The Medical Letter ® On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) Perampanel (Fycompa) for Epilepsy .,,,,,, p 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 Important Copyright Message The Medical Letter® publications are protected by US and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with US and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 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 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 randomized, double-blind, placebo-controlled trials in a total of about 1500 pa- www.medicalletter.org Take CME Exams tients >12 years old with refractory partial-onset seizures Each trial was divided into 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 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 doses of perampanel, but increasing the dose from 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 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 mg, 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 FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 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 mg once daily at bedtime (4 mg in patients taking enzyme-inducing AEDs) The dose can be increased by no more than 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 mg/day is $568.80.9 According to the manufacturer, the 10- and 12-mg tablets are not currently available CONCLUSION — Perampanel (Fycompa) appears to be effective for once-daily adjunctive treatment of partial-onset seizures in patients >12 years old, but it can cause serious psychiatric adverse effects Drugs for epilepsy Treat Guidel Med Lett 2013; 11:9 T Hanada et al Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy Epilepsia 2011; 52:1331 JA French et al Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304 Neurology 2012; 79:589 10 JA French et al Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305 Epilepsia 2013; 54:117 GL Krauss et al Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures Neurology 2012; 78: 1408 BJ Steinhoff et al Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies Epilepsia 2013; 54:1481 GL Krauss et al Perampanel, a selective, noncompetitive -amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, extension study 307 Epilepsia 2013; 54:126 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 Approximate wholesale acquisition cost (WAC) Source: Analy$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 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 Biologic Agents FDA-Approved for Psoriatic Arthritis Drug Source Some Available Formulations Usual Adult Dosage for Psoriatic Arthritis Cost1 $2526.50 TNF Inhibitors Etanercept (Enbrel – Amgen) Human 25 mg vial; 25 mg/0.5 mL, 50 mg/mL syringe 50 mg SC once/wk Infliximab (Remicade – Janssen) Mouse and human 100 mg vial mg/kg IV at 0, 2, and wks, then mg/kg q8wks 1687.102 Adalimumab (Humira – Abbvie) Human 40 mg vial; 20 mg/0.4 mL, 40 mg/0.8mL syringe 40 mg SC q2wks 2502.60 Golimumab (Simponi – Janssen) Human 50 mg/0.5 mL, 100 mg/mL syringe 50 mg SC once/month 2535.60 Certolizumab pegol (Cimzia – UCB) Humanized 200 mg vial; 200 mg/mL syringe 400 mg SC at 0, 2, and wks, then 200 mg q2wks or 400 mg q4wks 2769.20 Human 45 mg/0.5 mL, 90 mg/mL syringe 45 mg SC at and wks, then 45 mg q12wks3 2299.20 Interleukin-12/23 Antagonist Ustekinumab (Stelara – Janssen) Approximate wholesale acquisition cost (WAC) for weeks’ treatment with the maintenance dosage Source: Analy$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 Cost of the drug alone for a 70-kg patient For patients who also have moderate-to-severe plaque psoriasis and weigh >100 kg, the dosage is 90 mg SC at and 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 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 Drugs for inflammatory bowel disease Treat Guidel Med Lett 2012; 10:19 Drugs for rheumatoid arthritis Treat Guidel Med Lett 2012; 10:37 Drugs for acne, rosacea and psoriasis Treat Guidel Med Lett 2013; 11:1 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 PJ Mease Psoriatic arthritis – treatment update Bull NYU Hosp Jt Dis 2011; 69:243 American Academy of Dermatology Work Group Guidelines of care for the management of psoriasis and psoriatic arthritis: section 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 PJ Mease et al Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a phase double-blind randomised placebo-controlled study (RAPID-PsA) Ann Rheum Dis 2014; 73:48 IB McInnes et al Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 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 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 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 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 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 PRODUCTION COORDINATOR: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona FULFILLMENT & SYSTEMS MANAGER: Cristine Romatowski DIRECTOR OF MARKETING COMMUNICATIONS: Joanne F Valentino VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy Founded in 1959 by Arthur Kallet and Harold Aaron, M.D Copyright and Disclaimer: The Medical Letter is an independent nonprofit organization that provides health care professionals with unbiased drug prescribing recommendations The editorial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission Subscription Services Mailing Address: The Medical Letter, Inc 145 Huguenot St Ste 312 New Rochelle, NY 10801-7537 Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 Web Site: www.medicalletter.org E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Subscriptions (US): year - $98; years - $189; years - $279 $49.00 per year for students, interns, residents and fellows in the US and Canada E-mail site license inquiries to: info@medicalletter.org or call 800-211-2769 x315 Special fees for bulk subscriptions Special classroom rates are available Back issues are $12 each Major credit cards accepted Copyright 2014 ISSN 1523-2859 No quantitative results have been published to date In all trials, there were no serious complications of the procedure 12 The Medical Letter • Volume 56 • Issue 1435 • February 3, 2014 The Medical Letter ® Online Continuing Medical Education To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1435 Questions (Correspond to questions #13-18 in Comprehensive Exam #70, available July 2014) Perampanel (Fycompa) for Epilepsy 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% Adverse effects of perampanel have included: a rash b reversible posterior leukoencephalopathy c homicidal ideation d all of the above 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 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 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 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; 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Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org ... February 3, 2014 The Medical Letter ® Online Continuing Medical Education To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1 435 Questions (Correspond to questions # 13- 18.. .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 1 435 ) February 3, ... on controlled clinical trials, and on the opinions of its consultants The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the