The medical letter on drugs and therapeutics march 31 2014

Golimumab (Simponi) for Ulcerative Colitis The FDA has approved golimumab (Simponi – Janssen), a fully human monoclonal antibody specific for tumor necrosis factor (TNF) alpha, for induction and maintenance of remission in... A Long-Acting Depot Formulation of Testosterone (Aveed) The FDA has approved testosterone undecanoate (Aveed – Endo), an injectable depot formulation, for use in men with hypogonadism who require testosterone replacement therapy. In Brief: Otrexup - A Single-Use Auto-Injector Formulation of Methotrexate The FDA has approved a new injectable formulation of methotrexate (Otrexup – Antares) for use in rheumatoid arthritis and polyarticular juvenile idiopathic arthritis, and for severe...

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) Golimumab (Simponi) for Ulcerative Colitis p 25 A Long-Acting Depot Formulation of Testosterone (Aveed) p 26 In Brief: Otrexup – A Single-Use Auto-Injector Formulation of Methotrexate p 28 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 1439) March 31, 2014 www.medicalletter.org Take CME Exams ALSO IN THIS ISSUE A Long-Acting Depot Formulation of Testosterone (Aveed) p 26 In Brief: Otrexup – A Single-Use AutoInjector Formulation of Methotrexate p 28 Golimumab (Simponi) for Ulcerative Colitis The FDA has approved golimumab (Simponi – Janssen), a fully human monoclonal antibody specific for tumor necrosis factor (TNF) alpha, for induction and maintenance of remission in patients with moderate to severe ulcerative colitis who not respond to or cannot tolerate other therapies or who require continuous treatment with corticosteroids Golimumab was approved earlier for treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.1 It is the third TNF inhibitor to be approved for use in ulcerative colitis.2 TREATMENT OF ULCERATIVE COLITIS — For mild to moderate ulcerative colitis, an aminosalicylate such as mesalamine is generally the first drug tried for induction and maintenance of remission Oral prednisone is effective for inducing remission in patients who not respond to an aminosalicylate or have severe symptoms Corticosteroids are used systemically only until acute inflammation is under control, and then are tapered and discontinued Rectal administration of aminosalicylates and corticosteroids can be effective for treatment of distal disease.3 For moderate to severe disease, a thiopurine (mercaptopurine or azathioprine) is often used as a corticosteroid-sparing agent for maintenance of remission TNF inhibitors are effective for treatment of moderate to severe ulcerative colitis not responding to aminosalicylates or thiopurines or requiring chronic corticosteroids Infliximab and adalimumab have been effective in moderate to severe ulcerative colitis that did not respond to corticosteroids.4 Cyclosporine is an alternative for treatment of severe, steroid-refractory ulcerative colitis CLINICAL STUDIES — FDA approval of golimumab for ulcerative colitis was based on a 6-week induction trial and a 54-week maintenance trial in patients with moderate to severe ulcerative colitis that had not responded to standard treatments In the induction trial, 774 patients were randomized to receive a single dose of golimumab 200 mg or 400 mg or placebo, each followed weeks later by Table TNF Inhibitors for Ulcerative Colitis Route of Administration Some Formulations Usual Adult Dosage Mouse and human Intravenous 100 mg vials Induction: mg/kg at weeks 0, 2, and Maintenance: mg/kg q8 weeks Adalimumab – Humira (Abbvie) Human Subcutaneous 40 mg syringes and pen injectors Induction: 160 mg at week 0, then 80 mg at week Maintenance: 40 mg q2 weeks starting at week 5005.20 Golimumab – Simponi (Janssen) Human Subcutaneous 100 mg syringes and auto-injectors Induction: 200 mg at week 0, then 100 mg at week Maintenance: 100 mg q4 weeks 6234.30 Drug Source Infliximab – Remicade (Janssen) Cost1 $3374.20 Approximate wholesale acquisition cost (WAC) for weeks’ treatment of a 70-kg patient with the maintenance dosage Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) March 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 Costs associated with administration are not included FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 25 half the first dose At weeks, clinical response rates were 51.0% and 54.9% for the groups given 200 mg/100 mg and 400 mg/200 mg, respectively, and 30.3% for those receiving placebo.5 The maintenance trial randomized 464 patients who had responded to golimumab in the induction trial to 100 mg or 50 mg of golimumab or placebo every weeks for 52 weeks The rates of maintained clinical response were significantly higher with golimumab (49.7% with 100 mg, 47.0% with 50 mg) than with placebo (31.2%).6 These rates of response and maintained response are similar to those reported earlier with infliximab and adalimumab.7-11 ADVERSE EFFECTS — TNF inhibitors should not be given to patients with active localized or chronic infections Serious infections, including bacterial sepsis and reactivation of tuberculosis and hepatitis B, have been reported with all TNF inhibitors, especially during the first 2-7 months of treatment In the 54-week maintenance trial of golimumab, patients were found to have tuberculosis during the study; all of these patients were taking corticosteroids at the time of enrollment in the induction trial There were deaths during the maintenance trial, including one from disseminated tuberculosis and one from sepsis 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, but a cause-and-effect relationship has not been established A meta-analysis of 22 clinical trials found that use of TNF inhibitors for up to one year in patients with inflammatory bowel disease did not result in an increased risk of malignancy.12 TNF inhibitors generally should not be used in patients with a recent malignancy Concomitant use of TNF inhibitors with other biological agents such as abatacept (Orencia) or anakinra (Kineret) further increases the risk of infection and is not recommended Patients being treated with TNF inhibitors should not receive live vaccines Exacerbations and new onset of heart failure have occurred during treatment with TNF inhibitors These agents have been associated with development of autoantibodies, including anti-nuclear antibodies and antidsDNA antibodies, and, rarely, with induction of a lupuslike syndrome Pancytopenia and demyelinating disorders such as multiple sclerosis have also been reported CONCLUSION — Golimumab (Simponi) appears to be effective for treatment of ulcerative colitis that has 26 not responded to other therapies or requires continuous treatment with corticosteroids No clinical trials are available comparing it to other TNF inhibitors that are approved for the same indication and have been in use longer □ Golimumab (Simponi) for inflammatory arthritis Med Lett Drugs Ther 2009: 51:55 Drugs for inflammatory bowel disease Treat Guidel Med Lett 2012: 10:19 Budesonide (Uceris) for ulcerative colitis Med Lett Drugs Ther 2013; 55:23 A Kornbluth et al Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee Am J Gastroenterol 2010; 105:501 WJ Sandborn et al Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 2014; 146:85 WJ Sandborn et al Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis Gastroenterology 2014; 146:96 P Rutgeerts et al Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 2005; 353:2462 W Reinisch et al Long-term infliximab maintenance therapy for ulcerative colitic; the ACT-1 and -2 extension studies Inflamm Bowel Dis 2012; 18:201 W Reinisch et al Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial Gut 2011; 60:780 10 W Reinisch et al 52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants Inflamm Bowel Dis 2013; 19:1700 11 WJ Sandborn et al Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis Gastroenterology 2012; 142:257 12 CJ Williams et al Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor- therapy in inflammatory bowel disease Aliment Pharmacol Ther 2014; 39:447 A Long-Acting Depot Formulation of Testosterone (Aveed) The FDA has approved testosterone undecanoate (Aveed – Endo), an injectable depot formulation, for use in men with hypogonadism who require testosterone replacement therapy HYPOGONADISM — Failure of the testes to produce adequate amounts of testosterone can lead to loss of energy, decreased libido, erectile dysfunction, decreased axillary and pubic hair, loss of muscle mass, anemia, and osteoporosis Testosterone serum concentrations decrease by about 1-2% per year after age 40 The normal range (usually 300-1000 ng/dL) is based on serum concentrations in young men Older men with signs and symptoms of hypogonadism may have levels 1500 ng/dL was 7.7% A prospective uncontrolled trial in 1438 men with below-normal serum testosterone concentrations treated with up to testosterone undecanoate injections (formulations available outside the US) over a period of 9-12 months found that mental and psychosexual function improved markedly, mean waist circumference decreased by cm, and the incidence of moderate or severe erectile dysfunction decreased from 67% to 19%.1 ADVERSE EFFECTS — In clinical trials, the most common adverse effects of testosterone undecanoate injections were acne, injection site pain, and an increase in prostate specific antigen levels above ng/mL, all of which occurred in about 5% of patients Postmarketing surveillance of testosterone undecanoate products approved in other countries found that some patients developed pulmonary oil microembolism (POME) reactions that have included cough, dyspnea, throat tightening, chest pain, dizziness, and syncope occurring during or immediately after injection of the drug Some of these episodes lasted several hours, and some required hospitalization Life-threatening anaphylactic reactions have also been reported As a result, the US labeling includes a boxed warning requiring that patients be observed for 30 minutes after injections of Aveed, and use of the drug is restricted to healthcare providers and settings certified through a Risk Evaluation and Mitigation Strategy (REMS) program The recently published results of large retrospective studies have prompted the FDA to investigate the possibility of an increased risk of stroke, heart attack, and death in men treated with testosterone replacement products.2 An earlier randomized, placebo-controlled trial in 209 men >65 years old with low serum testoster- The Medical Letter • Volume 56 • Issue 1439 • March 31, 2014 27 one concentrations had found an increased incidence of cardiovascular adverse events in those treated with testosterone gel for months (23 vs with placebo).3 CONCLUSION — The new long-acting depot formulation of testosterone undecanoate (Aveed) offers a convenient schedule of administration of the hormone, but at the risk of serious pulmonary oil microembolism reactions and anaphylaxis M Zitzmann et al IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men J Sex Med 2013; 10:579 In brief: Testosterone and cardiovascular risk Med Lett Drugs Ther 2014; 56:17 S Basaria et al Adverse events associated with testosterone administration N Engl J Med 2010; 363:109 IN BRIEF Otrexup – A Single-Use Auto-Injector Formulation of Methotrexate The FDA has approved a new injectable formulation of methotrexate (Otrexup – Antares) for use in rheumatoid arthritis and polyarticular juvenile idiopathic arthritis, and for severe psoriasis in adults On its web site (www otrexup.com), the manufacturer states: “Otrexup is the first subcutaneous (SC) methotrexate (MTX) for selfadministration delivered once weekly by auto-injector.” Methotrexate has been available as a once-weekly injection (IM or SC) for these indications for many years,1 but not specifically for self-administration and not in a singledose auto-injector Methotrexate is generally given orally, but injectable formulations may be helpful for patients who have adverse gastrointestinal effects from the oral formulation or lose benefit over time because of poor absorption Otrexup auto-injectors are available in strengths of 10, 15, 20, and 25 mg of methotrexate per 0.4 mL The usual dosage of methotrexate for patients with rheumatoid arthritis ranges from 7.5 to 25 mg once weekly Otrexup should be administered SC in the abdomen or thigh Four 25-mg auto-injectors cost $548.00, compared to $5.00 for a single 4-mL vial of generic methotrexate containing 25 mg/mL.2 Nevertheless, some patients with rheumatoid arthritis who find it difficult to draw up methotrexate solution from a vial and inject it with a syringe may prefer Otrexup Coming Soon in The Medical Letter: Anoro Ellipta: An Inhaled Umeclidinium/Vilanterol Combination for COPD Ibrutinib (Imbruvica) for Chronic Lymphocytic Leukemia Sorafenib (Nexavar) for Thyroid Cancer 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 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exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1439 Questions (Correspond to questions #37-42 in Comprehensive Exam #70, available July 2014) Golimumab (Simponi) for Ulcerative Colitis Mild to moderate ulcerative colitis is generally treated first with: a prednisone b an aminosalicylate c a TNF inhibitor d a thiopurine In clinical induction trials, the rate of response to golimumab was about: a 30% b 50% c 70% d 90% Use of TNF inhibitors has been associated with: a reactivation of TB b reactivation of hepatitis B c heart failure d all of the above A Long-Acting Depot Formulation of Testosterone (Aveed) A 64-year-old man complaining of fatigue, depression, and erectile dysfunction asks if Aveed could relieve his symptoms You could tell him that: a FDA approval of the drug was based on its effect on testosterone levels b injections of testosterone products similar to Aveed have clearly been shown to improve mood and erectile dysfunction in older men c there is no reason to believe Aveed could have any adverse effects d all of the above After the first doses, Aveed is injected every: a weeks b weeks c 10 weeks d 26 weeks Aveed contains testosterone mixed in: a saline b mineral oil c a liposome suspension d castor oil ACPE UPN: Per Issue Exam: 0379-0000-14-439-H01-P; Release: March 31, 2014, Expire: March 31, 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 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Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org ... interns, residents and fellows in the US and Canada The Medical Letter • Volume 56 • Issue 1439 • March 31, 2014 The Medical Letter ® Online Continuing Medical Education To take CME exams and earn credit,... 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