The medical letter on drugs and therapeutics september 26 2016

The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1504 Volume 56 September 26, 2016 IN THIS ISSUE Drugs for Irritable Bowel Syndrome p 121 In Brief: An Over-the-Counter Retinoid for Acne p 126 Sebelipase Alfa (Kanuma) for Lysosomal Acid Lipase Deficiency .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 September 26, 2016 Take CME Exams ISSUE ISSUE No 1433 1504 Volume 56 ▶ ALSO IN THIS ISSUE In Brief: An Over-the-Counter Retinoid for Acne p 126 Sebelipase Alfa (Kanuma) for Lysosomal Acid Lipase Deficiency .online only Drugs for Irritable Bowel Syndrome Irritable bowel syndrome (IBS) is a common disorder characterized by chronic, intermittent abdominal pain or discomfort and altered bowel habits.1 It is subtyped according to the predominant bowel symptom as IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed type (IBS-M), or unclassified (IBS-U).2 Since the exact cause of IBS is unknown, the goal of treatment is symptom control.3 DIET — Many patients with IBS report symptoms associated with meals or specific foods.4 Avoidance of gluten, gas-producing foods, and fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) may be effective in reducing some IBS symptoms.5-8 FODMAPs are poorly absorbed, rapidly fermented short-chain carbohydrates that can increase gas production and induce osmosis in the intestinal lumen, causing bloating and abdominal pain Some common sources of FODMAPs are apples, cherries, onions, garlic, milk, yogurt, wheat, and highfructose corn syrup.9 ANTISPASMODICS — Antispasmodics such as hyoscyamine (Levsin, and others) and dicyclomine (Bentyl, and generics) induce intestinal smooth muscle relaxation through direct myorelaxant effects or anticholinergic mechanisms and improve abdominal pain and overall IBS symptoms.10 Antispasmodics are often used as needed for acute attacks of abdominal pain, or before meals in patients with postprandial symptoms such as pain, gas, bloating, or fecal urgency Adverse Effects – High doses of hyoscyamine and dicyclomine can cause anticholinergic effects including visual disturbances, confusion, dry mouth, urinary retention, palpitations, and constipation Antispasmodics should be used with caution in patients with IBS-C Recommendations for Treatment of IBS ▶ ▶ ▶ Mild symptoms often respond to dietary changes Antispasmodics can be used as needed for abdominal pain or postprandial symptoms Antidepressants can improve abdominal pain and global symptoms They may be considered for patients with moderate to severe symptoms IBS with Constipation (IBS-C) ▶ ▶ ▶ Fiber may relieve constipation in patients with mild symptoms Polyethylene glycol can increase the frequency of bowel movements, but may not improve overall symptoms or abdominal pain Lubiprostone or linaclotide can be tried in patients whose symptoms have not responded to polyethylene glycol IBS with Diarrhea (IBS-D) ▶ ▶ ▶ Taken as needed, loperamide can reduce postprandial urgency and stool frequency, but it does not improve global symptoms Rifaximin and eluxadoline have been modestly more effective than placebo in relieving symptoms Alosetron should be reserved for women with severe, chronic IBS-D that is unresponsive to other drugs Peppermint Oil – Peppermint oil blocks calcium channels, causing relaxation of gastrointestinal smooth muscle In one trial in 90 patients with IBS, significantly more patients taking an enteric-coated, delayed-release formulation of peppermint oil (187 mg three times daily prior to meals) were free from abdominal pain and discomfort at weeks than those taking placebo (43% vs 22%).11 In a small trial in patients with IBS-D or IBS-M, an entericcoated microsphere formulation of peppermint oil improved IBS symptom scores more than placebo did.12 Peppermint oil is generally well tolerated; the most common adverse effect is heartburn The optimal preparation and dosage of peppermint oil for treatment of IBS has not been established ANTIDEPRESSANTS — Antidepressants can reduce abdominal pain and alter gastrointestinal transit time They are generally used when symptoms (particularly abdominal pain) are moderate to severe 121 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter ® Vol 58 (1504) September 26, 2016 Table Some Oral Drugs for Irritable Bowel Syndrome Drugs Some Available Formulations Usual Adult Dosage1 Cost2 20-40 mg qid $23.20 86.30 44.60 Global Symptoms of Irritable Bowel Syndrome Antispasmodics Dicyclomine3 – generic Bentyl (Allergan) Hyoscyamine3 – generic Anaspaz (Ascher) Levsin (Meda) Levsin-SL extended-release – generic Levbid (Meda) Peppermint oil3 – generic Pepogest (Nature's Way) IBgard7 (IM Health Sciences) 10 mg caps; 20 mg tabs; 10 mg/5 mL soln 10 mg caps; 20 mg tabs 0.125 mg tabs; 0.125 mg ODT; 0.125 mg SL tabs; 0.125 mg/5 mL elixir; 0.125 mg/mL soln 0.125 mg ODT 0.125 mg tabs 0.125 mg SL tabs 0.375 mg ER tabs 0.375-0.75 mg bid 50 mg EC caps 0.2 mL EC caps 90 mg caps 1-3 caps tid4 cap tid4 180 mg tid8 Selective Serotonin Reuptake Inhibitors (SSRIs) Paroxetine3 – generic 10, 20, 30, 40 mg tabs Paxil (Apotex) 10, 20, 30, 40 mg tabs; 10 mg/5 mL susp extended-release – generic 12.5, 25, 37.5 mg ER tabs Paxil CR Citalopram3 – generic 10, 20, 40 mg tabs; 40 mg ODT; 10 mg/5 mL soln Celexa (Allergan) 10, 20, 40 mg tabs Fluoxetine3 – generic 10, 20, 40 mg caps; 10, 20 mg tabs; 20 mg/5 mL soln Prozac (Lilly) 10, 20, 40 mg caps Tricyclic Antidepressants (TCAs) Amitriptyline3 – generic 10, 25, 50, 75, 100, 150 mg tabs Desipramine3 – generic Norpramin (Validus) Nortriptyline3 – generic Pamelor (Mallinckrodt) 10, 25, 50, 75, 100, 150 mg tabs 10, 25, 50, 75 mg caps; 10 mg/5 mL soln 10, 25, 50, 75 mg caps 0.125-0.25 mg tid-qid 10-20 mg once/d 12.5-37.5 mg once/d 20-40 mg once/d 20 mg once/d 10-150 mg once/d or divided bid 12.5-125 mg once/d or divided bid 10-125 mg once/d or divided bid 19.00 197.82 197.82 67.40 225.10 10.005 24.006 120.009 8.30 165.30 139.70 163.20 4.80 226.70 5.50 353.40 4.20 20.26 27.90 8.50 1002.00 Irritable Bowel Syndrome with Constipation (IBS-C) Chloride Channel Activator Lubiprostone10 – Amitiza (Takeda) Guanylate Cyclase-C Receptor Agonist Linaclotide – Linzess (Allergan/Ironwood) 8, 24 mcg caps mcg bid11 330.30 145, 290 mcg caps 290 mcg once/d12 332.80 550 mg tid x 14d13 1282.8014 Irritable Bowel Syndrome with Diarrhea (IBS-D) Antibiotic Rifaximin – Xifaxan (Salix) 200, 550 mg tabs Mu-Opioid Receptor Agonist/Delta-Opioid Receptor Antagonist Eluxadoline15 – Viberzi (Allergan) 75, 100 mg tabs 5-HT Modulators Alosetron17 – generic 0.5, mg tabs Lotronex (Prometheus) Ondansetron – generic 4, 8, 24 mg tabs; 4, mg ODT; mg/5 mL soln Zofran (Novartis) 100 mg bid16 0.5-1 mg bid18 mg once/d 19 960.00 1264.20 1757.90 19.20 697.70 EC = enteric-coated; ER = extended-release; ODT = orally disintegrating tablets; soln = solution; SL = sublingual; susp = suspension Dosage may need to be adjusted for renal or hepatic impairment Approximate WAC for 30 days’ treatment at the lowest usual adult 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 September 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Not FDA-approved for treatment of IBS Should be taken 30 minutes before meals Approximate cost for 90 capsules manufactured by Mason Natural at walgreens.com Approximate cost for packages containing 60 capsules each at cvs.com Enteric-coated microsphere formulation marketed as a medical food Should be taken at least 30 minutes before or after food The capsules should not be crushed or chewed The capsule can be opened and the contents sprinkled on applesauce and ingested Approximate cost for packages containing 48 capsules each at cvs.com 10 FDA-approved for IBS-C in women ≥18 years old 11 Should be taken with meals and ≥8 ounces of water to minimize nausea 12 Should be taken in the morning 30 minutes before eating The capsules should not be crushed or chewed The capsules can be opened and the contents sprinkled on applesauce or dispersed in water and ingested 13 Can be repeated up to times if symptoms recur 14 Cost for 14 days’ treatment 15 Classified as a schedule IV controlled substance 16 The recommended dosage is 75 mg bid for patients who cannot tolerate the usual dosage, not have a gallbladder, are receiving concomitant treatment with an OATP1B1 inhibitor, or have mild to moderate hepatic impairment 17 Alosetron is FDA-approved only for use in women with severe IBS-D who have chronic symptoms (≥6 months), no abnormalities of the GI tract, and whose IBS has not responded adequately to conventional therapy Prescribers are expected to complete training as part of a Risk Evaluation and Mitigation Strategy (REMS) program 18 If IBS is not controlled after weeks of treatment with alosetron mg bid, the drug should be discontinued 19 K Garsed et al Gut 2014; 63:1617 122 The Medical Letter ® The results of studies examining the effects of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) for treatment of IBS have been variable One meta-analysis of 17 trials found that both TCAs and SSRIs were effective for treatment of IBS symptoms.13 In another metaanalysis that included 12 trials, a subgroup analysis found global symptoms of IBS improved with TCAs, but not with SSRIs.14 Adverse Effects – TCAs can cause fatigue, dizziness, weight gain, sedation, and anticholinergic effects including dry mouth, urinary retention, blurred vision, confusion, and constipation; they should be used with caution in patients with IBS-C SSRIs can cause weight gain, sexual dysfunction, and diarrhea PROBIOTICS — Changes in intestinal flora may contribute to IBS symptoms through a variety of mechanisms, including differential fermentation and gas production, changes in gut mucosa, and alterations in gut permeability.4 A meta-analysis of 24 randomized controlled trials in patients with IBS found that probiotics improved global symptoms, abdominal pain, bloating, and flatulence.15 The optimal species, strains, and dosages of probiotics for treatment of IBS have not been established Adverse Effects – Probiotics can cause gas, diarrhea, bloating, and hiccups; these effects are usually mild and transient.16 DRUGS FOR IBS-C FIBER — Fiber supplementation is effective in relieving IBS-related constipation, but its effect on other IBS symptoms is unclear In one study in 275 patients with IBS-C or IBS-D who were randomized to receive soluble fiber (psyllium), insoluble fiber (bran), or placebo, psyllium, but not bran, reduced symptom severity at months significantly more than placebo.17 A meta-analysis that included 12 studies found no improvement in abdominal pain or IBS symptom score with either soluble or insoluble fiber.10 Fiber can increase gas production and cause bloating and abdominal discomfort; slow titration of the dose can minimize these effects POLYETHYLENE GLYCOL — The osmotic laxative polyethylene glycol (PEG; Miralax, and generics) can increase the frequency of bowel movements in patients with IBS-C, but there is no evidence that it improves overall symptoms or abdominal pain associated with IBS.18 It is well tolerated and safe for long-term use Vol 58 (1504) September 26, 2016 LUBIPROSTONE — Lubiprostone (Amitiza) is a prostaglandin derivative that activates gastrointestinal chloride channels, stimulating intestinal fluid secretion.19 It is FDA-approved for treatment of IBS-C in women ≥18 years old In two 12-week, randomized, double-blind trials, lubiprostone provided greater relief of IBS symptoms than placebo; 18% of patients taking lubiprostone were considered overall responders compared to 10% of those taking placebo.20 In a withdrawal trial, lubiprostone responders were re-randomized to continue lubiprostone or switch to placebo After 4-weeks, there was no significant difference between the two groups in the percentage of patients who maintained a response (38% with lubiprostone vs 40% with placebo).21 Adverse Effects – Nausea and diarrhea are the most common adverse effects of lubiprostone Dyspnea has been reported rarely Pregnancy – There was a dose-dependent increase in fetal loss when pregnant guinea pigs were given lubiprostone in doses higher than those recommended for humans There are no adequate studies of lubiprostone in pregnant women Drug Interactions – Methadone may reduce activation of chloride channels in the gut by lubiprostone LINACLOTIDE — Linaclotide (Linzess), a peptide that activates guanylate cyclase-C receptors on the intestinal epithelium, resulting in increased luminal intestinal secretions and accelerated intestinal transit, is FDA-approved for treatment of IBS-C.22 In a 12-week, randomized, double-blind trial in 800 patients with IBS-C, significantly more patients taking linaclotide had a ≥30% decrease in abdominal pain and at least more spontaneous bowel movement for at least of 12 weeks than those taking placebo (34% vs 21%) A 26-week trial had similar results In both trials, there was an increase in overall IBS symptom relief and a decrease in bloating severity with linaclotide compared to placebo.23,24 Adverse Effects – The most common adverse effects of linaclotide are diarrhea, abdominal pain, flatulence, and abdominal distention The labeling includes a boxed warning against use of the drug in patients 3 alcoholic The Medical Letter ® beverages per day); such patients are at increased risk for pancreatitis Euphoria and feelings of drunkenness have been reported in clinical trials; eluxadoline is classified as a schedule IV controlled substance Pregnancy – Supratherapeutic doses of the drug did not affect prenatal or postnatal development in rats Eluxadoline has not been studied in pregnant women Drug Interactions – Coadministration of eluxadoline with other drugs that reduce GI motility, such as anticholinergics or systemically active opioids, could result in additive effects and should be avoided Loperamide can be administered with eluxadoline for acute treatment of severe diarrhea, but it should be discontinued if constipation occurs Eluxadoline is a substrate of organic anion transporting polypeptide (OATP) 1B1 and an inhibitor of OATP1B1 and breast cancer resistance protein (BCRP) Drugs that are substrates of both transporters such as rosuvastatin (Crestor, and generics) should be administered at the lowest effective dose if taken with eluxadoline 5-HT3 ANTAGONISTS — Serotonin (5-HT) plays a major role in the regulation of intestinal motility, secretion, and visceral sensitivity.2,3 Antagonism of 5-HT3 receptors has been shown to decrease pain and slow intestinal transit Alosetron (Lotronex, and generics), a 5-HT3 receptor antagonist, relieves abdominal pain and discomfort, decreases bowel urgency and stool frequency, and improves stool consistency.32 It was initially approved for treatment of women with IBS-D, but was withdrawn from the market in 2000 because it was associated with severe constipation and ischemic colitis It was reintroduced in 2002 with new labeling recommending a 50% lower starting dose and limiting the use of alosetron to women with severe chronic IBS-D refractory to conventional therapies Prescribers are expected to complete training as part of a Risk Evaluation and Mitigation Strategy (REMS) program.33 Ondansetron (Zofran, and generics) is a 5-HT3 receptor antagonist FDA-approved for prevention of chemotherapy-induced and postoperative nausea and vomiting In a randomized, double-blind, placebocontrolled, crossover study in 120 patients with IBS-D, ondansetron taken at a median dose of mg daily decreased the frequency of loose stools and reduced urgency and bloating, but it did not significantly improve pain scores.34 The most common adverse Vol 58 (1504) September 26, 2016 effect was constipation, which occurred in 9% of patients taking the drug BILE ACID SEQUESTRANTS — Bile acid malabsorption may play a role in IBS-D.35 Bile acids stimulate colonic secretions and motility, causing diarrhea The bile acid sequestrants cholestyramine (Questran, and others), colestipol (Colestid, and generics), and colesevelam (Welchol), which are FDA-approved for use in patients with hyperlipidemia, may increase colonic transit time and improve IBS symptoms, but data are limited.36,37 They can cause constipation, heartburn, nausea, eructation, flatulence and bloating, and can impair absorption of fat-soluble vitamins Colesevelam is better tolerated than cholestyramine or colestipol ■ WD Chey et al Irritable bowel syndrome: a clinical review JAMA 2015; 313:949 AC Ford et al American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation Am J Gastroenterol 2014; 109(suppl 1):S2 M Camilleri Peripheral mechanisms in irritable bowel syndrome N Engl J Med 2012; 367:1626 M Rajilić-Stojanović et al Intestinal microbiota and diet in IBS: causes, consequences, or epiphenomena? Am J Gastroenterol 2015; 110:278 JR Biesiekierski et al Gluten causes gastrointestinal symptoms in subjects without celiac disease: double-blind randomized placebo-controlled trial Am J Gastroenterol 2011; 106:508 JR Biesiekierski et al No effects of gluten in patients with selfreported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates Gastroenterology 2013; 145:320 HM Staudacher et al Fermentable carbohydrate restriction reduces luminal bifidobacteria and gastrointestinal symptoms in patients with irritable bowel syndrome J Nutr 2012; 142:1510 L Böhn et al Diet low in FODMAPs reduces symptoms of irritable bowel syndrome as well as traditional dietary advice: a randomized controlled trial Gastroenterology 2015; 149:1399 SJ Shepherd et al Short-chain carbohydrates and functional gastrointestinal disorders Am J Gastroenterol 2013; 108:707 10 L Ruepert et al Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome Cochrane Database Syst Rev 2011; 8:CD003460 11 S Merat et al The effect of enteric-coated, delayed-release peppermint oil on irritable bowel syndrome Dig Dis Sci 2010; 55:1385 12 BD Cash et al A novel delivery system of peppermint oil is an effective therapy for irritable bowel syndrome symptoms Dig Dis Sci 2016; 61:560 13 AC Ford et al Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis Am J Gastroenterol 2014; 109:1350 14 C Xie et al Efficacy and safety of antidepressants for the treatment of irritable bowel syndrome: a meta-analysis PLoS One 2015; 10:e0127815 15 AC Ford et al Efficacy of prebiotics, probiotics, and synbiotics in irritable bowel syndrome and chronic idiopathic constipation: systematic review and meta-analysis Am J Gastroenterol 2014; 109:1547 125 The Medical Letter ® 16 Probiotics revisited Med Lett Drugs Ther 2013; 55:3 17 CJ Bijkerk et al Soluble or insoluble fibre in irritable bowel syndrome in primary care? Randomised placebo controlled trial BMJ 2009; 339:b3154 18 RW Chapman et al Randomized clinical trial: macrogol/ PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowl syndrome Am J Gastroenterol 2013; 108:1508 19 Lubiprostone (Amitiza) for irritable bowel syndrome with constipation Med Lett Drugs Ther 2008; 50:53 20 DA Drossman et al Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome - results of two randomized, placebo-controlled studies Aliment Pharmacol Ther 2009; 29:329 21 FDA Medical review: lubiprostone Available at: www.access data.fda.gov/drugsatfda_docs/nda/2008/021908s005_MedR pdf Accessed September 15, 2016 22 Linaclotide (Linzess) for constipation Med Lett Drugs Ther 2012; 54:91 23 S Rao et al A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation Am J Gastroenterol 2012; 107:1714 24 WD Chey et al Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety Am J Gastroenterol 2012; 107:1702 25 FDA Postmarket drug safety information for patients and providers Zelnorm (tegaserod maleate) information Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrug SafetyInformationforPatientsandProviders/ucm103223.htm Accessed September 15, 2016 26 Rifaximin (Xifaxan) for irritable bowel syndrome with diarrhea Med Lett Drugs Ther 2015; 57:109 27 M Pimentel et al Rifaximin therapy for patients with irritable bowel syndrome without constipation N Engl J Med 2011; 364:22 28 A Lembo et al Repeat treatment with rifaximin is safe and effective in patients with diarrhea-predominant irritable bowel syndrome Gastroenterology 2016 Aug 12 (epub) 29 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2016 Aug (epub) Available at: http:// secure.medicalletter.org/downloads/CYP_PGP_Tables.pdf Accessed September 15, 2016 30 Eluxadoline (Viberzi) for irritable bowel syndrome with diarrhea Med Lett Drugs Ther 2016; 58:4 31 AJ Lembo et al Eluxadoline for irritable bowel syndrome with diarrhea N Engl J Med 2016; 374:242 32 Alosetron (Lotronex) revisited Med Lett Drugs Ther 2002; 44:67 33 FDA Postmarket drug safety information for patients and providers Lotronex (alosetron hydrochloride) information Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrug SafetyInformationforPatientsandProviders/ucm110450.htm Accessed September 15, 2016 34 K Garsed et al A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea Gut 2014; 63:1617 35 M Camilleri Bile acid diarrhea: prevalence, pathogenesis, and therapy Gut Liver 2015; 9:332 36 ST Odunsi-Shiyanbade et al Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on intestinal transit and bowel function Clin Gastroenterol Hepatol 2010; 8:159 37 P-O Stotzer et al Effect of cholestyramine on gastrointestinal transit in patients with idiopathic bile acid diarrhea: a prospective, open-label study Neuroenterology 2013; 2:1 126 Vol 58 (1504) September 26, 2016 IN BRIEF An Over-the-Counter Retinoid for Acne Differin Gel 0.1% (Galderma), a topical formulation of the retinoid adapalene, will soon be available over the counter (OTC) for once-daily treatment of acne in patients ≥12 years old It is the first topical retinoid to be approved for sale over the counter All topical retinoids normalize keratinization and appear to have anti-inflammatory effects; whether any one topical retinoid is more effective than any other is not clear Many dermatologists now recommend topical retinoids for first-line treatment of acne; they can be used alone or in combination with antibiotics to treat both inflamed and noninflamed acne lesions, or for maintenance treatment Retinoid/antimicrobial combinations are more effective than either component alone, particularly for patients with inflammatory lesions.1 Adverse effects of topical retinoids include dry skin, scaling, photosensitivity, erythema, burning, and pruritus Although only small amounts of the drug are absorbed systemically following topical application, adapalene is classified as category C (teratogenic in rats; no adequate studies in pregnant women) for use during pregnancy Adapalene (Differin, and generics) is available by prescription in 0.1% gel, cream, and lotion formulations and in a 0.3% gel formulation It is also available by prescription in combination with the oxidizing agent benzoyl peroxide (Epiduo; Epiduo Forte) The cost of one 45-gram tube ranges from about $157 for generic adapalene to $580 for Differin.2 The cost of OTC Differin Gel 0.1% was not available at the time of publication ■ Drugs for acne Med Lett Drugs Ther 2016; 58:13 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 September 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Available Online Sebelipase Alfa (Kanuma) for Lysosomal Acid Lipase Deficiency www.medicalletter.org/TML-article-1504c Coming Soon in The Medical Letter: Influenza Vaccine 2016-2017 Glycopyrrolate/Formoterol (Bevespi Aerosphere) for COPD Nitisinone (Orfadin) for Hereditary Tyrosinemia Drugs for Psychotic Disorders Follow us on Twitter Like us on Facebook 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 1504) ▶ September 26, 2016 Sebelipase Alfa (Kanuma) for Lysosomal Acid Lipase Deficiency The FDA has approved sebelipase alfa (Kanuma – Alexion), a recombinant form of lysosomal acid lipase (LAL), for enzyme replacement therapy in patients with LAL deficiency Sebelipase alfa is the first drug to be approved in the US for treatment of LAL deficiency, a rare autosomal recessive storage disease Pronunciation Key Sebelipase alfa: se" be lye' pase al' fa Kanuma: kuh new' muh LAL DEFICIENCY — LAL is a lysosomal glycoprotein enzyme that catalyzes the hydrolysis of cholesteryl esters and triglycerides A complete deficiency of the enzyme (Wolman disease; estimated prevalence 1:500,000 live births) causes malabsorption, growth failure, hepatomegaly, adrenal cortical insufficiency, and death within the first year of life Partial LAL deficiency (cholesteryl ester storage disease; estimated prevalence 1:40,000), which can present later in childhood or in adulthood, is associated with gastrointestinal symptoms, hepatosplenomegaly, elevated transaminase levels, and dyslipidemia, often progressing to hepatic fibrosis and cirrhosis and a need for liver transplantation.1-3 CLINICAL STUDIES — In an ongoing clinical trial in infants with rapidly progressive LAL deficiency in the first months of life, sebelipase alfa improved survival at 12 months of age compared with historical controls; of infants treated with sebelipase alfa were alive at 12 months of age, compared to of 21 untreated historical controls, who all died by months of age.4,5 In a double-blind trial, 66 patients ≥4 years old with LAL deficiency were randomized to receive sebelipase alfa (1 mg/kg IV every other week) or placebo for 20 weeks The alanine aminotransferase (ALT) level, the primary endpoint, was normal at 20 weeks in 11 of 36 (31%) patients who received sebelipase alfa and in of 30 (7%) who received placebo The mean reduction from baseline in ALT levels was 58 U/L with sebelipase alfa and U/L with placebo Both of these differences were statistically significant Lipid levels improved and reductions in hepatic fat content were reported in patients receiving the drug In an open-label extension of the trial, further reductions in LDL and non-HDL cholesterol were reported with sebelipase alfa.6,7 ADVERSE EFFECTS — Diarrhea, vomiting, fever, and rhinitis occurred in ≥50% of infants treated with sebelipase alfa In clinical trials, symptoms consistent with anaphylaxis occurred in of 106 patients treated with the drug; hypersensitivity reactions occurred in 21 of 106 patients, including of 14 infants Neutralizing antibodies to sebelipase alfa have developed; whether they reduce the efficacy of the drug is unknown Sebelipase alfa is prepared from eggs produced by genetically engineered chickens; it has not been studied in patients with a history of egg allergy DOSAGE, ADMINISTRATION, AND COST — Kanuma is available in 20 mg/10 mL single-use vials For infants with rapidly progressive LAL deficiency presenting before months of age, the recommended dosage of sebelipase alfa is mg/kg infused IV over ≥2 hours once weekly; the dose can be increased to mg/kg if the response is inadequate The dosage of sebelipase alfa for children and adults with LAL deficiency is mg/kg infused IV once every other week One 20 mg/10 mL single-use vial of Kanuma costs $10,000.8 CONCLUSION — Enzyme replacement therapy with sebelipase alfa (Kanuma) can be life-saving, or at least life-extending, in infants with rapidly progressive lysosomal acid lipase deficiency, and it improves lipid and hepatic abnormalities in older patients with the disease ■ AF Porto Lysosomal acid lipase deficiency: diagnosis and treatment of Wolman and cholesteryl ester storage diseases Pediatr Endocrinol Rev 2014; Suppl 1:125 DL Bernstein et al Cholesteryl ester storage disease: review of the findings in 135 reported patients with an underdiagnosed disease J Hepatol 2013; 58:1230 EP Hoffman et al Lysosomal acid lipase deficiency Gene reviews: University of Washington, Seattle; 2016 September Available at: www.ncbi.nlm.nih.gov/books/NBK305870 Accessed September 15, 2016 SA Jones et al Effect of sebelipase alfa on survival and liver function in infants with rapidly progressive lysosomal acid lipase deficiency Mol Genet Metab 2015;114:S59 e126 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 58 (1504) ® September 26, 2016 FDA Medical review: sebelipase alfa Available at: www accessdata.fda.gov/drugsatfda_docsnda/2015/125561Orig1s0 00MedR.pdf Accessed September 15, 2016 BK Burton et al A phase trial of sebelipase alfa in lysosomal acid lipase deficiency N Engl J Med 2015; 373:1010 DJ Rader Lysosomal acid lipase deficiency — a new therapy for a genetic lipid disease N Engl J Med 2015; 373:1071 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 September 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/ drugpricing-policy 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 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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 1504 Questions (Correspond to questions #61-70 in Comprehensive Exam #75, available January 2017) A 23-year-old woman with IBS-D complains of diarrhea, bloating, and abdominal cramps She has not taken any medications for IBS in the past She asks if she should take an antidiarrheal such as loperamide You could tell her that: a loperamide can reduce postprandial urgency and stool frequency b loperamide significantly reduces global IBS symptoms c she should take alosetron instead d all of the above Drugs for Irritable Bowel Syndrome Antispasmodics: a induce intestinal smooth muscle relaxation b should be used with caution in patients with IBS-C c can relieve abdominal pain d all of the above Antidepressants: a should be used for first-line treatment of mild IBS symptoms b can reduce abdominal pain and alter GI transit time c should only be used in patients with IBS-C d all of the above A 26-year-old woman with IBS-C claims that changes in her diet have not increased the frequency of her bowel movements or relieved her abdominal pain and bloating You consider recommending fiber supplementation Which of the following statements about the use of fiber in IBS is true? a It is effective in relieving IBS-related constipation b It reduces abdominal pain and bloating c Bran is superior to psyllium in improving IBS symptoms d all of the above A 25-year-old man with IBS-C has not had adequate relief of his symptoms with fiber supplementation and polyethylene glycol You could tell him that: a he should stop taking polyethylene glycol because it can only be used short term b lubiprostone has not been shown to reduce IBS symptoms in clinical trials c lubiprostone and linaclotide were more effective than placebo for treatment of IBS-C in clinical trials d linaclotide was significantly more effective than lubiprostone for treatment of IBS-C in clinical trials All of the following have been shown to relieve pain associated with IBS except: a linaclotide b rifaximin c polyethylene glycol d tricyclic antidepressants A 45-year-old man with IBS-D saw an advertisement on television for rifaximin and asks you if he should start taking the drug Which of the following should you tell him about rifaximin? a It is a minimally absorbed antibiotic b In a clinical trial, relapse occurred within 18 weeks in 64% of patients who initially responded to rifaximin c It is taken times/day for 14 days and two additional 14-day courses can be taken if symptoms recur d all of the above Eluxadoline can cause: a dehydration b hypokalemia c pancreatitis d Clostridium difficile-associated colitis Eluxadoline is contraindicated in patients who: a have a history of depression b drink more than alcoholic beverages per day c have IBS-D d have severe renal dysfunction 10 Your colleague is treating a patient with IBS-D and asks you about the use of 5-HT modulators for this indication You could tell him that: a antagonism of 5-HT3 receptors has been shown to decrease pain and slow intestinal transit b alosetron has been associated with severe constipation and ischemic colitis c a small trial reported a decrease in the frequency of loose stools with ondansetron d all of the above ACPE UPN: Per Issue Exam: 0379-0000-16-504-H01-P; Release: September 26, 2016, Expire: September 26, 2017 Comprehensive Exam 75: 0379-0000-17-075-H01-P; Release: January 2017, Expire: January 2018 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; years - $232; years - $345 $65 per year for students, interns, residents, and fellows in the US and Canada Reprints - $12 each Site License Inquiries: E-mail: info@medicalletter.org Call: 800-211-2769 ext 315 Special rates available for bulk subscriptions The Medical Letter ... distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Volume 58 (Issue 1504) ▶ September 26, 2016 Sebelipase... 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... E-mail: info@medicalletter.org Call: 800-211-2769 ext 315 Special rates available for bulk subscriptions The Medical Letter The Medical Letter ® Continuing Medical Education Program medicalletter.org/cme-program