The medical letter on drugs and therapeutics september 15 2014

The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 ISSUE ISSUE No 1433 1451 Volume 56 September 15, 2014 IN THIS ISSUE Vorapaxar (Zontivity) for Prevention of Thrombotic Cardiovascular Events p 85 Vedolizumab (Entyvio) for Inflammatory Bowel Disease p 86 Efinaconazole Topical Solution (Jublia) for Onychomycosis p 88 Miltefosine (Impavido) for Leishmaniasis p 89 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 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 Objective Drug Reviews Since 1959 Volume 56 ISSUE ISSUE No 1433 1451 Volume 56 ▶ September 15, 2014 Take CME Exams ALSO IN THIS ISSUE Vedolizumab (Entyvio) for Inflammatory Bowel Disease p 86 Efinaconazole Topical Solution (Jublia) for Onychomycosis p 88 Miltefosine (Impavido) for Leishmaniasis p 89 Vorapaxar (Zontivity) for Prevention of Thrombotic Cardiovascular Events The FDA has approved vorapaxar (Zontivity – Merck), an oral protease-activated receptor-1 (PAR-1) antagonist, for use with aspirin and/or clopidogrel to reduce the risk of thrombotic cardiovascular events in patients with peripheral arterial disease or a history of myocardial infarction (MI) It is the first PAR-1 antagonist to be approved by the FDA STANDARD ANTIPLATELET THERAPY — Aspirin plus clopidogrel, prasugrel, or ticagrelor is the standard of care for prevention of thrombotic cardiovascular events in patients with a history of MI Prasugrel and ticagrelor are more effective than clopidogrel, but they have been associated with a higher risk of bleeding In patients with peripheral arterial disease, the standard of care is aspirin alone; if a patient is intolerant to aspirin, clopidogrel can be used.1 Table Antiplatelet Drugs Drug Formulations Usual Maintenance Dosage Clopidogrel – Plavix (Sanofi) Prasugrel – Effient (Lilly) Ticagrelor – Brilinta (AstraZeneca) Vorapaxar – Zontivity2 (Merck) 75, 300 mg tabs 75 mg once/d $193.40 5, 10 mg tabs 10 mg once/d 270.00 90 mg tabs 90 mg bid 251.70 2.08 mg tabs 2.08 mg once/d 267.30 Cost1 Approximate wholesale acquisition cost (WAC) of 30 days' maintenance treatment Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) August 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 Zontivity is available as 2.5-mg vorapaxar sulfate tablets, equivalent to 2.08 mg of vorapaxar ACTIVITY — Thrombin potently activates platelets through an interaction with protease-activated receptors Vorapaxar blocks PAR-1, the major thrombin receptor on platelets, and inhibits thrombin-induced platelet aggregation Table Pharmacology Class Protease-activated receptor-1 (PAR-1) antagonist Formulation 2.08-mg tablets (equivalent to 2.5 mg vorapaxar sulfate) Route Oral Tmax 1-2 hours Half-life (terminal) days Metabolism Hepatic via CYP3A4 and CYP2J2 Elimination Feces (58%), urine (25%) CLINICAL STUDIES — An initial randomized, doubleblind, placebo-controlled trial (TRACER) evaluating the efficacy of vorapaxar in addition to standard therapy in 12,944 patients who had acute coronary syndromes without ST-segment elevation was stopped early because of a significantly increased risk of major bleeding, including intracranial hemorrhage, in vorapaxar-treated patients The preliminary clinical outcomes data showed no significant advantage of vorapaxar over placebo in preventing the primary composite endpoint of death from cardiovascular causes, MI, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.2 FDA approval of vorapaxar was based on a doubleblind trial (TRA 2°P-TIMI 50) in 26,449 patients with peripheral arterial disease or a history of MI or ischemic stroke who were randomized to receive either vorapaxar or placebo, in addition to standard care After years, the data and safety monitoring board recommended that patients with a history of stroke stop taking vorapaxar because of an increased 85 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® risk of intracranial hemorrhage found in such patients; the trial was continued in all other patients At years, cardiovascular death, MI, or stroke (the primary composite efficacy endpoint) had occurred in 9.3% of patients treated with vorapaxar, compared to 10.5% of those given placebo, a statistically significant difference.3 In a prespecified subgroup analysis, among the 17,779 patients with a previous MI, the primary endpoint occurred in 8.1% of those taking vorapaxar compared to 9.7% of those taking placebo, a statistically significant difference.4 In another subgroup analysis, among the 3787 patients who had peripheral arterial disease, vorapaxar was not more effective than placebo in preventing the primary endpoint, but it did significantly reduce the rate of hospitalization for acute limb ischemia (2.3% vs 3.9% with placebo).5 ADVERSE EFFECTS — Vorapaxar labeling warns of an increased bleeding risk with the drug, including intracranial and fatal bleeding, and states that it is contraindicated for use in patients with a history of stroke, transient ischemic attack (TIA), or intracranial hemorrhage, and in patients who have active pathological bleeding In the main clinical trial, moderate or severe bleeding occurred significantly more often in patients taking vorapaxar than in those taking placebo (4.2% vs 2.5%) Intracranial hemorrhage was also significantly more frequent with vorapaxar than with placebo (1.0% vs 0.5%) Other adverse effects that occurred in at least 2% of patients treated with vorapaxar and at a rate at least 10% higher than with placebo included anemia, depression, and rash Vorapaxar is classified as category B (no evidence of harm in animals; no adequate human studies) for use during pregnancy DRUG INTERACTIONS — Vorapaxar increases the risk of bleeding; additive effects may occur with concomitant use of other drugs that can cause bleeding, including nonsteroidal anti-inflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs), or serotonin norepinephrine reuptake inhibitors (SNRIs) It has not been studied in combination with more potent antiplatelet drugs such as prasugrel or ticagrelor; concurrent use of these drugs with vorapaxar should be avoided Vorapaxar is a substrate of CYP3A4; concurrent use with strong CYP3A4 inhibitors or inducers should be avoided.6 86 Vol 56 (1451) September 15, 2014 CONCLUSION — Vorapaxar (Zontivity) appears to be a modestly effective antiplatelet agent with a high risk of serious bleeding, including intracranial hemorrhage It should not be used in patients with a history of stroke or a transient ischemic attack Whether adding vorapaxar to standard therapy (aspirin and/or clopidogrel) offers any advantage over aspirin plus either prasugrel or ticagrelor remains to be established ■ Antithrombotic drugs Treat Guidel Med Lett 2011; 9:61 P Tricoci et al Thrombin-receptor antagonist vorapaxar in acute coronary syndromes N Engl J Med 2012; 366:20 DA Morrow et al Vorapaxar in the secondary prevention of atherothrombotic events N Engl J Med 2012; 366:1404 BM Scirica et al Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial Lancet 2012; 380:1317 MP Bonaca et al Vorapaxar in patients with peripheral artery disease: results from TRA2°P-TIMI 50 Circulation 2013; 127:1522 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 ▶ Vedolizumab (Entyvio) for Inflammatory Bowel Disease The FDA has approved vedolizumab (Entyvio-Takeda), an intravenous integrin receptor antagonist, for treatment of moderate to severe ulcerative colitis or Crohn’s disease in adults who have not responded to, lost response to, or cannot tolerate standard treatment Natalizumab (Tysabri), another integrin receptor antagonist, has been available for several years for treatment of Crohn’s disease and multiple sclerosis.1 STANDARD TREATMENT — Ulcerative Colitis – An aminosalicylate such as mesalamine is generally used first for induction and maintenance of remission in mild to moderate disease An immunomodulator such as azathioprine or mercaptopurine is often used for maintenance of remission in patients with moderate to severe disease Oral corticosteroids are effective for inducing remission in patients with moderate disease refractory to other drugs or in those with severe disease Corticosteroids are used systemically only until acute inflammation is under control, and then are tapered and discontinued Patients with corticosteroidrefractory disease may respond to a TNF inhibitor Crohn’s Disease – Corticosteroids are used to induce remission Azathioprine or mercaptopurine is used for maintenance of remission A TNF inhibitor alone or in combination with azathioprine or mercaptopurine can be used for both induction and maintenance of remission in patients with moderate to severe disease Methotrexate is an alternative to azathioprine and mercaptopurine for maintenance of remission.2 The Medical Letter ® Table Pharmacology Class Integrin receptor antagonist Formulation 300 mg per 20 mL vial (lyophilized powder) Route Intravenous Half-life ~25 days MECHANISM OF ACTION — Binding of the 4β7 integrin (a glycoprotein on the surface of lymphocytes) to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is expressed on the endothelium of intestinal mucosa, is thought to induce migration of lymphocytes to areas of inflammation in the gastrointestinal tract Vedolizumab is a humanized monoclonal antibody that specifically binds to 4β7 integrin, preventing its adhesion to MAdCAM-1 and migration of lymphocytes into the intestinal mucosa Unlike natalizumab, which blocks lymphocyte migration in the brain and gut by inhibiting 4β1 and 4β7 integrins and has been associated with progressive multifocal leukoencephalopathy (PML), vedolizumab apparently does not affect lymphocyte migration in the brain and therefore may not increase the risk of PML.3 CLINICAL STUDIES — Ulcerative Colitis – Use of vedolizumab for induction therapy was studied in a randomized, placebo-controlled, double-blind trial in 374 patients with moderate to severe ulcerative colitis who could not tolerate or had an inadequate response to one or more previous treatments with corticosteroids, immunomodulators, or TNF inhibitors After weeks, the clinical response rate was significantly higher in patients who received vedolizumab than in those who received placebo (47.1% vs 25.5%) Patients who had a clinical response to vedolizumab at weeks were enrolled in a maintenance trial and randomized to continue treatment with the drug every or weeks, or switch to placebo At week 52, clinical remission was achieved by significantly more patients treated with vedolizumab every weeks (41.8%) and every weeks (44.8%) than with placebo (15.9%).4 In a meta-analysis of biologic agents, which included vedolizumab and the TNF inhibitors infliximab, adalimumab, and golimumab, there was no conclusive evidence that any one was more effective than any other in maintaining clinical remission in patients with moderate to severe ulcerative colitis.5 Crohn’s Disease – The efficacy of vedolizumab was assessed in trials in patients with moderate to severe Crohn’s disease who could not tolerate or had an inadequate response to one or more previous Vol 56 (1451) September 15, 2014 treatments with corticosteroids, immunomodulators, or TNF inhibitors The first trial was an induction study in which 368 patients were randomized to vedolizumab or to placebo After weeks, 32 patients (14.5%) in the vedolizumab group and 10 (6.8%) in the placebo group were in clinical remission, a significant difference Clinical response rates with vedolizumab (31.4%) and placebo (25.7%) were not significantly different.6 Patients treated with vedolizumab who achieved a clinical response at weeks were enrolled in a maintenance trial and randomized to continue treatment with vedolizumab every or weeks, or to switch to placebo At week 52, 39.0% of patients in the every-8-week group and 36.4% of patients in the every-4-week group were in clinical remission, compared to 21.6% of those in the placebo group; both differences were significant.6 In another trial, 315 patients who could not tolerate or had an inadequate response to one or more TNF inhibitors were randomized to vedolizumab or to placebo The number of patients who achieved clinical remission at weeks, the primary endpoint, was not significantly different between the two groups (15.2% with vedolizumab vs 12.1% with placebo) The percentage of patients who achieved clinical remission at 10 weeks, a secondary endpoint, was significantly higher with vedolizumab (26.6% vs 12.1%).7 Table Integrin Receptor Antagonists for Inflammatory Bowel Disease Drug Usual Adult Dosage Cost1 Vedolizumab – Entyvio (Takeda) 300 mg IV at weeks 0, 2, and 6; then q8 weeks $4819.00 Natalizumab2 – Tysabri (Biogen Idec) 300 mg IV q4 weeks 9358.00 Approximate wholesale acquisition cost for weeks’ maintenance treatment Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) August 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 Not FDA-approved for treatment of ulcerative colitis ADVERSE EFFECTS — In clinical trials, hypersensitivity reactions to vedolizumab have occurred, including one case of anaphylaxis Patients receiving the drug may have an increased risk of infection Increased transaminases and bilirubin levels have been reported Progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the central nervous system caused by reactivation of the JC virus, has occurred with natalizumab; no cases of PML have been reported to date with vedolizumab 87 The Medical Letter ® Vol 56 (1451) September 15, 2014 Vedolizumab is classified as category B (no evidence of harm in animals; no human studies) for use during pregnancy does not interact with other drugs.3 Laser treatment appears to be at least temporarily effective in improving the appearance of infected nails, but it is expensive.4 DRUG INTERACTIONS — Concomitant use of vedolizumab with TNF inhibitors should be avoided because of the increased risk of infection Administration of live vaccines to patients taking vedolizumab also should be avoided unless the benefit outweighs the risk PHARMACOLOGY — Efinaconazole blocks ergosterol synthesis by inhibiting fungal lanosterol 14α-demethylase, which results in reduced integrity of the fungal cell membrane, morphological hyphal changes, and inhibition of fungal cell growth.5 It is more active in vitro against T rubrum and T mentagrophytes than ciclopirox or itraconazole.6 The low affinity of efinaconazole for keratin allows it to penetrate the nail bed and retain its antifungal activity within the nail plate.7 Topical application of efinaconazole to toenails of healthy volunteers and patients with severe onychomycosis resulted in minimal systemic absorption.8 CONCLUSION — Vedolizumab (Entyvio) can be effective for treatment of moderate to severe ulcerative colitis and Crohn’s disease in patients who had an inadequate response to or could not tolerate standard therapies, including tumor necrosis factor (TNF) inhibitors ■ Natalizumab (Tysabri) for Crohn’s disease Med Lett Drugs Ther 2008; 50:34 Drugs for inflammatory bowel disease Med Lett Drugs Ther 2014; 56:59 L Gilroy and PB Allen Is there a role for vedolizumab in the treatment of ulcerative colitis and Crohn’s disease? Clin Exp Gastroenterol 2014; 7:163 BG Feagan et al Vedolizumab as induction and maintenance therapy for ulcerative colitis N Engl J Med 2013; 369:699 S Danese et al Biological agents for moderately to severely active ulcerative colitis: a systematic review and network metaanalysis Ann Intern Med 2014; 160:704 WJ Sandborn et al Vedolizumab as induction and maintenance therapy for Crohn’s disease N Engl J Med 2013; 369:711 BE Sands et al Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed Gastroenterology 2014; 147:618 ▶ Efinaconazole Topical Solution (Jublia) for Onychomycosis The FDA has approved efinaconazole 10% solution (Jublia – Valeant) for topical treatment of toenail onychomycosis due to Trichophyton rubrum and/or Trichophyton mentagrophytes It is the first topical triazole antifungal drug to be approved for this indication A topical oxaborole antifungal solution, tavaborole 5% (Kerydin – Anacor), also recently approved by the FDA for the same indication will be reviewed in a future issue STANDARD TREATMENT — Toenail onychomycosis is most often caused by the dermatophytes T rubrum and T mentagrophytes, and rarely by yeasts and nondermatophyte molds Oral terbinafine or oral itraconazole is the drug of choice for treatment of dermatophyte toenail onychomycosis, but even with prolonged treatment, cure rates are low and relapse rates are high, and adverse effects and drug interactions are common.1,2 Topical treatment with ciclopirox 8% nail lacquer (Penlac, and generics) is less effective than systemic therapy, but it has no systemic toxicity and 88 CLINICAL STUDIES — FDA approval of efinaconazole 10% topical solution was based on the results of two 52-week randomized, double-blind, vehiclecontrolled trials in adults with distal lateral toenail onychomycosis (20-50% nail involvement without dermatophytomas or matrix involvement) Patients were randomized to efinaconazole or its vehicle alone once daily for 48 weeks In the first study in 870 patients, significantly more patients treated with efinaconazole achieved complete cure (0% clinical involvement of the target toenail plus negative KOH and negative fungal culture) weeks after stopping treatment compared to those treated with the vehicle alone (17.8% vs 3.3%) Table Drugs for Toenail Onychomycosis1 Drug Oral Terbinafine – generic Lamisil (Novartis) Itraconazole – generic Topical Ciclopirox 8% nail lacquer4 – generic Penlac (Valeant) Efinaconazole 10% solution – Jublia (Valeant) Usual Adult Dosage Cost2 250 mg PO once daily x 12 wks3 200 mg PO once daily (or 200 mg bid wk/mo) x mos3 $14.60 614.30 425.30 Once daily x 48 wks drop (2 drops for big toenail) once daily x 48 wks 30.205 784.705 449.006 Nail specimens should be obtained prior to drug therapy to confirm the diagnosis of onychomycosis Approximate wholesale acquisition cost (WAC) for 30 days’ treatment Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) August 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 Dosage adjustment may be needed for renal or hepatic impairment or when used with interacting drugs FDA-approved for treatment of mild-to-moderate distal superficial onychomycosis Cost of a 6.6-mL bottle Cost of a 4-mL bottle The Medical Letter ® In the second study in 785 patients, 15.2% of patients treated with efinaconazole and 5.5% of those treated with the vehicle alone achieved complete cure at 52 weeks, a statistically significant difference Mycologic cure (negative KOH and negative fungal culture) in both studies was achieved in about 55% of patients treated with the active drug and in 17% of those treated with the vehicle alone.9 ADVERSE EFFECTS — The most common adverse effects of efinaconazole topical solution in the clinical studies were ingrown toenails (2.3% of treated patients) and dermatitis, pain, and vesicles at the application site (1.1-2.2%) DOSAGE AND ADMINISTRATION — One drop of efinaconazole 10% solution (2 drops for the big toenail) should be applied to each affected toenail once daily for 48 weeks The drop(s) should be spread to cover the entire toenail (including underneath the nail), the cuticle, and the folds of skin on the sides of the toenail using the built-in flow-through brush applicator provided with the solution The solution should be applied to clean dry toenails and should not be applied within 10 minutes of showering, bathing, or washing the toenails CONCLUSION — Efinaconazole 10% solution (Jublia) appears to be modestly effective in treating toenail onychomycosis How it compares in efficacy to oral antifungal drugs or topical ciclopirox 8% nail lacquer remains to be established It is less likely than oral terbinafine or itraconazole to cause systemic adverse effects or to interact with other drugs ■ Antifungal drugs Treat Guidel Med Lett 2012; 10:61 A Shemer Update: medical treatment of onychomycosis Dermatol Ther 2012; 25:582 AK Gupta et al Therapies for onychomycosis: a systematic review and network meta-analysis of mycological cure J Am Podiatr Med Assoc 2014 July 17 (epub) Laser treatment of onychomycosis Med Lett Drugs Ther 2013; 55:15 Y Tatsumi et al Mechanism of action of efinaconazole, a novel triazole antifungal agent Antimicrob Agents Chemother 2013; 5:2405 WJ Jo Siu et al Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis Antimicrob Agents Chemother 2013; 57:1610 K Sugiura et al The low keratin affinity of efinaconazole contributes to its nail penetration and fungicidal activity in topical onychomycosis treatment Antimicrob Agents Chemother 2014; 58:3837 M Jarratt et al Safety and pharmacokinetics of efinaconazole 10% solution in healthy volunteers and patients with severe onychomycosis J Drugs Dermatol 2013; 12:1010 BE Elewski et al Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies J Am Acad Dermatol 2013; 68:600 Vol 56 (1451) ▶ September 15, 2014 Miltefosine (Impavido) for Leishmaniasis The FDA has approved miltefosine (Impavido – Knight Therapeutics), an oral alkylphosphocholine analog, for treatment of visceral, cutaneous, and mucosal leishmaniasis caused by some Leishmania species It is the first drug to be approved by the FDA for treatment of cutaneous and mucosal leishmaniasis and the first oral drug to be approved for treatment of visceral leishmaniasis Table Specific Leishmania Species for which Miltefosine is FDA-Approved1 Cutaneous L [V.] braziliensis, L [V.] guyanensis, L [V.] panamensis Mucosal L [V.] braziliensis Visceral L donovani FDA-approved for use in patients ≥12 years old who weigh ≥30 kg More than twenty Leishmania species cause infection in humans The efficacy of miltefosine for treatment of other Leishmania species than those listed above has not been evaluated There may be geographic variation in the response of the same Leishmania species to miltefosine LEISHMANIASIS — Leishmania parasites are transmitted to humans through sand fly bites The disease occurs primarily in the tropics, subtropics, and southern Europe; most US patients become infected overseas Cutaneous leishmaniasis usually presents as an ulcerative skin lesion at the site of the sand fly bite The lesion usually resolves spontaneously within several months, but generally leaves a scar Some New World (Western Hemisphere) Leishmania species may disseminate from the skin to the naso-oropharyngeal mucosa, resulting in mucosal leishmaniasis with potential destruction of nasal and oropharyngeal structures Untreated visceral leishmaniasis can be fatal; manifestations include fever, hepatosplenomegaly, and bone marrow involvement with pancytopenia.1 STANDARD TREATMENT – Liposomal amphotericin B (AmBisome) is the treatment of choice for visceral leishmaniasis in the US.2 Drugs used for treatment of cutaneous or mucosal infection in the US have included sodium stibogluconate and amphotericin B (both parenteral drugs), and oral azole antifungal drugs.3 MECHANISM OF ACTION — The exact mechanism of action of miltefosine for treatment of leishmaniasis is unknown, but it may involve alterations in internal lipid metabolism, inhibition of mitochondrial function, modulation of macrophage responses, and induction of apoptosis.4 89 The Medical Letter ® Table Pharmacology Class Alkylphosphocholine analog antileishmanial drug Formulation 50-mg capsules Route Oral Half-life 6-9 days Metabolism Hepatic, primarily by phospholipase D-like cleavage and oxidation to palmitic acid Elimination Urine (