al Effi cacy 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 -amino-3-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.

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.

patients taking certolizumab pegol had an ACR20

response (20% improvement on the American

Col-lege of Rheumatology scale) than those treated with

placebo At week 12, 58% and 52% of patients

treat-ed with certolizumab pegol 200 mg q2 weeks and

400 mg q4 weeks, respectively, and 24% of those

A trial in 615 patients with active psoriatic

arthri-tis (PSUMMIT 1) found that patients treated with

ustekinumab 45 mg or 90 mg were signifi cantly 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

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

pa-tients with active localized or chronic infections

Tu-berculin skin testing and chest radiography are

rec-ommended 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

Some Available Usual Adult Dosage

TNF Inhibitors

Etanercept (Enbrel – Amgen) Human 25 mg vial; 25 mg/0.5 mL, 50 mg SC once/wk $2526.50

50 mg/mL syringe

Infl iximab (Remicade – Janssen) Mouse and human 100 mg vial 5 mg/kg IV at 0, 2, and 6 wks, 1687.10 2

then 5 mg/kg q8wks

Adalimumab (Humira – Abbvie) Human 40 mg vial; 20 mg/0.4 mL, 40 mg SC q2wks 2502.60

40 mg/0.8mL syringe

Golimumab (Simponi – Janssen) Human 50 mg/0.5 mL, 100 mg/mL 50 mg SC once/month 2535.60

syringe

Certolizumab pegol (Cimzia – UCB) Humanized 200 mg vial; 200 mg/mL 400 mg SC at 0, 2, and 2769.20

syringe 4 wks, then 200 mg

q2wks or 400 mg q4wks

Interleukin-12/23 Antagonist

Ustekinumab (Stelara – Janssen) Human 45 mg/0.5 mL, 90 mg/mL 45 mg SC at 0 and 4 wks, 2299.20

syringe then 45 mg q12wks 3

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.

Table 1 Biologic Agents FDA-Approved for Psoriatic Arthritis

Exacerbations and new onset of heart failure have oc-curred with TNF inhibitor treatment TNF inhibitors have been associated with development of auto-antibodies, including nuclear antibodies and dsDNA anti-bodies, and, rarely, with induction of a lupus-like syn-drome Pancytopenia and demyelinating disorders such

as multiple sclerosis have also been reported

Ustekinumab – Ustekinumab can cause serious

infec-tions (especially tuberculosis), malignancies, hypersen-sitivity reactions, and reversible posterior leukoenceph-alopathy Screening for tuberculosis is recommended before treatment

Pregnancy – All of the TNF inhibitors and ustekinumab

are classifi ed as category B (no evidence of risk in ani-mals; no adequate human studies) for use during preg-nancy

CONCLUSION — Certolizumab pegol (Cimzia) is the

fi fth 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 fi rst 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 infl ammatory 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®

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 Pfl omm, Pharm.D

ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D.,

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CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D CONTRIBUTING EDITORS:

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David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre Richard B Kim, M.D., University of Western Ontario

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Copyright 2014 ISSN 1523-2859

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

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

Addendum:

Renal Sympathetic Denervation for

Hyper-tension (Med Lett Drugs Ther 2012; 54:55)

Our July 9, 2012 article on renal sympathetic

denerva-tion 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

antihyperten-sive drugs That conclusion was based on the results of

2 studies SYMPLICITY HTN-1 compared outcomes to

baseline blood pressures SYMPLICITY HTN-2

random-ized patients to renal denervation or usual care

Medtronic has issued a press release (January 9,

2014) announcing that SYMPLICITY HTN-3, a

double-blind trial with sham controls, failed to meet its primary

effi cacy endpoint, the change in offi ce blood pressure

from baseline to 6 months (www.medtronic.com)

No quantitative results have been published to date In

all 3 trials, there were no serious complications of the

procedure

Dis 2011; 69:243.

6 American Academy of Dermatology Work Group Guidelines of

care for the management of psoriasis and psoriatic arthritis:

sec-tion 6 Guidelines of care for the treatment of psoriasis and

psori-atic arthritis: case-based presentations and evidence-based

con-clusions J Am Acad Dermatol 2011; 65:137.

7 PJ Mease et al Effect of certolizumab pegol on signs and

symp-toms 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 Effi cacy and safety of ustekinumab in patients

with active psoriatic arthritis: 1 year results of the phase 3,

multi-centre, double-blind, placebo-controlled PSUMMIT 1 trial Lancet

2013; 382:780.

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 signifi cant

difference between rosiglitazone and metformin/

sulfonylurea in the risk of cardiovascular (or unknown

1 FDA Drug Safety Communication: FDA requires removal of some

prescribing and dispensing restrictions for

rosiglitazone-contain-ing diabetes medicines Available at

www.fda.gov/drugs/drugsafe-ty/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.

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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:

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

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1 Review the effi cacy and safety of perampanel (Fycompa) for adjunctive treatment of partial-onset seizures.

2 Review the effi cacy and safety of certolizumab pegol (Cimzia) and ustekinumab (Stelara) for treatment of psoriatic

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