The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1491 Volume 56 March 28, 2016 IN THIS ISSUE Seebri Neohaler and Utibron Neohaler for COPD p 39 Lumacaftor/Ivacaftor (Orkambi) for Cystic Fibrosis p 41 Cobimetinib (Cotellic) for Metastatic Melanoma p 43 A Recombinant C1 Esterase Inhibitor (Ruconest) for Hereditary Angioedema online only Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein online only In Brief: Dinutuximab (Unituxin) for High-Risk Neuroblastoma online only In Brief: Uridine Triacetate (Xuriden) for Hereditary Orotic Aciduria 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 Volume 58 March 28, 2016 Take CME Exams ALSO IN THIS ISSUE ISSUE ISSUE No 1433 1491 Volume 56 ▶ Lumacaftor/Ivacaftor (Orkambi) for Cystic Fibrosis p 41 Cobimetinib (Cotellic) for Metastatic Melanoma p 43 A Recombinant C1 Esterase Inhibitor (Ruconest) for Hereditary Angioedema online only Inhibitors and Inducers of CYP Enzymes and P-Glycoprotein online only In Brief: Dinutuximab (Unituxin) for High-Risk Neuroblastoma online only In Brief: Uridine Triacetate (Xuriden) for Hereditary Orotic Aciduria online only Seebri Neohaler and Utibron Neohaler for COPD Table Long-Acting Anticholinergic/Beta2-Adrenergic Agonist Combination Inhalers: Ease of Use Anoro Ellipta The FDA has approved two new inhalers for longterm maintenance treatment of chronic obstructive pulmonary disease (COPD) Seebri Neohaler (Novartis) contains the long-acting anticholinergic glycopyrrolate Utibron Neohaler (Novartis) contains both glycopyrrolate and the long-acting beta2adrenergic agonist (LABA) indacaterol Glycopyrrolate/ indacaterol is the third fixed-dose combination of a long-acting anticholinergic and a LABA to become available in the US; umeclidinium/vilanterol (Anoro Ellipta)1 and tiotropium/olodaterol (Stiolto Respimat)2 were approved earlier Pronunciation Key Glycopyrrolate : glye" koe pir' oh late Seebri : see' bree Indacaterol : in" da ka' ter ol Utibron : yoo tee' bron ▶ Dry powder inhaler; drug delivery to the lungs is dependent upon ability to perform a rapid, deep inhalation ▶ Once-daily dosing ▶ No assembly or priming required ▶ Indicator shows how many doses are left ▶ Doses may be wasted if inhaler is opened/closed accidentally Stiolto Respimat ▶ Inhalation spray inhaler; drug delivery to the lungs is not dependent on strength of breath intake ▶ Once-daily dosing ▶ Assembly may be difficult for some patients ▶ Indicator shows approximately how many doses are left Utibron Neohaler ▶ Dry powder inhaler; drug delivery to the lungs is dependent upon ability to perform a rapid, deep inhalation ▶ Twice-daily dosing ▶ Removal of the capsule from the foil pack and insertion of the capsule into the inhaler may be difficult for some patients ▶ Transparent capsules may be helpful in determining if the full dose was inhaled GLYCOPYRROLATE — Glycopyrrolate has been available for many years in a parenteral formulation for multiple indications An oral formulation is available for reduction of chronic severe drooling in children with certain neurologic conditions MAINTENANCE TREATMENT OF COPD — In patients with moderate to severe COPD, regular treatment Table Pharmacology Glycopyrrolate Indacaterol Class Long-acting anticholinergic Long-acting beta2adrenergic agonist Route Oral inhalation Oral inhalation Tmax minutes 15 minutes Metabolism Multiple CYP enzymes UGT1A1 and CYP3A4 Elimination Urine (60-70%) Feces (54% unchanged) Half-life 33-53 hours 40-56 hours with an inhaled long-acting bronchodilator (an anticholinergic or a beta2-adrenergic agonist) can relieve symptoms, improve lung function, and reduce the frequency of exacerbations For patients inadequately controlled with a single agent, combining a LABA and a long-acting anticholinergic has resulted in additional improvement in lung function For patients with severe COPD who experience frequent exacerbations despite treatment with a long-acting anticholinergic and a LABA, addition of an inhaled corticosteroid is recommended.3,4 CLINICAL STUDIES — Glycopyrrolate – In two unpublished, double-blind trials (summarized in the package insert), 867 patients with moderate to severe COPD were randomized to twice-daily treatment with inhaled glycopyrrolate or placebo 39 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter March 28, 2016 Vol 58 (1491) ® Table Some Inhaled Drugs for Maintenance Treatment of COPD Drug Formulation Delivery Device Usual Adult Dosage Cost1 400 mcg/inh 15.6 mcg/cap2 18 mcg/cap2 DPI (30, 60 inh/unit) DPI (60 inh/unit) DPI (5, 30, 90 inh/unit) inh bid inh bid3 inh once/d3 $301.10 297.80 315.70 2.5 mcg/inh 62.5 mcg/inh ISI (60 inh/unit) DPI (7, 30 inh/unit) inh once/d inh once/d 315.70 252.60 inh once/d3 inh once/d 213.60 155.70 inh bid 322.60 inh bid3 297.80 inh once/d 315.70 inh once/d 315.70 Long-Acting Anticholinergics Aclidinium – Tudorza Pressair (AstraZeneca) Glycopyrrolate – Seebri Neohaler (Novartis) Tiotropium – Spiriva HandiHaler (Boehringer Ingelheim) Spiriva Respimat Umeclidinium – Incruse Ellipta (GSK) Long-Acting Beta2-Adrenergic Agonists Indacaterol – Arcapta Neohaler (Novartis) 75 mcg/cap2 DPI (30 inh/unit) Olodaterol – Striverdi Respimat 2.5 mcg/inh ISI (28, 60 inh/unit) (Boehringer Ingelheim) Salmeterol – Serevent Diskus (GSK) 50 mcg/blister DPI (28, 60 inh/unit) Long-Acting Anticholinergic/Long-Acting Beta2-Adrenergic Agonist Combinations Glycopyrrolate/indacaterol – Utibron Neohaler 15.6 mcg/27.5 mcg/cap2 DPI (6, 60 inh/unit) (Novartis) Tiotropium/olodaterol – Stiolto Respimat 2.5 mcg/2.5 mcg/inh ISI (60 inh/unit) (Boehringer Ingelheim) Umeclidinium/vilanterol – Anoro Ellipta (GSK) 62.5 mcg/25 mcg/blister DPI (7, 30 inh/unit) inh = inhalation; DPI = dry powder inhaler; cap = capsule; ISI = inhalation spray inhaler 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 March 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Capsules should not be swallowed Multiple inhalations from the same capsule may be needed to deliver the full dose After 12 weeks, patients treated with glycopyrrolate had significantly larger mean increases from baseline in FEV1 AUC0-12 (forced expiratory volume in second area under the curve from 0-12 hours); the difference between glycopyrrolate and placebo was 139 mL in trial and 123 mL in trial Glycopyrrolate/Indacaterol – In two double-blind trials (FLIGHT and FLIGHT 2), a total of 2038 patients with moderate to severe COPD were randomized to twice-daily glycopyrrolate/indacaterol, glycopyrrolate alone, indacaterol alone, or placebo At 12 weeks, the combination increased FEV1 AUC0-12 significantly more than glycopyrrolate or indacaterol alone: by 98 and 94 mL in trial and 79 and 112 mL in trial Patients treated with glycopyrrolate/ indacaterol also had a significant reduction in rescue inhaler use compared to those treated with placebo The combination improved scores on a healthrelated quality of life questionnaire significantly more than placebo.5 ADVERSE EFFECTS — The most common adverse effects reported in clinical trials were upper respiratory tract infection and nasopharyngitis with glycopyrrolate alone and nasopharyngitis and hypertension with glycopyrrolate/indacaterol Systemic absorption of inhaled anticholinergics could cause urinary retention and increased intraocular 40 pressure, but glycopyrrolate is minimally bioavailable and systemic adverse effects are unlikely to occur with inhaled use Systemic adverse effects of inhaled beta2-adrenergic agonists include palpitations, tachycardia, chest pain, tremor, nervousness, insomnia, QTc interval prolongation, hypokalemia, and hyperglycemia Tolerance to the therapeutic effects of these drugs may occur with chronic use PREGNANCY — Inhaled glycopyrrolate and glycopyrrolate/indacaterol are classified as category C (no teratogenic effects in animals given high doses; no adequate studies in pregnant women) for use during pregnancy Beta2-adrenergic agonists may interfere with uterine contractility during labor DRUG INTERACTIONS — The hypokalemic effects of indacaterol may be potentiated by concomitant use of a corticosteroid, a non-potassium-sparing diuretic, or a xanthine derivative such as theophylline Use of indacaterol with monoamine oxidase (MAO) inhibitors, tricyclic antidepressants, or other drugs that prolong the QTc interval could result in additive effects Concomitant use of beta blockers can decrease the effectiveness of indacaterol DOSAGE AND ADMINISTRATION — Both products are supplied with a Neohaler inhalation device and 60 blister-packaged capsules containing 15.6 mcg of The Medical Letter ® glycopyrrolate alone (Seebri Neohaler) or combined with 27.5 mcg of indacaterol (Utibron Neohaler) The recommended dosage of Seebri Neohaler or Utibron Neohaler is twice-daily inhalation of the contents of one capsule The device is prepared for administration by placing one capsule inside the Neohaler chamber The patient pushes buttons on both sides of the device at the same time to puncture the capsule and then exhales fully before taking deep, rapid but steady breaths through the mouthpiece until there is no powder remaining in the capsule; this requires or inhalations for most patients After inhaling the contents of the capsule, the patient should remove the inhaler from his/her mouth and wait at least 5-10 seconds before exhaling CONCLUSION — New inhalers containing the longacting anticholinergic glycopyrrolate alone (Seebri ▶ Lumacaftor/Ivacaftor (Orkambi) for Cystic Fibrosis The FDA has approved a fixed-dose combination of lumacaftor and ivacaftor (Orkambi – Vertex) for oral treatment of cystic fibrosis (CF) in patients ≥12 years old who are homozygous for the F508del mutation About 50% of patients in the US with CF are homozygous for the F508del (also called Phe508del) mutation This is the first approved indication for lumacaftor; ivacaftor is available alone as Kalydeco for treatment of CF in patients ≥2 years old with other mutations.1 Orkambi is the first drug to be approved in the US for treatment of patients with the F508del mutation Pronunciation Key Lumacaftor : loo" ma kaf' tor Orkambi : or kam' bee Ivacaftor : eye" va kaf' tor MECHANISM OF ACTION — The cystic fibrosis transmembrane conductance regulator (CFTR) protein functions as a regulated chloride channel The F508del mutation causes CFTR protein misfolding, a reduced quantity of CFTR protein at the cell surface, and decreased stability of the CFTR protein Lumacaftor improves the conformational stability of the protein and increases the amount of CFTR protein at the cell surface Ivacaftor is a CFTR potentiator that increases chloride transport through CFTR channels Vol 58 (1491) March 28, 2016 Neohaler) or in combination with the long-acting beta2adrenergic agonist indacaterol (Utibron Neohaler) can improve lung function in patients with moderate to severe COPD How they compare in efficacy and safety with other inhaled drugs for this indication remains to be determined, but some of the older products offer the advantage of once-daily dosing ■ Anoro Ellipta: an inhaled umeclidinium/vilanterol combination for COPD Med Lett Drugs Ther 2014; 56:30 Tiotropium/olodaterol (Stiolto Respimat) for COPD Med Lett Drugs Ther 2015; 57:161 Global Initiative for Chronic Obstructive Lung Disease (GOLD) Global strategy for the diagnosis, management, and prevention of COPD Available at www.goldcopd.org Accessed March 17, 2016 Drugs for asthma and COPD Treat Guidel Med Lett 2013; 11:75 DA Mahler et al FLIGHT1 and FLIGHT2: efficacy and safety of QVA149 (indacaterol/glycopyrrolate) versus its monocomponents and placebo in patients with chronic obstructive pulmonary disease Am J Respir Crit Care Med 2015; 192:1068 Table Pharmacology Lumacaftor Ivacaftor Tmax ~4 hours (with food) ~4 hours (with food) Metabolism Not extensive (mainly by oxidation and glucuronidation) Primarily hepatic by CYP3A Elimination Feces (51% unchanged); urine (8.6%) Feces (87.8%); urine (6.6%) Half-life ~26 hours (CF patients) ~9 hours (healthy subjects) CLINICAL STUDIES — In clinical trials, neither ivacaftor nor lumacaftor alone has been shown to be effective in patients with CF who are homozygous for the F508del mutation.2,3 Approval of the lumacaftor/ivacaftor combination was based on the results of two 24-week, doubleblind trials (TRAFFIC and TRANSPORT) in a total of 1108 patients ≥12 years old with stable CF who were homozygous for the F508del mutation and had a forced expiratory volume in second (FEV1) that was 40-90% of the predicted normal value Patients were randomized to receive ivacaftor (250 mg every 12 hours) plus lumacaftor (400 mg every 12 hours or 600 mg once daily) or placebo In a pooled analysis, lumacaftor 400 mg/ivacaftor 250 mg every 12 hours (the FDA-approved dosage) produced statistically significant improvements from baseline in the absolute change in percent predicted FEV1 (a difference from placebo of +2.8 percentage 41 The Medical Letter ® points) The rate of pulmonary exacerbations, including those leading to hospitalization and use of IV antibiotics, was significantly lower in patients taking lumacaftor/ivacaftor than in those taking placebo Patients taking the combination also had greater placebo-corrected increases from baseline in BMI.4 ADVERSE EFFECTS — The most common adverse effects of lumacaftor/ivacaftor in clinical trials (occurring in ≥10% of patients and more frequently than with placebo) were dyspnea, nasopharyngitis, nausea, diarrhea, and upper respiratory tract infection More patients taking the combination discontinued treatment because of adverse effects (4.2% vs 1.6% with placebo) Increases in hepatic transaminase and bilirubin levels have occurred during treatment with lumacaftor/ ivacaftor Hepatic encephalopathy has been reported in patients with advanced liver disease taking the combination DRUG INTERACTIONS — Lumacaftor is a strong inducer of CYP3A The combination can reduce the serum concentrations and efficacy of the many drugs that are metabolized by this enzyme, including some corticosteroids and azole antifungals Lumacaftor/ ivacaftor may also decrease the efficacy of hormonal contraceptives; use of a nonhormonal contraceptive is recommended during treatment Lumacaftor may inhibit and induce P-glycoprotein (P-gp); serum concentrations of P-gp substrates such as digoxin may increase or decrease if taken with lumacaftor/ivacaftor Lumacaftor may also induce CYP2B6, 2C8, 2C9, and 2C19 and inhibit CYP2C8 and 2C9; serum concentrations of drugs metabolized by these pathways may increase or decrease if taken concurrently with lumacaftor/ivacaftor Ivacaftor is a CYP3A substrate Concurrent administration of a CYP3A inhibitor and lumacaftor/ ivacaftor is not expected to significantly increase steady-state ivacaftor concentrations because of the CYP3A-inducing effects of lumacaftor Concurrent administration of a strong CYP3A inducer and lumacaftor/ivacaftor can decrease ivacaftor serum concentrations and is not recommended.5 In laboratory studies, prolonged exposure to ivacaftor reduced the efficacy of lumacaftor.6 DOSAGE, ADMINISTRATION, AND COST — Orkambi tablets contain 200 mg of lumacaftor and 125 mg of ivacaftor The recommended dosage of lumacaftor/ ivacaftor is tablets taken every 12 hours The 42 Vol 58 (1491) March 28, 2016 combination should be taken with fat-containing food, which increases lumacaftor exposure 2-fold and ivacaftor exposure 3-fold Liver function should be measured before starting treatment, quarterly during the first year of treatment, and annually thereafter Treatment with the combination should be interrupted if significant increases occur in hepatic transaminase and bilirubin levels Patients with moderate hepatic impairment should take two tablets in the morning and one in the evening Although the combination has not been studied in patients with severe hepatic impairment, the manufacturer recommends a starting dosage of one tablet in the morning and one in the evening for such patients Patients starting lumacaftor/ivacaftor treatment, or resuming treatment after an interruption of >7 days, who are currently taking a strong CYP3A inhibitor should take one tablet once daily for days (to allow for induction of CYP3A by lumacaftor) before continuing with the usual recommended dosage If a dose is missed, it should be skipped unless ≤6 hours have passed since the scheduled dosing time One year of treatment with Orkambi at the usual dosage costs about $260,000.7 CONCLUSION — The fixed-dose combination of lumacaftor and ivacaftor (Orkambi) is the first disease-modifying therapy to be approved for the 50% of patients with cystic fibrosis who are homozygous for the F508del mutation Orkambi improves pulmonary function and reduces exacerbations, but its long-term efficacy and safety have not been established, it interacts with many other drugs, and it is very expensive ■ Ivacaftor (Kalydeco) for cystic fibrosis Med Lett Drugs Ther 2012; 54:29 PA Flume et al Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation Chest 2012; 142:718 JP Clancy et al Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation Thorax 2012; 67:12 CE Wainwright et al Lumacaftor-ivacaftor in patients with cystic fibrosis homozygous for Phe508del CFTR N Engl J Med 2015; 373:220 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2016; 58:e46 PB Davis Another beginning for cystic fibrosis therapy N Engl J Med 2015; 373:274 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 March 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy The Medical Letter ▶ Vol 58 (1491) ® Cobimetinib (Cotellic) for Metastatic Melanoma The FDA has approved the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor cobimetinib (Cotellic – Genentech) for use in combination with the BRAF kinase inhibitor vemurafenib (Zelboraf) for treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation Pronunciation Key Cobimetinib : koe" bi me' ti nib Cotellic : koe tel' ik STANDARD TREATMENT — BRAF mutations are present in about 50% of melanomas; BRAF V600E accounts for 70-80% of these mutations and BRAF V600K for 5-15% The BRAF inhibitors vemurafenib and dabrafenib (Tafinlar) have been highly effective in treating BRAF mutation-positive unresectable or metastatic melanoma.1,2 Adding the MEK inhibitor trametinib (Mekinist) improved overall survival compared with use of a BRAF inhibitor alone.3 Immunotherapy with the programmed death receptor-1 (PD-1) inhibitors pembrolizumab (Keytruda) or nivolumab (Opdivo), or with nivolumab plus ipilimumab (Yervoy) has also been effective for treatment of unresectable or metastatic melanoma with BRAF V600 mutations.4-6 MECHANISM OF ACTION — Cobimetinib and vemurafenib act on two different kinases in the same signaling pathway The combination was more March 28, 2016 Table Pharmacology Formulation 20 mg tablets Route Oral Tmax 2.4 hours Metabolism Primarily by CYP3A oxidation and UGT2B7 glucuronidation Elimination Feces (76%); urine (18%) Half-life 23-70 hours effective than either drug alone in inducing apoptosis in vitro and reducing tumor growth in mouse models of melanoma cells with BRAF V600E mutations PHARMACOLOGY — Cobimetinib is well absorbed after oral administration, but extensive intestinal firstpass metabolism limits its systemic exposure.7 CLINICAL STUDIES — FDA approval of cobimetinib was based on the results of a randomized trial comparing the combined use of vemurafenib and cobimetinib with vemurafenib alone in 495 patients with previously untreated, unresectable, locally advanced or metastatic BRAF V600 mutation-positive melanoma Median progression-free survival, the primary endpoint, was 9.9 months with the combination and 6.2 months with vemurafenib alone (p