The medical letter on drugs and therapeutics march 3 2014

In Brief: Testosterone and Cardiovascular Risk Prompted by the recent publication of 2 retrospective studies, the FDA has announced that it is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone... Riociguat (Adempas) for Pulmonary Hypertension The FDA has approved the sGC stimulator riociguat (rye" oh sig'' ue at; Adempas – Bayer) for oral treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary... Low-Dose Diclofenac (Zorvolex) for Pain The FDA has approved Zorvolex (Iroko), a low-dose oral formulation of the relatively COX-2 selective NSAID diclofenac, for treatment of mild-to-moderate acute pain in adults.

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) In Brief: Testosterone and Cardiovascular Risk p 17 Riociguat (Adempas) for Pulmonary Hypertension p 17 Low-Dose Diclofenac (Zorvolex) for Pain p 19 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 publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 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 1437) March 3, 2014 ALSO IN THIS ISSUE Low-Dose Diclofenac (Zorvolex) for Pain p 19 IN BRIEF Testosterone and Cardiovascular Risk Prompted by the recent publication of retrospective studies, the FDA has announced that it is investigating the risk of stroke, heart attack, and death in men taking FDA-approved testosterone products.1 The first study examined the records of 8709 men with low testosterone levels (65 years old it was 2.19 and in younger men with a history of heart disease it was 2.90 In men who received a prescription for sildenafil or tadalafil, the rate ratio was 1.08 for all ages, 1.15 for those >65 years old, and 1.40 for younger men with a history of heart disease.3 A recent meta-analysis of randomized, placebo-controlled trials of testosterone therapy also found an increased risk of cardiovascular-related events in men treated with the hormone (odds ratio [OR] 1.54; 95% CI 1.09-2.18); an analysis by funding source found that the risk was greater in trials not funded by the pharmaceutical industry (OR 2.06 vs 0.89).4 www.medicalletter.org Take CME Exams FDA Drug Safety Communication January 31, 2014: FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products Available at www.fda.gov/drugs/drugsafety/ucm383904.htm Accessed February 24, 2014 R Vigen et al Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels JAMA 2013; 310:1829 WD Finkle et al Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men PLoS One 2014; 9:e85805 L Xu et al Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebocontrolled randomized trials BMC Med 2013; 11:108 Riociguat (Adempas) for Pulmonary Hypertension The FDA has approved the sGC stimulator riociguat (rye” oh sig’ ue at; Adempas – Bayer) for oral treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) following surgery or when surgery is not an option It is the first drug to be approved for treatment of CTEPH Table Pharmacology Drug class Soluble guanylate cyclase (sGC) stimulator Route Oral Formulation 0.5, 1, 1.5, 2, 2.5 mg tablets Tmax 1.5 hrs Metabolism Primarily by CYP1A1, 3A, 2C8 and 2J2 Elimination Feces (53%); urine (40%) Elimination half-life 12 hrs (patients), hrs (healthy subjects) DRUGS FOR PAH — Current management of PAH usually includes warfarin (Coumadin, and others) and furosemide (Lasix, and generics) Oral drugs approved for PAH include the phosphodiesterase type (PDE5) inhibitors sildenafil (Revatio, and generics) and tadalafil (Adcirca), the endothelin receptor antagonists bosentan (Tracleer), ambrisentan (Letairis), and, most recently, macitentan (Opsumit), a nonselective endothelin receptor antagonist derived from bosentan.1 Patients with more advanced disease can be treated with a systemic prostacyclin (see Table 2) FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 17 Table Some Drugs for Pulmonary Arterial Hypertension Drug Route Some Formulations Usual Adult Dosage Cost1 0.5, 1, 1.5, 2, 2.5 mg tabs 1-2.5 mg tid $7500.00 Soluble Guanylate Cyclase (sGC) Stimulator Riociguat – Adempas (Bayer) Oral Endothelin Receptor Antagonists Nonselective Macitentan – Opsumit (Actelion) Oral 10 mg tabs 10 mg once/day 6840.00 Bosentan – Tracleer (Actelion) Oral 62.5, 125 mg tabs 62.5 mg bid (for wks) then 125 mg bid 7050.00 Oral 5, 10 mg tabs 5-10 mg once/day 6893.30 Oral 20 mg tabs 20 mg tabs 20 mg tid 239.40 2102.84 Oral 20 mg tabs 40 mg once/day 1899.00 Iloprost – Ventavis (Actelion) Inhalation 10 and 20 mcg ampules 2.5-5 mcg/inhalation 6-9 times/day Epoprostenol – generic Flolan (Gilead) Veletri (Actelion) Continuous IV infusion 0.5 and 1.5 mg in 17 mL single-use vials 0.5 and 1.5 mg in 10 mL single-use vials 20-40 ng/kg/min4 1145.545 1850.745 1849.925 Continuous SC or IV infusion Inhalation 1, 2.5, 5, 10 mg/mL multi-dose vials 1.74 mg/2.9 mL ampules8 40-160 ng/kg/min7 7132.955 Selective Ambrisentan – Letairis (Gilead) Phosphodiesterase (PDE5) Inhibitors Sildenafil – generic Revatio2 (Pfizer) Tadalafil – Adcirca (Eli Lilly) Prostacyclins Treprostinil6 – Remodulin (United Therapeutics) Tyvaso (United Therapeutics) breaths (54 mcg) qid 15,210.003 13,018.009 Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at the lowest usual dosage Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) February 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 Ancillary costs will substantially increase the cost of non-oral drugs Also available in an IV formulation for patients on oral sildenafil who are temporarily unable to take oral medication Also approved in a powder for oral suspension Cost of 180 ampules of either strength Initial dosage recommended is ng/kg/min with subsequent increases of ng/kg/min every 15 minutes or longer as tolerated Dosage requirements tend to increase over time Average dosage after months is about 20-40 ng/kg/min Cost for a 70-kg patient The FDA recently approved an extended-release oral formulation of treprostinil (Orenitram) that will be available soon Initial dosage recommended is 1.25 ng/kg/min, or half if poorly tolerated, with subsequent increases of 1.25 ng/kg/min weekly for the first weeks, then 2.5 ng/kg/min weekly thereafter Average dosage after months is about 60 ng/kg/min Initial dosage is breaths (18 mcg) times daily, or 1-2 breaths if poorly tolerated then increasing to breaths The dosage should be increased by an additional breaths at 1-2 week intervals as tolerated The target and maximum dosage is breaths (54 mcg) times daily Cost of foil pouches containing ampules each TREATMENT OF CTEPH — In CTEPH, residual thromboemboli obstruct pulmonary arteries, leading to an increase in pulmonary vascular resistance and subsequently to progressive pulmonary hypertension and right heart failure The treatment of choice is pulmonary endarterectomy, which can be curative but is not an option in many patients because of distal occlusion or comorbidities About 10% of patients who undergo surgery continue to experience pulmonary hypertension.2 Drugs for PAH have been used off-label to treat patients with CTEPH.3 MECHANISM OF ACTION — Riociguat is a soluble guanylate cyclase (sGC) stimulator sGC binds to nitric oxide (NO), forming an enzyme that promotes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP) Pulmonary hypertension is associated with impaired synthesis of NO and insufficient stimulation of the NO-sGC-cGMP pathway Riociguat acts both by directly stimulating sGC inde- 18 pendently of NO, and by increasing the sensitivity of sGC to NO CLINICAL STUDIES — PAH – In a 12-week, doubleblind trial (PATENT-1), 443 patients with symptomatic PAH were randomized to individually adjusted dosages of riociguat capped at either 1.5 or 2.5 mg times daily, or to placebo.4 At the end of the study, the mean 6-minute walk distance was longer by 31 meters in the 1.5-mg group and by 30 meters in the 2.5-mg group, compared to a decrease of meters in the placebo group Time to clinical worsening, a secondary endpoint, was also longer in patients treated with riociguat CTEPH – A 16-week, double-blind trial (CHEST-1) in 261 patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension despite surgery found that riociguat titrated to a maximum of 2.5 mg times daily increased 6-minute walk distance by 39 meters, compared to a decrease of meters with placebo.5 The Medical Letter • Volume 56 • Issue 1437 • March 3, 2014 Extension Trials – In long-term extensions of both trials (PATENT-2 and CHEST-2), treatment was unblinded after weeks Exploratory analyses at 12 weeks found that patients taking riociguat increased their 6-minute walk distance from the original baseline by 53 meters in PATENT-2 and by 63 meters in CHEST-2.4,5 ADVERSE EFFECTS — Adverse effects of riociguat (>5%) that occurred more frequently than with placebo in clinical trials were headache, dyspepsia/gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation Hypotension occurred in 10% of patients taking riociguat compared to 4% of those taking placebo Serious hemorrhagic events, including one fatal case, occurred in 2.4% of patients treated with the drug and in none with placebo PREGNANCY — Riociguat is contraindicated for use during pregnancy (category X) It is available for women only through a restricted access program DRUG INTERACTIONS — Because of the risk of hypotension, riociguat is contraindicated for use with nitrates, nitric oxide donors (such as amyl nitrite), PDE5 inhibitors (such as sildenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline) Concomitant use of riociguat with strong CYP and Pglycoprotein/breast cancer resistance protein (P-gp/ BCRP) inhibitors (such as ketoconazole, itraconazole, and ritonavir) can increase riociguat serum concentrations and the risk of hypotension Plasma concentrations of riociguat are reduced by 5060% in smokers compared to nonsmokers Antacids such as aluminum hydroxide/magnesium hydroxide reduce absorption of riociguat DOSAGE AND ADMINISTRATION — The recommended starting dosage of riociguat is mg times daily The dose can be increased by 0.5 mg every weeks up to the maximum of 2.5 mg times daily In patients who cannot tolerate the drug’s hypotensive effects, or in those taking concomitant strong CYP and P-gp/BCRP inhibitors, the starting dosage can be lowered to 0.5 mg times daily Riociguat dosages higher than 2.5 mg times daily may be considered for patients who smoke Dosage reductions may be necessary for patients who stop smoking Antacids should not be taken within hour of taking riociguat CONCLUSION — Riociguat (Adempas) can improve exercise capacity in patients with pulmonary arterial hypertension (PAH) and in those with chronic thromboembolic pulmonary hypertension (CTEPH) □ Macitentan (Opsumit) for pulmonary arterial hypertension Med Lett Drugs Ther 2014; 56:15 J Pepke-Zaba et al Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry Circulation 2011; 124:1973 M Delcroix Chronic post-embolic pulmonary hypertension: a new target for medical therapies? Eur Respir Rev 2013; 22:258 HA Ghofrani et al Riociguat for the treatment of pulmonary arterial hypertension N Engl J Med 2013; 369:330 HA Ghofrani et al Riociguat for the treatment of chronic thromboembolic pulmonary hypertension N Engl J Med 2013; 369:319 Low-Dose Diclofenac (Zorvolex) for Pain The FDA has approved Zorvolex (Iroko), a low-dose oral formulation of the relatively COX-2 selective NSAID diclofenac, for treatment of mild-to-moderate acute pain in adults Zorvolex is available as 18- and 35-mg capsules Other oral formulations of diclofenac include immediaterelease, extended-release, and enteric-coated tablets and capsules in strengths ranging from 25 to 100 mg Diclofenac is also available topically as a transdermal patch (Flector), a gel (Voltaren Gel), and a solution (Pennsaid) THE NEW FORMULATION — Each capsule of Zorvolex contains diclofenac as submicron particles The reduction in particle size increases surface area, leading to faster dissolution and absorption of the drug A single-dose crossover study compared the new 35-mg formulation of diclofenac to diclofenac potassium 50 mg in healthy subjects Taken without food, Tmax was about hour for both formulations; Cmax and AUC were about 26% and 23% lower, respectively, with the new formulation Taking Zorvolex with food delayed its Tmax by 2.32 hours and reduced its Cmax by 60% and its AUC by 11% CLINICAL STUDIES — Approval of Zorvolex was based on the results of a double-blind clinical trial in 428 patients with moderate-to-severe pain following bunionectomy Patients were randomized to diclofenac 18 mg or 35 mg times daily, celecoxib 200 mg twice daily after a 400-mg loading dose, or placebo At 12 hours, pain intensity with diclofenac 18 and 35 mg was reduced from baseline by 48% and 51%, respectively, compared to 24% with placebo At 24 hours, pain intensity was reduced by 69% and 73% versus 52% All of these differences from placebo were statistically significant Compared with celecoxib, overall reductions in pain intensity were greater with diclofenac 35 mg and similar with diclofenac 18 mg.1 The Medical Letter • Volume 56 • Issue 1437 • March 3, 2014 19 In a randomized, double-blind trial in 305 patients with osteoarthritis, diclofenac 35 mg three times daily for 12 weeks was significantly more effective than placebo in relieving pain; twice-daily administration of the drug was not significantly better than placebo.2 ADVERSE EFFECTS — NSAIDs frequently cause small increases in aminotransferase activity; serious hepatotoxicity is rare, but may occur more frequently with diclofenac An increased risk of serious cardiovascular events has been reported with some NSAIDs; the risk appeared to be highest with diclofenac.3 In the 12-week osteoarthritis trial, no serious gastrointestinal, cardiovascular, or renal adverse events were reported with diclofenac 35 mg times daily.4 DRUG INTERACTIONS — Diclofenac is metabolized primarily by CYP2C9; co-administration with CYP2C9 inhibitors (such as fluconazole) may increase its serum concentrations and toxicity.5 Like other NSAIDs, diclofenac may decrease the effectiveness of diuretics, beta blockers, ACE inhibitors and some other antihypertensive drugs, may increase the toxicity of lithium, methotrexate, and cyclosporine, and may increase the risk of gastrointestinal bleeding in patients taking warfarin DOSAGE, ADMINISTRATION, AND COST — The recommended dosage of Zorvolex is 18 mg or 35 mg three times daily It can be taken with or without food, but its effectiveness may be reduced when taken with food A single Zorvolex capsule of either strength costs $2.50, compared to about $0.70 for one 50-mg tablet of generic diclofenac potassium.6 CONCLUSION — NSAIDs can cause serious adverse effects and should be used in the lowest effective dosage Zorvolex, a new low-dose oral formulation of diclofenac, is more effective than placebo in relieving acute pain How it compares in efficacy or safety to oral immediaterelease diclofenac potassium, which is available generically, or to any other traditional NSAID, is unknown □ A Gibofsky et al Lower-dose diclofenac submicron particle capsules provide early and sustained acute patient pain relief in a phase study Postgrad Med 2013; 125:130 A Gibofsky et al A phase study of lower-dose diclofenac submicron particle capsules demonstrates effective pain relief in patients with osteoarthritis Osteoarthritis Cartilage 2013; 21(4) suppl:S267 Abs 518 Drugs for pain Treat Guidel Med Lett 2013; 11:31 C Young and MC Hochberg Safety of lower-dose diclofenac submicron particle capsules dosed up to 12 weeks in patients with osteoarthritis Arthritis Rheum 2013; 65(10) suppl:S915 Abs 2149 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 Approximate wholesale acquisition cost (WAC) Source: Analy$ource Monthly (Selected from FDB MedKnowledge™) February 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 20 Coming Soon in The Medical Letter: Golimumab (Simponi) for Ulcerative Colitis Drugs for Gout Tobramycin Inhalation (Bethkis) for Cystic Fibrosis Coming Soon in Treatment Guidelines: Drugs for Peptic Ulcer Disease and GERD 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 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 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sildenafil d all of the above Riociguat taken for 12 weeks increased the 6-minute walk distance from baseline by about: a 10 meters b 30 meters c 50 meters d 70 meters In clinical trials, 10% of patients treated with riociguat experienced: a hypotension b hypertension c bradycardia d tachycardia Low-Dose Diclofenac (Zorvolex) for Pain Compared to diclofenac potassium 50 mg, the AUC and Cmax of Zorvolex 35 mg were about: a 10% higher b 25% higher c 25% lower d 50% lower A 56-year-old woman with mild osteoarthritis of the knee treated fairly successfully with acetaminophen has seen advertisements for Zorvolex and asks if she could try it instead She has had atrial fibrillation for 10 years, for which she takes warfarin and a beta blocker You could tell her that: a Zorvolex may be less convenient than acetaminophen because taking it with food could decrease its effectiveness b diclofenac could increase the risk of gastrointestinal bleeding in patients taking warfarin c diclofenac could decrease the effectiveness of the beta blocker d all of the above Compared to other NSAIDs, diclofenac is more likely to cause: a gastric ulcer b renal toxicity c serious hepatotoxicity d all of the above ACPE UPN: Per Issue Exam: 0379-0000-14-437-H01-P; Release: March 3, 2014, Expire: March 3, 2015 Comprehensive Exam 70: 0379-0000-14-070-H01-P; Release: July 2014, Expire: July 2015 Over The Medical Letter® Continuing Medical Education Program medicalletter.org/cme Earn Up to 26 Category AMA PRA credits Choose CME from The Medical Letter in the format that’s right for you! Comprehensive Exam – Available online or in print to Medical Letter subscribers, this 78 question test enables you to earn 13 credits immediately upon successful completion of the test A score of 70% or greater is required to pass the exam Our Comprehensive exams allow you to test at your own pace in the comfort of your home or office Comprehensive tests are offered every January and July enabling you to earn up to 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Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org ... Copyright 2014 ISSN 15 23- 2859 The Medical Letter • Volume 56 • Issue 1 437 • March 3, 2014 The Medical Letter ® Online Continuing Medical Education To take CME exams and earn credit, go to: medicalletter.org/CMEstatus... 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. .. information call: 800-211-2769 The Medical Letter ® On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume