The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1486 Volume 56 January 18, 2016 IN THIS ISSUE Durlaza – A 24-Hour Extended-Release Aspirin p Fluad – An Adjuvanted Seasonal Influenza Vaccine for Older Adults p Talimogene Laherparepvec (Imlygic) for Unresectable Melanoma p Elvitegravir (Vitekta) for HIV p 10 Mepolizumab (Nucala) for Severe Eosinophilic Asthma p 11 Correction p 12 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 Volume 58 ISSUE ISSUE No 1433 1486 Volume 56 ▶ January 18, 2016 ALSO IN THIS ISSUE Fluad – An Adjuvanted Seasonal Influenza Vaccine for Older Adults p Talimogene Laherparepvec (Imlygic) for Unresectable Melanoma p Elvitegravir (Vitekta) for HIV p 10 Mepolizumab (Nucala) for Severe Eosinophilic Asthma p 11 Durlaza — A 24-Hour ExtendedRelease Aspirin The FDA has approved Durlaza (New Haven Pharmaceuticals), a 24-hour extended-release (ER) aspirin formulation available only by prescription, for secondary prevention of myocardial infarction (MI) and stroke Pronunciation Key Durlaza: dur lah’ za RATIONALE — Aspirin’s antiplatelet effects are irreversible and persist for the life of the platelet Immediate-release (IR) aspirin is cleared from serum within hours after a dose New platelets released into the systemic circulation after IR aspirin is cleared will be active until the next dose is taken Patients with diabetes and coronary artery disease (CAD) may have high platelet turnover; a study in patients with CAD and type diabetes treated with once-daily low-dose IR aspirin found increased platelet aggregation at the end of the 24-hour dosing interval.1 An ER formulation that releases acetylsalicylic acid (ASA) over a 24-hour period could inhibit platelet aggregation throughout the dosing interval CLINICAL STUDIES — Approval of Durlaza was based on earlier clinical trials that established the efficacy of low-dose aspirin in preventing secondary cardiovascular events and on a bioequivalence study in which it was compared to IR aspirin Fifty healthy adults were each randomized to receive of possible single doses of ER aspirin (20, 40, 81, 162.5, or 325 mg) and IR aspirin (5, 10, 20, 40, or 81 mg) in a total of periods, each separated by a washout period of ≥14 days Both ER and IR aspirin produced dose-dependent inhibition of all pharmacodynamic parameters (serum thromboxane B2 [TXB2], urine 11-dehydro-TXB2, and arachidonic acid-induced platelet aggregation) A 2-fold higher dose of ER aspirin was required to produce the same level of TXB2 inhibition as IR aspirin Dose-normalized peak serum concentrations of ASA were 6-fold higher with IR aspirin than with ER aspirin ASA concentrations were measurable for up to hours after a dose of IR aspirin, and for hours, which was the last study assessment, with the ER formulation.2 In an unpublished 14-day study (available only as an abstract), the antiplatelet effects of Durlaza persisted for 24 hours in 40 patients with type diabetes and cardiovascular risk factors.3 DOSAGE, ADMINISTRATION, AND COST — Durlaza is available as 162.5-mg capsules The recommended dosage is one capsule taken once daily with a full glass of water The capsule must be swallowed whole and should not be crushed or chewed Taking Durlaza with alcohol could result in immediate release of aspirin; it should not be taken within hours before or one hour after drinking alcohol One Durlaza capsule costs $6.4 CONCLUSION — There is no evidence that the new extended-release aspirin formulation (Durlaza), which is available only by prescription, is as safe or as effective as low-dose immediate-release aspirin in preventing cardiovascular events ■ KH Christensen et al Reduced antiplatelet effect of aspirin during 24 hours in patients with coronary artery disease and type diabetes Platelets 2015; 26:230 J Patrick et al A randomized trial to assess the pharmacodynamics and pharmacokinetics of a single dose of an extendedrelease aspirin formulation Postgrad Med 2015; 127:573 PA Gurbel et al Durability of antiplatelet effect of a novel extended-release formulation of acetylsalicylic acid, Durlaza in patients with diabetes Circulation 2015; 132 (suppl 3): Abstract 19503 Approximate WAC 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 January 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ▶ ® Fluad – An Adjuvanted Seasonal Influenza Vaccine for Older Adults The FDA has approved Fluad (Seqirus), an adjuvanted trivalent seasonal influenza vaccine, for immunization of adults >65 years old It will become available later this year for use during the 2016-2017 influenza season Fluad is the second influenza vaccine to be approved in the US specifically for older adults; Fluzone High-Dose was the first.1 Fluad has been available in other countries for many years THE NEW VACCINE — Older adults may have a lower antibody response to influenza vaccination than younger adults and their antibody levels may decline more rapidly Fluad contains MF59, an oil-in-water emulsion of squalene oil that increases the immune response by recruiting antigen-presenting cells to the injection site and promoting uptake of influenza virus antigens Like all trivalent seasonal influenza vaccines available in the US, Fluad contains antigens from two influenza A viruses and one influenza B virus It may also contain trace amounts of egg protein, neomycin, kanamycin, and/or barium Table Seasonal Influenza Vaccines for Older Adults Vaccine Formulation Composition Fluad (Seqirus) 0.5 mL syringe Trivalent; 15 mcg HA from each strain Fluzone High-Dose (Sanofi Pasteur) 0.5 mL syringe Trivalent; 60 mcg HA from each strain HA = hemagglutinin antigen CLINICAL STUDIES — FDA approval of Fluad was based on the results of a randomized controlled trial in 7082 adults >65 years old that found the immunogenicity of the new vaccine to be noninferior to that of an unadjuvanted trivalent seasonal influenza vaccine (Agriflu) Compared to Agriflu, Fluad elicited significantly greater antibody responses against all three strains weeks after vaccination, but the differences did not meet the prespecified criteria for superiority Pain and tenderness at the injection site occurred more frequently with Fluad than with the unadjuvanted vaccine.2 In observational studies, older adults who received the adjuvanted influenza vaccine were less likely than those who received an unadjuvanted standard-dose trivalent vaccine to have symptomatic influenza illness or be hospitalized for influenza.3,4 Versus Fluzone High-Dose – No studies are available comparing Fluad with Fluzone High-Dose Fluzone High-Dose has induced significantly greater antibody responses and was more effective than standard-dose Vol 58 (1486) January 18, 2016 vaccines in preventing laboratory-confirmed influenza in older adults.5,6 Injection-site reactions occur more frequently with Fluzone High-Dose than with standarddose vaccines CONCLUSION — Fluad appears to be more immunogenic in adults ≥65 years old than an unadjuvanted trivalent seasonal influenza vaccine How Fluad compares to Fluzone High-Dose in efficacy and safety remains to be determined ■ Influenza vaccine for 2015-2016 Med Lett Drugs Ther 2015; 57:125 SE Frey et al Comparison of the safety and immunogenicity of an MF59-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects Vaccine 2014; 32:5027 PG Van Buynder et al The comparative effectiveness of adjuvanted and unadjuvanted trivalent inactivated influenza vaccine (TIV) in the elderly Vaccine 2013; 31:6122 S Mannino et al Effectiveness of adjuvanted influenza vaccination in elderly subjects in northern Italy Am J Epidemiol 2012; 176:527 CA DiazGranados et al Efficacy of high-dose versus standarddose influenza vaccine in older adults N Engl J Med 2014; 371:635 CA DiazGranados et al Prevention of serious events in adults 65 years of age or older: a comparison between high-dose and standard-dose inactivated influenza vaccines Vaccine 2015; 33:4988 ▶ Talimogene Laherparepvec (Imlygic) for Unresectable Melanoma The FDA has approved talimogene laherparepvec (Imlygic – Amgen), a genetically modified herpes simplex virus, for intralesional treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with melanoma that has recurred following surgery It is the first oncolytic virotherapy to become available in the US Pronunciation Key Talimogene laherparepvec: tal im’ oh jeen la her” pa rep’ vek Imlygic: im lye’ jik MECHANISM OF ACTION — Melanoma tumors are immunogenic and often accessible, which makes them good targets for intralesional viral immunotherapy.1,2 Talimogene laherparepvec (T-VEC) is a herpes simplex type virus (HSV-1) that has been modified to reduce its pathogenicity in healthy cells and promote its replication in tumor cells The virus is also encoded with the gene for granulocyte macrophage-colony stimulating factor (GM-CSF), which induces T-cell proliferation and activation.3 Virus-induced tumor lysis causes the release of tumor antigens, which together with GM-CSF is thought to produce an antitumor immune response The Medical Letter ® Exogenous GM-CSF has been studied for treatment of melanoma In an open-label trial in 245 patients with unresectable stage III or IV melanoma, treatment with the anti-CTLA4 monoclonal antibody ipilimumab (Yervoy) plus subcutaneous sargramostim (a human recombinant GM-CSF product available as Leukine) significantly increased median overall survival compared to ipilimumab alone (17.5 vs 12.7 months) The rate of survival at year was also higher with the combination (68.9% vs 52.9%), and it caused less grade 3+ toxicity.4 CLINICAL STUDIES — In an open-label trial, 436 patients with unresectable stage IIIB-IV melanoma accessible to direct or ultrasound-guided injection were randomized to receive intralesional T-VEC or subcutaneous GM-CSF for at least 24 weeks Patients with bone metastases, growing hepatic metastases, or >3 visceral nonpulmonary metastases were excluded from the trial The durable response rate (defined as an objective response lasting ≥6 months) was significantly greater with T-VEC than with GMCSF (16.3% vs 2.1%) T-VEC was more likely to induce a durable response in patients with stage III melanoma than in those with stage IV disease (33% vs 8%).5 Median overall survival was 22.9 months with T-VEC and 19.0 months with GM-CSF; this difference was not statistically significant.6 ADVERSE EFFECTS — In the clinical trial, the most common adverse effects of T-VEC (occurring in ≥10% of patients and more commonly than with GM-CSF) were fatigue, chills, pyrexia, influenza-like illness, injectionsite pain, nausea, vomiting, diarrhea, constipation, headache, myalgia, arthralgia, and pain in extremities; severe adverse reactions were uncommon Clinical herpetic infections, including cold sores and keratitis, have been reported in patients receiving T-VEC; the drug should not be used in immunocompromised patients Accidental exposure to T-VEC can lead to herpetic transmission among caregivers and close contacts of patients Cellulitis, systemic bacterial infection, impaired injection-site healing, and immune-mediated events have also been reported PREGNANCY — No data on the use of T-VEC during pregnancy are available, but wild-type HSV-1 has the potential to cross the placenta and the virus can be transmitted during parturition Fetuses and neonates infected with wild-type HSV-1 are at risk for serious adverse effects, including multi-organ failure and death T-VEC should not be used in pregnant women, Vol 58 (1486) January 18, 2016 and healthcare providers who are pregnant should not prepare or administer the drug DRUG INTERACTIONS — Concurrent administration of acyclovir (Zovirax, and generics) or another antiviral drug could interfere with the effectiveness of T-VEC DOSAGE, ADMINISTRATION, AND COST — Imlygic is available in 1-mL single-use vials containing 106 or 108 plaque-forming units (PFU) of T-VEC in a frozen suspension Patients should receive the 106 PFU/ mL concentration at week and the 108 PFU/mL concentration at week and every weeks thereafter Injection volume per lesion ranges from 0.1-4 mL, depending on lesion size; no more than mL should be injected per treatment session Lesions that have developed since the previous treatment should be treated first, with remaining lesions prioritized based on size Treatment should be continued for at least months or until all injectable lesions have been treated, unless another drug therapy is required T-VEC treatment can be restarted if new lesions appear A 1-mL vial of Imlygic containing 108 PFU of talimogene laherparepvec costs $4400.7 CONCLUSION — Injection of the genetically modified herpes simplex virus talimogene laherparepvec (Imlygic) into unresectable cutaneous, subcutaneous, and nodal melanoma lesions appears to be only modestly effective How it compares in efficacy and safety with the numerous other agents now available for treatment of melanoma remains to be determined All of them, including Imlygic, are very expensive ■ SS Agarwala Intralesional therapy for advanced melanoma: promise and limitation Curr Opin Oncol 2015; 27:151 N Dharmadhikari et al Oncolytic virus immunotherapy for melanoma Curr Treat Options Oncol 2015; 16:326 HL Kaufman et al Current status of granulocyte-macrophage colony-stimulating factor in the immunotherapy of melanoma J Immunother Cancer 2014; 2:11 FS Hodi et al Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial JAMA 2014; 312:1744 RH Andtbacka et al Talimogene laherparepvec improves durable response rate in patients with advanced melanoma J Clin Oncol 2015; 33:2780 YA Luo Statistical review – Imlygic Available at: www.fda gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM474614.pdf Accessed January 7, 2016 Approximate WAC 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 January 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy The Medical Letter ▶ ® Elvitegravir (Vitekta) for HIV The FDA has approved elvitegravir (Vitekta – Gilead), an integrase strand transfer inhibitor (INSTI), for use with a protease inhibitor (PI) plus ritonavir and other antiretroviral drugs for treatment of HIV-1 infection in treatment-experienced adults Elvitegravir is also available in a fixed-dose combination (Stribild) with the pharmacokinetic enhancer cobicistat and the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) emtricitabine and tenofovir disoproxil fumarate (DF).1 A similar combination (Genvoya) that includes tenofovir alafenamide instead of tenofovir DF was recently approved by the FDA and will be reviewed in a future issue Pronunciation Key Elvitegravir: el” vi teg’ veer Vitekta: vye tek’ tuh TREATMENT OF HIV — First-line therapy for HIV usually consists of two NRTIs in combination with either darunavir boosted with ritonavir or an INSTI The choice of drugs for treatment-experienced patients depends on their previous treatment and resistance mutations.2 INSTIs — INSTIs block the activity of HIV-1 integrase, preventing viral DNA from integrating with cellular DNA Dolutegravir is taken once daily and is available alone (Tivicay)3 and in combination with the NRTIs abacavir and lamivudine (Triumeq).4 Raltegravir (Isentress) is generally well tolerated and is not metabolized by CYP3A, but must be taken twice daily and is not available in fixed-dose combinations with NRTIs.5 HIV strains that become resistant to raltegravir are usually cross-resistant to elvitegravir, and vice Vol 58 (1486) January 18, 2016 versa, but often remain susceptible to dolutegravir.6 Dolutegravir resistance mutations have not been reported with use of the drug in first-line therapy.2 CLINICAL STUDIES — In a double-blind trial, 702 treatment-experienced patients with HIV-1 infection were randomized to receive elvitegravir 150 mg once daily (85 mg once daily with a background regimen containing atazanavir or lopinavir) or raltegravir 400 mg twice daily All patients were also taking a background regimen consisting of a PI boosted with ritonavir and a second antiretroviral drug Elvitegravir was found to be noninferior to raltegravir; the percentages of patients who achieved and maintained a virologic response (HIV RNA