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Which Oral Anticoagulant for Atrial Fibrillation? Direct-to-consumer advertisements continue to urge patients who take warfarin (Coumadin, and others) for atrial fibrillation to ask their doctors about the benefits of one or another of... Buprenorphine Buccal Film (Belbuca) for Chronic Pain Belbuca (Endo), a buccal formulation of the partial opioid agonist buprenorphine, has been approved by the FDA for management of pain severe enough to require daily, around-the-clock,... Calcipotriene/Betamethasone Foam (Enstilar) for Psoriasis The FDA has approved Enstilar (Leo), an aerosol foam formulation of the synthetic vitamin D3 analog calcipotriene and the high-potency corticosteroid betamethasone dipropionate,... Dichlorphenamide (Keveyis) for Periodic Paralysis Dichlorphenamide (Keveyis – Taro), an oral carbonic anhydrase inhibitor, has been approved by the FDA for treatment of primary hypokalemic and hyperkalemic periodic paralysis and related...
The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1492 Volume 56 April 11, 2016 IN THIS ISSUE Which Oral Anticoagulant for Atrial Fibrillation? p 45 Buprenorphine Buccal Film (Belbuca) for Chronic Pain p 47 Calcipotriene/Betamethasone Foam (Enstilar) for Psoriasis p 48 Dichlorphenamide (Keveyis) for Periodic Paralysis p 50 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 April 11, 2016 Take CME Exams ISSUE ISSUE No 1433 1492 Volume 56 ▶ ALSO IN THIS ISSUE Buprenorphine Buccal Film (Belbuca) for Chronic Pain p 47 Calcipotriene/Betamethasone Foam (Enstilar) for Psoriasis p 48 Dichlorphenamide (Keveyis) for Periodic Paralysis p 50 Which Oral Anticoagulant for Atrial Fibrillation? Related article(s) since publication Direct-to-consumer advertisements continue to urge patients who take warfarin (Coumadin, and others) for atrial fibrillation to ask their doctors about the benefits of one or another of the newer oral anticoagulants WARFARIN — In patients with nonvalvular atrial fibrillation, warfarin reduces the risk of thromboembolic stroke by about 60%.1 If necessary, vitamin K, prothrombin complex concentrate, or fresh frozen plasma can reverse its anticoagulant effect.2 Drawbacks of warfarin include unpredictability and variability in dosage requirements, dietary restrictions, interactions with many other drugs, and the need for close monitoring to keep the international normalized ratio (INR) in the therapeutic range (2-3) DIRECT ORAL ANTICOAGULANTS — The direct thrombin inhibitor dabigatran etexilate (Pradaxa) and the direct factor Xa inhibitors apixaban (Eliquis), edoxaban (Savaysa), and rivaroxaban (Xarelto) not require routine monitoring of coagulation times and they have fewer drug interactions than warfarin Table Oral Anticoagulants for Atrial Fibrillation Drug Usual Dosage Comments Cost1 Apixaban2 – Eliquis (BMS) mg bid3 Interacts with inhibitors and inducers of CYP3A4 and P-gp4 $333.60 Edoxaban2 – Savaysa (Daiichi Sankyo) 60 mg once/d5 Should not be used in patients with a CrCl >95 mL/min; avoid use with the P-gp inducer rifampin 291.30 Rivaroxaban2 – Xarelto (Janssen) 20 mg once/d6 Should be taken with the evening meal; interacts with inhibitors and inducers of CYP3A4 and P-gp7 333.30 Direct Thrombin Inhibitor Dabigatran etexilate2 – Pradaxa (Boehringer Ingelheim) 150 mg bid8 Must be dispensed and stored in the original container (once the bottle is opened, use within months); tablets should not be broken, crushed, or chewed; dyspepsia is common; interacts with inhibitors and inducers of P-gp9; reversal agent available; dialyzable 333.60 Vitamin K Antagonist Warfarin – generic Coumadin (BMS) 2-10 mg once/d10 Interacts with many other drugs; has dietary restrictions; INR monitoring required; reversal agents available 8.50 58.80 Direct Factor Xa Inhibitors P-gp = P-glycoprotein; INR = international normalized ratio Approximate WAC for 30 days’ treatment at 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 March 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy FDA-approved for use in patients with nonvalvular atrial fibrillation Dosage is 2.5 mg bid for patients with ≥2 of the following: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL In patients taking strong inhibitors of both CYP3A4 and P-gp, reduce the dosage of apixaban by 50% to a minimum of 2.5 mg bid; avoid coadministration in patients already taking 2.5 mg bid Avoid use with strong inducers of both CYP3A4 and P-glycoprotein Dosage is 30 mg once/d for patients with a CrCl 15-50 mL/min Not recommended for use in patients with a CrCl 95 mL/min was 2.16 Drawbacks of the direct oral anticoagulants include absence of any method for monitoring the extent of their anticoagulant effect, short half-lives that increase the risk of thrombosis with missed doses, lack of data on their use in patients with end-stage renal disease, and higher drug costs Efficacy – In the pivotal clinical trials against warfarin that led to their approval by the FDA, all of the direct oral anticoagulants were at least noninferior to warfarin for prevention of stroke or systemic embolism in patients with atrial fibrillation In patients taking warfarin, the INR was in the therapeutic range only 55-65% of the time.3-6 Edoxaban was less effective than warfarin for prevention of stroke or systemic embolism in patients with a CrCl >95 mL/min; it was more effective in those with a CrCl between 50 and 80 mL/min.7 Bleeding – All of the direct oral anticoagulants had significantly lower rates of intracranial bleeding and hemorrhagic stroke than warfarin in the pivotal clinical trials Compared to warfarin, the rates of major bleeding with dabigatran and rivaroxaban were similar and the rates with apixaban and edoxaban were significantly lower Reversibility – In 2015, the FDA approved idarucizumab (Praxbind) for urgent reversal of the anticoagulant effect of dabigatran.8 No specific antidote is available in the US for the three direct factor Xa inhibitors, but in one study in healthy volunteers, an investigational synthetic product (andexanet alfa) reversed the anticoagulant effects of apixaban and rivaroxaban within minutes.9 The results of some studies suggest that the anticoagulant effects of all of the direct oral anticoagulants may be reversed by prothrombin complex concentrate.10 46 CONCLUSION — The direct oral anticoagulants dabigatran (Pradaxa), apixaban (Eliquis), edoxaban (Savaysa), and rivaroxaban (Xarelto) have been at least as effective as warfarin (Coumadin, and others) in preventing stroke or systemic embolism in patients with nonvalvular atrial fibrillation, and they appear to be safer Patients well controlled on warfarin (INR stable in the therapeutic range) could stay on it For all others, one of the direct oral anticoagulants might be a better choice Head-to-head comparisons of the new drugs are lacking ■ RG Hart et al Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation Ann Int Med 2007; 146:857 Kcentra: a 4-factor prothrombin complex concentrate for reversal of warfarin anticoagulation Med Lett Drugs Ther 2013; 55:53 SJ Connolly et al Dabigatran versus warfarin in patients with atrial fibrillation N Engl J Med 2009; 361:1139 MR Patel et al Rivaroxaban versus warfarin in nonvalvular atrial fibrillation N Engl J Med 2011; 365:883 CB Granger et al Apixaban versus warfarin in patients with atrial fibrillation N Engl J Med 2011; 365:981 RP Giugliano et al Edoxaban versus warfarin in patients with atrial fibrillation N Engl J Med 2013; 369:2093 FDA draft briefing document for the Cardiovascular and Renal Drugs Advisory Committee NDA 206316 October 30, 2014 Available at www.fda.gov/downloads/Advisory Committees/CommitteesMeetingMaterials/Drugs/Cardio vascularandRenalDrugsAdvisoryCommittee/UCM420704 pdf Accessed March 31, 2016 Idarucizumab (Praxbind) – an antidote for dabigatran Med Lett Drugs Ther 2015; 57:157 DM Siegal et al Andexanet alfa for the reversal of factor Xa inhibitor activity N Engl J Med 2015; 373:2413 10 JS Kalus Pharmacologic interventions for reversing the effects of oral anticoagulants Am J Health Syst Pharm 2013; 70 (Suppl 1):S12 The Medical Letter ▶ ® Buprenorphine Buccal Film (Belbuca) for Chronic Pain Belbuca (Endo), a buccal formulation of the partial opioid agonist buprenorphine, has been approved by the FDA for management of pain severe enough to require daily, around-the-clock, long-term opioid treatment Buprenorphine is also available as a transdermal patch (Butrans) and in a parenteral formulation (Buprenex, and generics) for treatment of pain A sublingual formulation of buprenorphine and buccal and sublingual formulations containing buprenorphine and the opioid antagonist naloxone are approved for use as alternatives to methadone for treatment of opioid dependence.1,2 Pronunciation Key Buprenorphine : bue" pre nor' feen Belbuca : bel bue' kuh MECHANISM OF ACTION — Buprenorphine binds with high affinity to, and slowly dissociates from, the muopioid receptor In the dosage range for which Belbuca is approved, buprenorphine produces typical opioid agonist effects In higher doses, its agonist effects reach a ceiling and it can act as an antagonist.3 Used alone, it may be less likely to cause respiratory depression than full opioid agonists such as fentanyl or morphine.4 Table Pharmacology Class Partial mu-opioid agonist Route Buccal Formulation 75, 150, 300, 450, 600, 750, 900 mcg buccal films Tmax (single 300-mcg dose) 2.5-3.0 hours1 Metabolism N-dealkylation, primarily by CYP3A4, and glucuronidation Elimination Feces (69%); urine (30%) Half-life 27.6 hours Steady-state concentrations were achieved prior to the 6th dose CLINICAL STUDIES — Approval of Belbuca was based on two double-blind, placebo-controlled trials in patients with moderate to severe chronic low back pain Each trial included an 8-week open-label phase in which patients were titrated to an effective and tolerable analgesic dose of buprenorphine Patients who were successfully titrated were eligible to enter a 12-week, double-blind treatment phase in which they were randomized to continue taking buprenorphine or switch to placebo In one trial, 461 (out of 749) opioid-naive patients entered the treatment phase after being successfully titrated to an adequate analgesic dose The increase in mean daily pain intensity score from baseline to week 12, the primary endpoint, was significantly greater in patients who were switched to placebo than in those who continued Vol 58 (1492) April 11, 2016 taking buprenorphine (1.59 vs 0.94 points on a scale of 0-10) Significantly more patients who continued buprenorphine had a ≥30% reduction in pain score from the start of titration to the end of the study compared to those who were switched to placebo (63% vs 47%).5 In the other trial, which is unpublished but summarized in the package insert, 491 (out of 810) opioid-experienced patients entered the treatment phase after being successfully titrated to an adequate analgesic dose The mean pain score after 12 weeks, the primary endpoint, was significantly lower among patients who continued taking buprenorphine Significantly more patients who continued buprenorphine had a ≥30% reduction in pain scores compared to those who were switched to placebo (64% vs 31%) According to the package insert, a third study in patients with chronic low back pain did not show a statistically significant difference in pain reduction between buprenorphine buccal film and placebo ADVERSE EFFECTS — The most common adverse effects reported with use of buprenorphine buccal film in clinical trials were nausea, constipation, vomiting, headache, dizziness, and somnolence QTc interval prolongation and hepatotoxicity have occurred Respiratory depression (particularly in elderly, cachectic, and debilitated patients), severe hypotension, and physical and psychological dependence can occur Belbuca is classified as a schedule III controlled substance PREGNANCY — Prolonged opioid use during pregnancy can result in neonatal withdrawal syndrome Opioids administered immediately before labor can cross the placenta and cause excess sedation, respiratory depression, and other adverse effects in the newborn Excess sedation and respiratory depression may also occur in infants exposed to buprenorphine in breast milk, and withdrawal symptoms may occur when breastfeeding is stopped or maternal buprenorphine use is discontinued DRUG INTERACTIONS — Buprenorphine is metabolized primarily by CYP3A4 Inhibitors of CYP3A4 can increase plasma concentrations of buprenorphine and inducers of CYP3A4 can decrease them.6 Additive effects can occur when buprenorphine is used with other CNS depressant drugs; coma and death have occurred in patients taking buprenorphine and benzodiazepines concurrently Mixed agonist/ antagonist and partial agonist opioid analgesics such as butorphanol and pentazocine (Talwin) should not be used with buprenorphine because they can reduce its efficacy and/or precipitate withdrawal symptoms 47 The Medical Letter Vol 58 (1492) ® Table Belbuca vs Butrans for Chronic Pain Route Belbuca Buccal Butrans Initial dosage (opioid-naive) 75 mcg once/d or q12h mcg/hr Maximum dosage 900 mcg q12 hours 20 mcg/hr Oral MSE of maximum daily dose 160 mg 80 mg Cost1 $255.60 $204.50 Transdermal (7-day patch) MSE = morphine sulfate equivalent Approximate WAC for 30 days’ treatment with Belbuca or 28 days' treatment with Butrans at the initial dosage in opioid-naive patients 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 Buprenorphine should not be taken concurrently with other drugs that prolong the QT interval.7 DOSAGE AND ADMINISTRATION — For opioid-naive patients, the starting dosage of Belbuca is 75 mcg once daily or every 12 hours; after days, the dosage can be increased to 150 mcg every 12 hours If analgesia is inadequate, the dosage can be increased every days in increments of 150 mcg twice daily; the maximum approved dosage is 900 mcg every 12 hours Dosages of Belbuca >900 mcg every 12 hours can increase the risk of QTc interval prolongation and are not recommended For patients already taking an opioid, the Belbuca package insert provides detailed dosing instructions The dosage should be reduced in patients with oral mucositis because they may absorb buprenorphine more rapidly CONCLUSION — Buprenorphine buccal film (Belbuca) appears to be effective for treatment of moderate to severe chronic pain Head-to-head trials comparing the buccal film with the buprenorphine transdermal patch (Butrans) or other opioids are lacking ■ Transdermal buprenorphine (Butrans) for chronic pain Med Lett Drugs Ther 2011; 53:31 Bunavail: another buprenorphine/naloxone formulation for opioid dependence Med Lett Drugs Ther 2015; 57:19 Center for Substance Abuse Treatment Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2004 (Treatment Improvement Protocol [TIP] Series, No 40) Pharmacology Available at: www.ncbi nlm.nih.gov/books/NBK64236 Accessed March 31, 2016 J Pergolizzi et al Current knowledge of buprenorphine and its unique pharmacological profile Pain Pract 2010; 10:428 RL Rauck et al Efficacy and tolerability of buccal buprenorphine in opioid-naive patients with moderate to severe chronic low back pain Postgrad Med 2016; 128:1 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2016; 58:e46 RL Woosley and KA Romero QT drugs list Available at: www crediblemeds.org Accessed March 31, 2016 48 ▶ April 11, 2016 Calcipotriene/Betamethasone Foam (Enstilar) for Psoriasis The FDA has approved Enstilar (Leo), an aerosol foam formulation of the synthetic vitamin D3 analog calcipotriene and the high-potency corticosteroid betamethasone dipropionate, for topical treatment of plaque psoriasis in adults Topical ointment and suspension formulations of the same combination have been available for many years Pronunciation Key Calcipotriene : kal" si poe trye' een Enstilar : en' stil ar Betamethasone : bay" ta meth' a sone STANDARD TREATMENT — Mild to moderate psoriasis is generally treated with a topical corticosteroid Vitamin D3 analogs and the retinoid tazarotene (Tazorac) are topical alternatives When used alone, calcipotriene is about as effective in treating psoriasis as a mediumpotency steroid The combination of calcipotriene and betamethasone is more effective and better tolerated than either component alone.1,2 Phototherapy and systemic therapy, including biologic agents, are options for patients with moderate to severe disease.3 THE NEW FORMULATION — Calcipotriene/ betamethasone aerosol foam is available in a 60gram pressurized aluminum spray can containing flammable propellants, dimethyl ether and butane An in vitro study found that steady-state levels of both calcipotriene and betamethasone were significantly higher in skin samples treated with the foam than in those treated with the ointment.4 CLINICAL STUDIES — In a randomized, double-blind trial (PSO-FAST) in 426 adults with mostly moderate psoriasis of the trunk and/or limbs, significantly more patients using calcipotriene/betamethasone foam once daily for up to weeks achieved the primary endpoint of treatment success according to physician’s global assessment (defined as clear or almost clear with at least moderate disease at baseline or clear with mild disease at baseline) compared to those using the vehicle alone (53.3% vs 4.8%) The mean amount of foam used per week was about 30 grams.5 An unpublished, randomized, double-blind trial (available only as an abstract) compared weeks of treatment with calcipotriene/betamethasone foam to its components in 302 patients with mostly moderate psoriasis, including 66% with scalp involvement Treatment success on the trunk and limbs, the primary endpoint, occurred significantly more often with the The Medical Letter Vol 58 (1492) ® Table Some Calcipotriene and Betamethasone Products Drug Some Formulations Betamethasone Dipropionate, Augmented (0.05%) generic 15, 50 g cream 15, 45, 50 g ointment 30, 60 mL lotion 15, 50 g gel Diprolene AF (Merck) 15, 50 g cream Diprolene 15, 50 g ointment 30, 60 mL lotion Calcipotriene (0.005%) generic 60, 120 g cream 60, 120 g ointment 60 mL solution Dovonex (Leo) 60, 120 g cream Sorilux (GSK) 60, 120 g foam Cost $74.40 133.60 150.50 109.30 180.20 180.20 182.10 335.60 295.60 238.60 632.40 648.70 Calcipotriene/Betamethasone Dipropionate (0.005%/0.064%) generic 60, 100 g ointment 644.30 Taclonex (Leo) 60, 100 g ointment 895.80 60, 100 g suspension 831.00 Enstilar (Leo) 60 g foam 831.00 Approximate WAC for 60 g or 60 mL of calcipotriene or calcipotriene/betamethasone dipropionate or for 50 g or 60 mL of betamethasone dipropionate 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 combination than with calcipotriene or betamethasone alone (45% vs 14.9% and 30.7%, respectively) Treatment success on the scalp occurred significantly more often with calcipotriene/betamethasone than with calcipotriene but not betamethasone (53% vs 35.6% and 47.5%, respectively).6 Foam vs Ointment — A 4-week, randomized trial in adults with mostly moderate psoriasis of the trunk and limbs compared calcipotriene/betamethasone foam with an ointment formulation Treatment success at weeks, the primary endpoint, occurred in 54.6% of patients using the foam and in 43.0% of those using the ointment, a significant difference The foam was superior to the ointment as early as week 2.7 ADVERSE EFFECTS — Calcipotriene is generally well tolerated, but burning and itching can occur Hypercalcemia has been reported rarely Animal data suggest that exposure to ultraviolet radiation while using topical calcipotriene may increase the risk of skin tumor development; the manufacturer recommends limiting or avoiding use of phototherapy in patients being treated with calcipotriene Topical corticosteroids such as betamethasone can induce adrenal suppression when applied to large body surface areas Local cutaneous adverse effects such as dermal and epidermal atrophy, telangiectasias, and irreversible striae can occur An open-label study in 37 patients with moderate to severe psoriasis found that use of calcipotriene/beta- April 11, 2016 methasone foam once daily for weeks did not result in clinically relevant hypothalamic-pituitary-adrenal (HPA) axis suppression or affect calcium homeostasis.8 PREGNANCY — The calcipotriene/betamethasone combination is classified as category C (fetotoxicity in animals with calcipotriene; teratogenicity in animals with betamethasone; no adequate studies in women) for use during pregnancy DOSAGE AND ADMINISTRATION — Enstilar foam should be applied to affected areas once daily for up to weeks It should not be used on the face, groin, or axillae, or under occlusion A maximum of 60 grams of foam should be used every days Exposure of Enstilar-treated skin to natural or artificial sunlight or phototherapy may cause degradation of calcipotriene; applying the foam at night might minimize this effect CONCLUSION — Enstilar, an aerosol foam formulation of the vitamin D3 analog calcipotriene and the highpotency corticosteroid betamethasone dipropionate, provides another option for topical treatment of psoriasis Some patients may find the foam more convenient to apply and more cosmetically acceptable than an ointment, and it might be somewhat more effective For treatment of scalp psoriasis, Enstilar has not been shown to be more effective than topical betamethasone alone All calcipotriene/betamethasone combination products are expensive ■ PL McCormack Calcipotriol/betamethasone dipropionate: a review of its use in the treatment of psoriasis vulgaris of the trunk, limbs and scalp Drugs 2011; 71:709 A Mason et al Topical treatments for chronic plaque psoriasis: an abridged Cochrane systematic review J Am Acad Dermatol 2013; 69:799 Drugs for psoriasis Med Lett Drugs Ther 2015; 57:81 L Hollesen Basse et al Enhanced in vitro skin penetration and antipsoriatic effect of fixed combination calcipotriol plus betamethasone dipropionate in an innovative foam vehicle J Invest Dermatol 2014; 134 (suppl 2): S33, abstract 192 C Leonardi et al Efficacy and safety of calcipotriene plus betamethasone dipropionate aerosol foam in patients with psoriasis vulgaris – a randomized phase III study (PSO-FAST) J Drugs Dermatol 2015; 14:1468 M Lebwohl et al A novel aerosol foam formulation of calcipotriene (Cal) 0.005% plus betamethasone dipropionate (BD) 0.064% is more efficacious than Cal and BD foam alone in treating psoriasis vulgaris: a randomized, double-blind, multicenter, threearm, phase II study Presented at the 73rd Annual Meeting of the American Academy of Dermatology, San Francisco, March 2024, 2015 Abstract 1670 Available at: www.aad.org/eposters/ view/Abstract.aspx?id=1670 Accessed March 31, 2016 J Koo et al Superior efficacy of calcipotriene and betamethasone dipropionate aerosol foam versus ointment in patients with psoriasis vulgaris – a randomized phase II study J Dermatolog Treat 2016; 27:120 V Taraska et al A novel aerosol foam formulation of calcipotriol and betamethasone has no impact on HPA axis and calcium homeostasis in patients with extensive psoriasis vulgaris J Cutan Med Surg 2016: 20:44 49 The Medical Letter ▶ ® Dichlorphenamide (Keveyis) for Periodic Paralysis Dichlorphenamide (Keveyis – Taro), an oral carbonic anhydrase inhibitor, has been approved by the FDA for treatment of primary hypokalemic and hyperkalemic periodic paralysis and related variants Dichlorphenamide is the first drug to be approved in the US for this indication It was approved as Daranide in 1958 for treatment of glaucoma, but had not been marketed since 2002 Pronunciation Key Dichlorphenamide : dye" klor fen' a mide Keveyis : keh vay' iss THE DISEASE — Periodic paralysis is a rare hereditary disorder caused by sodium or calcium channel defects in skeletal muscle The disease is characterized by episodes of muscle weakness, paralysis, and often hypo- or hyperkalemia Acetazolamide (Diamox, and generics), another oral carbonic anhydrase inhibitor, has been used off-label for treatment of periodic paralysis for years; in an observational study, 34 of 74 patients with hypokalemic periodic paralysis (46%) benefited from acetazolamide therapy.1 MECHANISM OF ACTION — Carbonic anhydrase inhibitors are thought to decrease the frequency and severity of periodic paralysis attacks by opening calcium-activated potassium channels on myocytes, allowing for influx or efflux of potassium.2 CLINICAL STUDIES — In a randomized, doubleblind, 9-week trial in 44 adults with hypokalemic periodic paralysis, the median weekly attack rate was lower in patients taking dichlorphenamide than in those taking placebo (0.3 vs 2.4) In a similar trial in 21 adults with hyperkalemic periodic paralysis, the median weekly attack rate was also lower with dichlorphenamide (0.9 vs 4.8 with placebo), but the difference was not statistically significant None of the patients taking the active drug in either trial had acute worsening of disease.3 In a double-blind crossover trial, 42 adults with hypokalemic periodic paralysis were treated with dichlorphenamide and placebo for weeks each, with a 9-week washout period between treatments An intolerable increase in attack severity or frequency, the primary endpoint, occurred during both treatment periods in patients, only during treatment with dichlorphenamide in patients, and only during treatment with placebo in 11 patients In a similar trial, 31 adults with hyperkalemic periodic paralysis experienced a mean of 2.3 fewer attacks per week with dichlorphenamide than with placebo.4 50 Vol 58 (1492) April 11, 2016 ADVERSE EFFECTS — The most common adverse effects of dichlorphenamide in clinical trials were paresthesia, cognitive disorder, confusion, and dysgeusia PREGNANCY — Dichlorphenamide is classified as category C (teratogenic effects in animals; no adequate studies in women) for use during pregnancy DRUG INTERACTIONS — Like acetazolamide, dichlorphenamide can increase salicylate levels in patients taking aspirin and can cause hypokalemia and metabolic acidosis Concurrent use of high-dose aspirin and dichlorphenamide has been associated with serious adverse effects including anorexia, tachypnea, and coma and is contraindicated Lowdose aspirin should be used with caution in patients taking dichlorphenamide Taking dichorphenamide with other drugs that can cause hypokalemia or metabolic acidosis may increase the likelihood and/or severity of these effects DOSAGE, ADMINISTRATION, AND COST — The recommended starting dosage of dichlorphenamide is 50 mg (one tablet) twice daily The dosage can be increased at weekly intervals up to a maximum of 200 mg daily Use of dichlorphenamide in patients with hepatic insufficiency, severe pulmonary disease, or a history of sulfonamide allergy is contraindicated Serum potassium and bicarbonate levels should be measured periodically The cost of a 30-day supply of Keveyis (50 mg twice daily) is $9828.00 A 30-day supply of generic acetazolamide (250 mg twice daily) costs $154.70.5 CONCLUSION — The carbonic anhydrase inhibitor dichlorphenamide (Keveyis) reduces the frequency of primary hypokalemic or hyperkalemic periodic paralysis attacks, with minimal adverse effects How it compares to acetazolamide (Diamox, and generics), which has been used off-label for years and costs much less, remains to be determined ■ E Matthews et al Acetazolamide efficacy in hypokalemic periodic paralysis and the predictive role of genotype Neurology 2011; 77:1960 D Tricarico et al Carbonic anhydrase inhibitors ameliorate the symptoms of hypokalaemic periodic paralysis in rats by opening the muscular Ca2+-activated-K+ channels Neuromuscul Disord 2006; 16:39 VA Sansone et al Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis Neurology 2016 February 10 (epub) R Tawil et al Randomized trials of dichlorphenamide in the periodic paralyses Working Group on Periodic Paralysis Ann Neurol 2000; 47:46 Approximate wholesale acquisition cost (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 ® Continuing Medical Education Program medicalletter.org/cme-program Earn Up To 52 Credits Per Year Choose CME from The Medical Letter in the format that’s right for you! ▶ 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educational content in the form of self-study material The expected outcome of the CME program is to increase the participant’s ability to know, or apply knowledge into practice after assimilating, information presented in materials contained in The Medical Letter The Medical Letter will strive to continually improve the CME program through periodic assessment of the program and activities The Medical Letter aims to be a leader in supporting the professional development of healthcare providers through Core Competencies by providing continuing medical education that is unbiased and free of industry influence The Medical Letter is supported solely by subscription fees and accepts no advertising, grants, or donations GOAL: Through this program, The Medical Letter expects to provide the healthcare community with unbiased, reliable, and timely educational content that they will use to make independent and informed therapeutic choices in their practice LEARNING OBJECTIVES: Activity participants will read and assimilate unbiased reviews of FDA-approved and off-label uses of drugs and other treatment modalities Activity participants will be able to select and prescribe, or confirm the appropriateness of the prescribed usage of, the drugs and other therapeutic modalities discussed in The Medical Letter with specific attention to clinical trials, pathophysiology, dosage and administration, drug metabolism and interactions, and patient management Activity participants will make independent and informed therapeutic choices in their practice Upon completion of this program, the participant will be able to: Discuss the available options for anticoagulation in patients with nonvalvular atrial fibrillation Review the efficacy and safety of buprenorphine buccal film (Belbuca) for management of chronic pain Review the efficacy and safety of calcipotriene/betamethasone foam (Enstilar) for treatment of plaque psoriasis Review the efficacy and safety of dichlorphenamide (Keveyis) for treatment of hypokalemic and hyperkalemic periodic paralysis Privacy and Confidentiality: The Medical Letter guarantees our firm commitment to your privacy We not sell any of your information Secure server software (SSL) is used for commerce transactions through VeriSign, Inc No credit card information is stored IT Requirements: Windows 7/8/10, Mac OS X+; current versions of Microsoft IE/Edge, Mozilla Firefox, Google Chrome, Safari, or any other compatible Web browser Highspeed connection Have any questions? Call us at 800-211-2769 or 914-235-0500 or e-mail us at: custserv@medicalletter.org Questions start on next page The Medical Letter ® Online Continuing Medical Education DO NOT FAX OR MAIL THIS EXAM To take CME exams and earn credit, go to: medicalletter.org/CMEstatus Issue 1492 Questions (Correspond to questions #71-80 in Comprehensive Exam #74, available July 2016) Belbuca has been shown to be more effective for chronic pain than: a placebo b gabapentin c Butrans d all of the above Which Oral Anticoagulant for Atrial Fibrillation? Drawbacks of warfarin include: a variability in dosage requirements b need for close monitoring c many drug interactions d all of the above Belbuca has been shown to be more effective than placebo for treatment of: a osteoarthritis of the knee b polymyalgia rheumatica c chronic low back pain d all of the above In clinical trials compared to warfarin, all of the direct oral anticoagulants had significantly lower rates of: a GI bleeding b intracranial bleeding c ischemic stroke d all of the above Drawbacks of the direct oral anticoagulants include: a lack of data on their use in end-stage renal disease b very long half-lives c need for regular monitoring of coagulation parameters d all of the above A 41-year-old man with longstanding nonvalvular atrial fibrillation and normal renal function has taken warfarin uneventfully for many years with an INR that in recent years has been stable in the therapeutic range He has seen advertisements on television extolling the benefits of the direct oral anticoagulants, and he wonders if he should switch to one of them You could tell him that: a edoxaban is preferred for patients like him with normal renal function b he would save money if he made the switch c the new drugs have more dietary restrictions d he could stay on warfarin Buprenorphine Buccal Film (Belbuca) for Chronic Pain Which of the following statements about buprenorphine is true? a in dosages of 75-1800 mcg per day, it has typical opioid agonist effects b there is no ceiling for its agonist effects c it is more likely than morphine to cause respiratory depression d it should not be used with strong CYP2D6 inhibitors Calcipotriene/Betamethasone Foam (Enstilar) for Psoriasis In clinical trials, approximately what percentage of patients achieved treatment success with Enstilar? a 30% b 50% c 70% d 90% A 29-year-old woman with psoriasis is in her second month of pregnancy She has been given a prescription for Enstilar by her dermatologist, but has not filled it because she is concerned about possible adverse effects on her baby You could tell her that: a in animal studies calcipotriene has had toxic effects on the fetus b betamethasone has had teratogenic effects in animals c there are no adequate studies of the drug’s safety in pregnant women d all of the above Dichlorphenamide (Keveyis) for Periodic Paralysis 10 Dichlorphenamide is a: a potassium-sparing diuretic b mineralocorticoid c carbonic anhydrase inhibitor d bisphosphonate ACPE UPN: Per Issue Exam: 0379-0000-16-492-H01-P; Release: April 11, 2016, Expire: April 11, 2017 Comprehensive Exam 74: 0379-0000-16-074-H01-P; Release: July 2016, Expire: July 2017 PRESIDENT: Mark Abramowicz, M.D.; VICE PRESIDENT AND EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR IN CHIEF: Jean-Marie Pflomm, Pharm.D.; ASSOCIATE EDITORS: Susan M Daron, Pharm.D., Amy Faucard, MLS, Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D CONTRIBUTING EDITORS: Carl W Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K Dalton, M.D., M.P.H., University of Michigan Medical School; Eric J Epstein, M.D., Albert Einstein College of Medicine; Jane P Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Franco M Muggia, M.D., New York University Medical Center; Sandip K Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M Roden, M.D., Vanderbilt University School of Medicine; Esperance A.K Schaefer, M.D., M.P.H., Harvard Medical School; F Estelle R Simons, M.D., University of Manitoba; Neal H Steigbigel, M.D., New York University School of Medicine; Arthur M F Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown EXECUTIVE DIRECTOR OF SALES: Gene Carbona; FULFILLMENT AND SYSTEMS MANAGER: Cristine Romatowski; EXECUTIVE DIRECTOR OF MARKETING AND COMMUNICATIONS: Joanne F Valentino; VICE PRESIDENT AND PUBLISHER: Yosef Wissner-Levy Founded in 1959 by Arthur Kallet and Harold Aaron, M.D Copyright and Disclaimer: The Medical Letter, Inc is an independent nonprofit organization that provides healthcare professionals with unbiased drug prescribing recommendations The editorial process used for its publications relies on a review of published and unpublished literature, with an emphasis on controlled clinical trials, and on the opinions of its consultants The Medical Letter, Inc is supported solely by subscription fees and accepts no advertising, grants, or donations No part of the material may be reproduced or transmitted by any process in whole or in part without prior permission in writing The editors not warrant that all the material in this publication is accurate and complete in every respect The editors shall not be held responsible for any damage resulting from any error, inaccuracy, or omission Subscription Services Address: The Medical Letter, Inc 145 Huguenot St Ste 312 New Rochelle, NY 10801-7537 www.medicalletter.org Get Connected: Customer Service: Call: 800-211-2769 or 914-235-0500 Fax: 914-632-1733 E-mail: custserv@medicalletter.org Permissions: To reproduce any portion of this issue, please e-mail your request to: permissions@medicalletter.org Copyright 2016 ISSN 1523-2859 Subscriptions (US): year - $129; 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