The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1482 Volume 56 November 23, 2015 IN THIS ISSUE Idarucizumab (Praxbind) – An Antidote for Dabigatran p 157 Bexsero – A Second Serogroup B Meningococcal Vaccine p 158 Cobicistat (Tybost) and Combinations for HIV p 159 Tiotropium/Olodaterol (Stiolto Respimat) for COPD p 161 In Brief: Technivie for HCV Genotype Infection online only 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 57 ISSUE ISSUE No 1433 1482 Volume 56 ▶ November 23, 2015 ALSO IN THIS ISSUE Bexsero — A Second Serogroup B Meningococcal Vaccine .p 158 Cobicistat (Tybost) and Combinations for HIV p 159 Tiotropium/Olodaterol (Stiolto Respimat) for COPD p 161 In Brief: Technivie for HCV Genotype Infection online only Idarucizumab (Praxbind) – An Antidote for Dabigatran The FDA has approved idarucizumab (Praxbind – Boehringer Ingelheim) for urgent reversal of the anticoagulant effect of the direct thrombin inhibitor dabigatran etexilate (Pradaxa).1 Idarucizumab is the first specific reversal agent to become available for one of the new oral anticoagulants.2 Pronunciation Key Idarucizumab : eye dare" yoo' siz u mab Praxbind: prax' bind RISK OF BLEEDING WITH DABIGATRAN — As with all anticoagulants, severe, potentially fatal bleeding can occur with dabigatran Unlike warfarin, routine laboratory monitoring to determine the extent of anticoagulation is not required with dabigatran and no specific agent has been available to reverse its anticoagulant effect in the event of life-threatening bleeding or emergency surgery Dabigatran is dialyzable, but dialysis may not be feasible in patients with acute bleeding.3 MECHANISM OF ACTION — Idarucizumab is a humanized monoclonal antibody fragment that binds to dabigatran and its acylglucuronide metabolites, neutralizing their anticoagulant effects It binds to dabigatran with higher affinity than dabigatran binds to thrombin Idarucizumab does not reverse the anticoagulant effects of the factor Xa inhibitors apixaban (Eliquis), edoxaban (Savaysa), and rivaroxaban (Xarelto) CLINICAL STUDIES — Idarucizumab received accelerated approval from the FDA based on an interim analysis of an ongoing prospective singlearm trial (RE-VERSE AD) in patients taking dabigatran who developed overt, uncontrolled, or life-threatening bleeding or needed an urgent procedure that could Table Pharmacology Class Humanized monoclonal antibody fragment Formulation 2.5 g/50 mL single-use vials Route Intravenous Metabolism Protein catabolism, primarily in the kidney Elimination Urine (32-33%); idarucizumab-dabigatran complex renally cleared Half-life 47 minutes (initial); 10.3 hours (terminal) not be delayed for ≥8 hours Among 90 such patients, unbound dabigatran serum concentrations fell below 20 ng/mL (a level that produces little or no anticoagulant effect) immediately after administration of idarucizumab in all but one patient, resulting in normalization of dilute thrombin time and ecarin clotting time Normal intraoperative hemostasis was reported in 92% of patients who underwent an urgent procedure At 12 and 24 hours after idarucizumab administration, 93% and 79% of patients, respectively, had unbound dabigatran serum concentrations 3% of patients taking tiotropium/ olodaterol and at a higher rate than with one or both of the individual components were nasopharyngitis, cough, and back pain Like other inhaled anticholinergics, tiotropium may cause urinary retention and increased intraocular pressure It should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction All US products that contain a long-acting beta2agonist such as olodaterol have a boxed warning about an increased risk of asthma-related death; there is no evidence to date that patients with COPD are at risk Systemic adverse effects of inhaled beta2-agonists can include skeletal muscle tremors, insomnia, palpitations, tachycardia, QTc interval prolongation, hypokalemia, and hyperglycemia Tolerance to their therapeutic effects can occur with chronic use 161 The Medical Letter Vol 57 (1482) ® November 23, 2015 Table Some Inhaled Drugs for Maintenance Treatment of COPD Drug Formulations Long-Acting Beta2-Agonists Formoterol – Foradil Aerolizer (MSD) 12 mcg/capsule Indacaterol – Arcapta Neohaler (Novartis) 75 mcg/capsule Olodaterol – Striverdi Respimat 2.5 mcg/inhalation (Boehringer Ingelheim) Salmeterol – Serevent Diskus (GSK) 50 mcg/blister Long-Acting Anticholinergics Aclidinium – Tudorza Pressair (AstraZeneca) 400 mcg/inhalation Glycopyrrolate – Seebri Neohaler (Novartis) 15.6 mcg/capsule Tiotropium – Spiriva HandiHaler 18 mcg/capsule (Boehringer Ingelheim) Spiriva Respimat (Boehringer Ingelheim) 2.5 mcg/inhalation Umeclidinium – Incruse Ellipta (GSK) 62.5 mcg/inhalation Long-Acting Anticholinergic/Long-Acting Beta2-Agonist Combinations Glycopyrrolate/indacaterol – Utibron Neohaler 15.6 mcg/27.5 mcg/capsule (Novartis) Tiotropium/olodaterol – Stiolto Respimat 2.5 mcg/2.5 mcg/inhalation (Boehringer Ingelheim) Umeclidinium/vilanterol – Anoro Ellipta (GSK) 62.5 mcg/25 mcg/blister Delivery Device Usual Adult Dosage Cost1 DPI (12, 60 inh/unit) DPI (30 inh/unit) ISI (28, 60 inh/unit) 12 mcg bid 75 mcg once/d mcg once/d $243.00 201.50 155.70 DPI (28, 60 inh/unit) 50 mcg bid 280.50 DPI (30, 60 inh/unit) DPI (60 inh/unit) DPI (5, 30, 90 inh/unit) 400 mcg bid 15.6 mcg bid 18 mcg once/d 281.40 N.A 315.70 ISI (28, 60 inh/unit) DPI (7, 30 inh/unit) mcg once/d 62.5 mcg once/d 315.70 238.30 DPI (6.60 inh/unit) 15.6/27.5 mcg bid ISI (28, 60 inh/unit) 5/5 mcg once/d 315.70 DPI (7, 30 inh/unit) 62.5/25 mcg once/d 297.80 N.A DPI = dry powder inhaler; ISI = inhalation spray inhaler; inh = inhalation; N.A = Not yet available Approximate WAC for 30 days’ treatment WAC = wholesaler acquisition cost, or manufacturer’s published price to wholesalers; WAC represents published catalogue or list prices and may not represent an actual transactional price Source: AnalySource® Monthly November 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Meta-analyses of randomized clinical trials have found that single-agent tiotropium delivered as an aqueous solution by the Respimat inhaler increased the risk of death compared to placebo, particularly in patients with underlying cardiovascular disease.7,8 However, a long-term (mean follow-up 2.3 years), manufacturersponsored, randomized, double-blind trial in >17,000 patients with COPD found no difference in the risk of death or the risk of the first exacerbation of COPD between the tiotropium Respimat spray inhaler and the tiotropium Handihaler dry powder inhaler.9 In an earlier trial, use of the Handihaler was not associated with an increased risk of death compared to placebo.10 necessary to insert a cartridge and prime the inhaler The recommended dosage is two inhalations once daily taken at the same time every day PREGNANCY — Stiolto Respimat is classified as category C (fetal toxicity with very high doses in animals; no adequate studies in women) for use during pregnancy Spiriva Respimat - an oral inhalation spray for COPD Med Lett Drugs Ther 2015; 57:49 Olodaterol (Striverdi Respimat) for COPD Med Lett Drugs Ther 2015; 57:1 S Muruganandan and L Jayaram Profile of a fixed-dose combination of tiotropium/olodaterol and its potential in the treatment of COPD Int J Chron Obstruct Pulmon Dis 2015; 10:1179 Drugs for asthma and COPD Treat Guidel Med Lett 2013; 11:75 Anoro Ellipta: an inhaled umeclidinium/vilanterol combination for COPD Med Lett Drugs Ther 2014; 56:30 R Buhl et al Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4) Eur Respir J 2015; 45: 969 S Singh et al Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials BMJ 2011; 342:d3215 YH Dong et al Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials Thorax 2013; 68:48 RA Wise et al Tiotropium Respimat inhaler and the risk of death in COPD N Engl J Med 2013; 369:1491 10 DP Tashkin et al A 4-year trial of tiotropium in chronic obstructive pulmonary disease N Engl J Med 2008; 359:1543 DRUG INTERACTIONS — Concomitant use of other adrenergic and anticholinergic drugs can add to the effects of Stiolto Respimat The hypokalemic effects of olodaterol may be potentiated when it is administered with xanthine derivatives, steroids, or non-potassium sparing diuretics Use of olodaterol with monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, or other drugs that increase the QTc interval could result in additive cardiovascular effects Concomitant use of beta blockers can decrease the effectiveness of olodaterol DOSAGE AND ADMINISTRATION — The Respimat inhaler does not use a propellant and is not dependent on the strength of the patient’s breath intake Before the inhaler can be used for the first time, it is 162 CONCLUSION — Once-daily combination therapy with tiotropium/olodaterol (Stiolto Respimat) can improve lung function in patients with moderate to severe chronic obstructive pulmonary disease (COPD) whose symptoms are inadequately controlled on monotherapy How Stiolto Respimat compares with other fixed-dose combinations of a long-acting anticholinergic and a long-acting beta2-agonist remains to be determined ■ 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 57 (Issue 1482) November 23, 2015 IN BRIEF Technivie for HCV Genotype Infection The FDA has approved Technivie (Abbvie), a fixed-dose combination of the direct-acting antiviral agents ombitasvir and paritaprevir and the pharmacokinetic enhancer ritonavir, for oral treatment of chronic hepatitis C virus (HCV) genotype infection in patients without cirrhosis It is indicated for use in combination with ribavirin Ombitasvir/ paritaprevir/ritonavir copackaged with dasabuvir, an HCV RNA polymerase inhibitor that has little activity against HCV genotype 4, is approved as Viekira Pak for treatment of HCV genotype infection.1 HCV genotype is uncommon in the US and Canada It is the most prevalent strain of HCV in Central sub-Saharan Africa, North Africa, and the Middle East.2 Technivie plus ribavirin was the first all-oral treatment approved for treatment of HCV genotype Ledipasvir/sofosbuvir (Harvoni)3 was also recently approved for this indication; it does not require coadministration with ribavirin and can be used in patients with or without cirrhosis Its use for this and other new indications will be reviewed in a future issue FDA approval of Technivie was based on an open-label trial (PEARL-I) in 86 treatment-naive and 49 treatmentexperienced non-cirrhotic patients with HCV genotype infection Treatment-naive patients were randomized to receive Technivie with or without ribavirin for 12 weeks; all treatment-experienced patients received the combination plus ribavirin for 12 weeks The rate of sustained virologic response 12 weeks after stopping treatment (SVR12), the primary endpoint, was 91% (40/44) in treatmentnaive patients not receiving ribavirin and was 100% in both treatment-naive (42/42) and treatment-experienced (49/49) patients receiving the combination plus ribavirin.4 Adverse effects observed with Technivie in the clinical trial included asthenia, fatigue, nausea, insomnia, pruritus, and skin reactions Like Viekira Pak, Technivie has been associated with serious, sometimes fatal cases of hepatic decompensation and is contraindicated in patients with moderate to severe (Child-Pugh B/C) hepatic impairment.5 It is also contraindicated in patients taking ethinyl estradiol (because of a risk of ALT elevation), CYP3A4 inducers such as rifampin, or certain sensitive CYP3A4 substrates such as midazolam or simvastatin.6 Each Technivie tablet contains 12.5 mg of ombitasvir, 75 mg of paritaprevir, and 50 mg of ritonavir The recommended dosage is two tablets taken once daily in the morning with a meal for 12 weeks Ribavirin should be coadministered with Technivie at a daily dose of 1000 mg in patients weighing