The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1490 Volume 56 March 14, 2016 IN THIS ISSUE Safety of Testosterone Replacement Therapy p 33 Zarxio – A Filgrastim Biosimilar p 34 Low-Dose Meloxicam (Vivlodex) for Osteoarthritis Pain p 35 Isavuconazonium Sulfate (Cresemba) – A New Antifungal Drug p 37 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S 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 U.S 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 Published by The Medical Letter, Inc • A Nonprofit Organization Revised 5/2/16: Footnote has been added to Table 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 Volume 58 ISSUE ISSUE No 1433 1490 Volume 56 ▶ March 14, 2016 ALSO IN THIS ISSUE Zarxio – A Filgrastim Biosimilar p 34 Low-Dose Meloxicam (Vivlodex) for Osteoarthritis Pain p 35 Isavuconazonium Sulfate (Cresemba) – A New Antifungal p 37 Safety of Testosterone Replacement Therapy Three coordinated double-blind, placebo-controlled clinical trials have evaluated the efficacy of one year of testosterone replacement therapy in improving sexual function, physical function, and vitality in a total of 790 men ≥65 years old with moderately low serum testosterone concentrations and symptoms suggesting hypoandrogenism Sexual function improved modestly, and there appeared to be marginal benefits in some areas of physical function and vitality as well The trials were not designed to evaluate the safety of testosterone replacement therapy.1 ADVERSE EFFECTS — Testosterone administration has been associated with development of acne, gynecomastia, peripheral edema, and polycythemia Injections of testosterone undecanoate rarely have caused pulmonary oil microembolism (POME) and anaphylactic reactions The main concern with testosterone replacement therapy, however, has been the possibility that it could increase the risk of prostate cancer and cardiovascular disease Table Some Testosterone Replacement Products Drug Injectable Testosterone cypionate – generic Depo-Testosterone (Pfizer) Testosterone enanthate – generic Delatestryl (Endo) Testosterone undecanoate – Aveed (Endo) Transdermal Androderm (Actavis) Testosterone 1% gel packet – generic3 AndroGel 1.62% (Abbvie) Axiron (Lilly) Testosterone 2% gel – generic Fortesta (Endo) Testosterone 1% gel – generic Vogelxo (Upsher Smith) Testim (Auxilium/Endo) Intranasal Natesto (Trimel/Endo) Buccal Striant (Auxilium/Endo) Some Available Formulations Usual Adult Dosage Cost1 1, 10 mL vial (100 mg/mL, 200 mg/mL)2,7 50-400 mg IM q2-4 wks 50-400 mg IM q2-4 wks 750 mg IM at and wks, then q10 wks $45.30 73.50 68.00 82.80 850.00 mg once nightly 50 mg once/d 471.30 mL vial (200 mg/mL)7 mL vial (250 mg/mL) 2, mg/d patch 2.5 g gel packet (25 mg test.); g gel packet (50 mg test.); 75 g MDP (12.5 mg test in 1.25 g gel/act) 1.25 g gel packet (20.25 mg test.); 2.5 g gel packet (40.5 mg test.); 75 g MDP (20.25 mg test in 1.25 g gel/act) 90 mL MDP (30 mg test in 1.5 mL soln/act) 60 g MDP (10 mg test in 0.5 g gel/act) 40.5 mg once/d 60 mg once/d4 40 mg once/d 374.30 489.00 521.80 341.30 383.50 309.60 445.50 490.20 g tube of gel (50 mg test.); g gel packet (50 mg test.)5; 88 g MDP (12.5 mg test in 1.25 g gel/act) g tube of gel (50 mg test.) 50 mg once/d 11 g MDP (5.5 mg test in 0.122 g gel/act) 11 mg tid6 650.70 30 mg buccal tablet 30 mg bid 545.50 act = actuation; MDP = metered-dose pump; test = testosterone Approximate wholesale acquisition cost (WAC) for one 10-mL vial (100 mg/mL) of testosterone cypionate, one 5-mL vial of testosterone enanthate, one 3-mL vial of Aveed, or a 30-day supply of transdermal, intranasal, or buccal formulations at the usual adult dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly February 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drugpricing-policy Cost of administration is not included The 100 mg/mL formulation is only available in a 10-mL vial AndroGel 1%, the reference product for these formulations, is no longer manufactured Should be administered as pump actuation (30 mg) to each axilla Tubes and packets are therapeutically equivalent to Testim Should be administered as pump actuation (5.5 mg) in each nostril Vial should be discarded within 28 days after being opened or accessed (United States Pharmacopeia General Chapter 797) 33 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® Prostate Cancer – Testosterone replacement therapy has been associated with increases in serum prostate-specific antigen (PSA) concentrations In the coordinated trials, which excluded men at high risk for prostate cancer, a PSA increase of ≥1.0 ng/mL occurred in 23 men treated with testosterone and treated with placebo Four men developed prostate cancer during the trials or in the subsequent year; three were in the testosterone group Large randomized controlled trials are lacking, but recent reviews have found no convincing evidence that higher testosterone levels increase the risk of prostate cancer.2,3 Cardiovascular Disease – Some studies have found an association between testosterone replacement therapy and cardiovascular events In the coordinated trials, men in each treatment group had a major cardiovascular event In an earlier 6-month randomized trial in 209 men ≥65 years old with a high prevalence of cardiac risk factors, 23 treated with testosterone gel had cardiovascularrelated adverse events, compared to who received placebo (HR 2.4; p=0.05).4 A meta-analysis of randomized, placebo-controlled trials also found an increased risk of cardiovascular-related adverse events in men treated with testosterone (OR 1.54; 95% CI 1.09-2.18); an analysis by funding source found that the risk was greater in trials not sponsored by the pharmaceutical industry (OR 2.06 vs 0.89).5 Other studies have not found an association between testosterone replacement therapy and cardiovascular risk, and some have found a reduced incidence of myocardial infarction and mortality in men treated with testosterone.6-8 CONCLUSION — The safety of testosterone replacement therapy remains unclear There is no convincing evidence to date that it increases the risk of prostate cancer Some studies have found an increased incidence of cardiovascular events in men treated with testosterone, but others have not ■ PJ Snyder et al Effects of testosterone treatment in older men N Engl J Med 2016; 374:611 JE Michaud et al Testosterone and prostate cancer: an evidence-based review of pathogenesis and oncologic risk Ther Adv Urol 2015; 7:378 P Boyle et al Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate specific antigen (PSA): a meta-analysis BJU Int 2016 January 18 (epub) S Basaria et al Adverse events associated with testosterone administration N Engl J Med 2010; 363:109 34 Vol 58 (1490) March 14, 2016 L Xu et al Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials BMC Med 2013; 11:108 G Corona et al Cardiovascular risk associated with testosterone-boosting medications: a systematic review and metaanalysis Expert Opin Drug Saf 2014; 13:1327 R Sharma et al Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men Eur Heart J 2015; 36:2706 A Morgentaler et al Testosterone therapy and cardiovascular risk: advances and controversies Mayo Clin Proc 2015; 90:224 ▶ Zarxio – A Filgrastim Biosimilar The FDA has approved filgrastim-sndz (Zarxio – Sandoz), a biosimilar of the recombinant human granulocyte colony-stimulating factor filgrastim (G-CSF; Neupogen), which has been available in the US since 1991 Zarxio is the first biosimilar product to be approved in the US; it has been available in Europe as Zarzio since 2009 Filgrastim : fil gra' stim Pronunciation Key Zarxio : zar' zee oh BIOSIMILARS — The FDA defines a biosimilar as a biologic product that is highly similar to an approved biologic product (reference product) with no clinically meaningful differences in safety, purity, or potency; minor differences in clinically inactive components are allowed An approved biosimilar product must have the same mechanism of action, route of administration, dosage form, and strength as the reference product Biosimilars can only be approved for the indications for which the reference product is approved; they may be approved for fewer indications than the reference product A biosimilar that is approved as an “interchangeable product” (see Table 1) can be substituted by a pharmacist for the reference product.1 Table FDA Criteria for Interchangeability of Biosimilars ▶ The biosimilar product can be expected to produce the same clinical result as the reference product in any given patient ▶ If the biosimilar product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biosimilar product and the reference product is not greater than the risk of using the reference product without such alternation or switch Zarxio was approved for all of the same indications as the US-licensed reference product Neupogen (see Table 2), but was not reviewed for interchangeability CLINICAL STUDIES — In a phase 1, randomized, double-blind, two-way crossover trial in 28 healthy subjects, no statistically significant pharmacokinetic The Medical Letter Vol 58 (1490) ® Table Approved Indications for Neupogen and Zarxio ▶ Decrease the incidence of infection‚ as manifested by febrile neutropenia‚ in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a significant incidence of severe neutropenia with fever ▶ Reduce the time to neutrophil recovery and the duration of fever, following induction or consolidation chemotherapy treatment of patients with acute myeloid leukemia ▶ Reduce the duration of neutropenia and neutropeniarelated clinical sequelae‚ e.g.‚ febrile neutropenia, in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation ▶ Mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis ▶ Reduce the incidence and duration of sequelae of severe neutropenia (e.g.‚ fever‚ infections‚ oropharyngeal ulcers) in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia or pharmacodynamic differences were detected between 10 mcg/kg doses of filgrastim-sndz and Neupogen The safety profiles of the two products were also similar.2 In a double-blind noninferiority trial, 218 women with breast cancer who were being treated with myelosuppressive chemotherapy were randomized to receive mcg/kg/day of subcutaneous Zarxio or Neupogen, or an alternating course of the two drugs over six chemotherapy cycles Doses were administered from day of each cycle until the absolute neutrophil count recovered or for a maximum of 14 days The mean duration of severe neutropenia in cycle 1, the primary endpoint, was similar with Zarxio and Neupogen Alternating between the two products produced no clinically meaningful differences in efficacy or safety.3 Table Neupogen and Zarxio Drug Available Formulations Cost1 Filgrastim – 300 mcg/0.5 mL, 480 mcg/0.8 mL Neupogen (Amgen) prefilled syringe; 300 mcg/1 mL, $516.45 480 mcg/1.6 mL vial Filgrastim-sndz – Zarxio (Sandoz) 300 mcg/0.5 mL, 480 mcg/0.8 mL prefilled syringe 438.98 Approximate WAC for one 480 mcg/0.8 mL prefilled syringe WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly February 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy ADVERSE EFFECTS — In clinical trials, there were no significant differences in adverse effects between Zarxio and Neupogen The most common doseand cycle-related adverse effects of filgrastim have been pyrexia, pain (including bone and chest pain), rash, thrombocytopenia, nausea, fatigue, dizziness, cough, and dyspnea March 14, 2016 CONCLUSION — Filgrastim-sndz (Zarxio) is the first product to be approved by the FDA as a biosimilar It is similar to filgrastim (Neupogen) in efficacy and safety, and it costs less ■ FDA Biosimilars Guidances Available at: www.fda.gov/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ ucm290967.htm Accessed March 3, 2016 F Sörgel et al Comparability of biosimilar filgrastim with originator filgrastim: protein characterization, pharmacodynamics, and pharmacokinetics BioDrugs 2015; 29:123 K Blackwell et al Comparison of EP2006, a filgrastim biosimilar, to the reference: a phase III, randomized, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy Ann Oncol 2015; 26:1948 ▶ Low-Dose Meloxicam (Vivlodex) for Osteoarthritis Pain The FDA has approved Vivlodex (Iroko), a low-dose formulation of the nonsteroidal anti-inflammatory drug meloxicam (Mobic, and generics), for management of osteoarthritis pain According to the manufacturer, the new formulation aligns with stronger FDA warnings about the cardiovascular risks of NSAIDs and the recommendation to use the lowest possible doses of these drugs.1 Pronunciation Key Meloxicam : mel ox' i kam Vivlodex : viv loe' dex STANDARD TREATMENT — Acetaminophen is generally the first-line pharmacologic treatment for osteoarthritis pain Full doses of NSAIDs are more effective than full doses of acetaminophen, but NSAIDs have many more adverse effects, especially in elderly patients Intra-articular injection of a corticosteroid is a reasonable alternative Opioids can be used as a last resort for treatment of intractable osteoarthritis pain.2 THE NEW FORMULATION — Vivlodex is available as 5- and 10-mg capsules; standard meloxicam tablets contain 7.5 or 15 mg of the drug Like Zorvolex (diclofenac)3 and Tivorbex (indomethacin),4 two other low-dose NSAIDs available from the same manufacturer, Vivlodex is formulated as capsules containing submicron particles Absorption of meloxicam occurs more rapidly with the capsules than with standard tablets In a study comparing the new 10-mg capsules with 15-mg tablets in fasting healthy adults, mean maximum serum concentrations (Cmax) of meloxicam were 35 The Medical Letter Vol 58 (1490) ® Table Meloxicam Products Meloxicam Available Formulations generic 7.5, 15 mg tabs Mobic (Boehringer Ingelheim) Vivlodex (Iroko) 5, 10 mg caps Usual Adult Dosage Cost1 7.5-15 mg once/d $2.30 208.60 5-10 mg once/d 594.003 Approximate WAC for 30 days’ treatment with the lowest usual dosage WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price Source: AnalySource® Monthly February 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Also available as a 7.5 mg/5 mL PO suspension The 5- and 10-mg strengths cost the same similar with the two formulations, but the median time to reach peak serum concentrations (Tmax) was shorter with the new formulation (2 vs hours) Mean systemic meloxicam exposure (AUC) was 33% lower with the low-dose capsules.5 As with the standard formulation, taking the new meloxicam capsules with food decreases the rate but not the extent of absorption (Tmax delayed by hours, mean Cmax 22% lower, no significant effect on AUC) CLINICAL STUDIES — FDA approval of Vivlodex was based on the results of a randomized, double-blind trial in 403 patients ≥40 years old with confirmed hip or knee osteoarthritis who had experienced significant pain flares after discontinuation of acetaminophen or an NSAID Patients were randomized to receive 5- or 10-mg capsules of meloxicam or placebo once daily for 12 weeks Both the 5- and 10-mg capsules reduced pain significantly more than placebo and were similar in efficacy.6 ADVERSE EFFECTS — In the 12-week clinical trial, only a small percentage of patients reported adverse effects; diarrhea, nausea, and abdominal discomfort occurred in 2-3% of patients taking low-dose meloxicam versus 0-1% of those taking placebo No serious adverse effects were reported Dyspepsia and GI ulceration, perforation, and bleeding can occur with all NSAIDs Serious GI complications may occur without warning High doses, prolonged use, previous peptic ulcer disease, concomitant use of systemic corticosteroids or aspirin (even 81 mg/day), excessive alcohol intake, and advanced age increase the risk of these complications All NSAIDs inhibit renal prostaglandins, decrease renal blood flow, cause fluid retention, and may cause 36 March 14, 2016 hypertension and renal failure in some patients, particularly the elderly Diminished renal function or decreased effective intravascular volume due to diuretic therapy, cirrhosis, or heart failure increases the risk of NSAID-induced renal toxicity Use of NSAIDs has also been associated with an increased risk of myocardial infarction and stroke, sometimes occurring during the first few weeks of treatment, in patients with and without risk factors for cardiovascular disease NSAIDs frequently cause small elevations of hepatic transaminases; serious hepatotoxicity is rare PREGNANCY — Use of NSAIDs in the third trimester of pregnancy can cause premature closure of the fetal ductus arteriosus In animal studies, NSAIDs have not been teratogenic, but they can delay parturition, leading to an increased incidence of stillbirth DRUG INTERACTIONS — NSAIDs may decrease the effectiveness of diuretics, beta-blockers, ACE inhibitors, and some other antihypertensive drugs, and may increase the toxicity of lithium and methotrexate If taken with warfarin, they can increase the INR Concomitant use of NSAIDs with warfarin or other anticoagulants is generally discouraged Patients taking aspirin for cardiovascular protection should not take NSAIDs regularly (except for celecoxib) because they can interfere with the antiplatelet effect of aspirin CONCLUSION — Low-dose meloxicam (Vivlodex) appears to be effective in relieving osteoarthritis pain, but how it compares in efficacy and safety to standard-dose meloxicam, which costs much less, is unknown NSAIDs can be dangerous, particularly in elderly patients Acetaminophen is preferred for first-line treatment of osteoarthritis pain ■ FDA Drug Safety Communication: FDA strengthens warnings that non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can cause heart attacks or strokes July 9, 2015 Available at: www.fda.gov/Drugs/DrugSafety/ucm451800.htm Accessed March 3, 2016 Drugs for osteoarthritis Med Lett Drugs Ther 2014; 56:80 Low-dose diclofenac (Zorvolex) for pain Med Lett Drugs Ther 2014; 56:19 In brief: Low-dose indomethacin (Tivorbex) for pain Med Lett Drugs Ther 2014; 56:64 A Hussaini et al Pharmacokinetic properties of low-dose SoluMatrix meloxicam in healthy adults Clin Rheumatol 2015 Dec (epub) R Altman et al Efficacy and safety of low-dose SoluMatrix meloxicam in the treatment of osteoarthritis pain: a 12-week, phase study Curr Med Res Opin 2015; 31:2331 The Medical Letter ▶ ® Isavuconazonium Sulfate (Cresemba) – A New Antifungal The FDA has approved isavuconazonium sulfate (Cresemba – Astellas) for intravenous and oral treatment of invasive aspergillosis and invasive mucormycosis in adults Isavuconazonium sulfate is a prodrug of isavuconazole, a broad-spectrum triazole antifungal Pronunciation Key Isavuconazonium : eye" sa vue koe" na zoe' nee um Isavuconazole: eye" sa vue kon' a zole Cresemba : cree sem' bah STANDARD TREATMENT — Voriconazole (Vfend, and generics) is the preferred treatment for invasive aspergillosis Some experts recommend addition of an echinocandin (see Table 2), but the role of combination therapy for initial treatment has not been well established.1 A lipid formulation of amphotericin B (AmBisome, Abelcet) is generally used in patients who cannot tolerate voriconazole Patients who not respond to monotherapy are usually treated with an echinocandin in addition to voriconazole or a lipid formulation of amphotericin B Posaconazole (Noxafil) has been used off-label as salvage therapy Invasive mucormycosis is generally treated with a lipid formulation of amphotericin B and surgical debridement Posaconazole has been used off-label for oral step-down therapy in patients who have responded to amphotericin B and as salvage therapy Vol 58 (1490) March 14, 2016 Table Pharmacology of Isavuconazole Class Triazole antifungal Formulation 186 mg capsules (100 mg isavuconazole); 372 mg single-use vials containing lyophilized powder for reconstitution (200 mg isavuconazole) Route Oral or IV Metabolism Hepatic via CYP3A4 and 3A5, followed by UGT Bioavailability 98% Tmax Oral: 2-3 hours Half-life IV : 130 hours Elimination Oral: Urine (