The medical letter on drugs and therapeutics july 21 2014

In Brief: Generic Celecoxib The FDA has authorized two manufacturers (Teva, Mylan) to market generic formulations of celecoxib (Celebrex – Pfizer), the only COX-2 selective inhibitor remaining on the US market.... Extended-Release Oxycodone and Acetaminophen (Xartemis XR) The FDA has approved a fixed-dose extended-release formulation of oxycodone and acetaminophen (Xartemis XR – Mallinckrodt) for oral treatment of acute pain severe enough to require an... Oral Propranolol (Hemangeol) for Infantile Hemangioma The FDA has approved an oral solution of the nonselective beta-adrenergic blocker propranolol (Hemangeol – Pierre Fabre) for treatment of proliferating infantile hemangiomas. Ceritinib (Zykadia) for Non-Small Cell Lung Cancer Ceritinib (Zykadia – Novartis), an oral tyrosine kinase inhibitor, has received accelerated approval from the FDA for treatment of patients with anaplastic lymphoma kinase (ALK)-positive... A Responsive Neurostimulator Device (RNS System) for Epilepsy The FDA has approved the use of a responsive neurostimulator device (RNS System – NeuroPace) for adjunctive treatment of adults with partial-onset seizures that are not controlled with... In Brief: Esomeprazole Strontium The FDA has approved the proton pump inhibitor (PPI) esomeprazole strontium for use in adults for the same indications as esomeprazole magnesium (Nexium): treatment of gastroesophageal... In Brief: Low-Dose Indomethacin (Tivorbex) for Pain The same pharmaceutical company (Iroko) that recently marketed low-dose diclofenac (Zorvolex) for treatment of mild to moderate acute pain1 has now received approval from the FDA to market...

The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 ISSUE ISSUE No 1433 1447 Volume 56 July 21, 2014 IN THIS ISSUE In Brief: Generic Celecoxib p 61 Extended-Release Oxycodone and Acetaminophen (Xartemis XR) p 61 Oral Propanolol (Hemangeol) for Infantile Hemangiomas p 61 Ceritinib (Zykadia) for Non-Small Cell Lung Cancer p 62 A Responsive Neurostimulator Device (RNS System) for Epilepsy p 63 In Brief: Esomeprazole Strontium p 64 In Brief: Low-Dose Indomethacin (Tivorbex) p 64 Important Copyright Message FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS The Medical Letter, Inc publications are protected by U.S and international copyright laws Forwarding, copying or any distribution of this material is prohibited Sharing a password with a non-subscriber or otherwise making the contents of this site available to third parties is strictly prohibited By accessing and reading the attached content I agree to comply with U.S and international copyright laws and these terms and conditions of The Medical Letter, Inc For further information click: Subscriptions, Site Licenses, Reprints or call customer service at: 800-211-2769 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter publications are protected by US and international copyright laws Forwarding, copying or any other distribution of this material is strictly prohibited For further information call: 800-211-2769 The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 56 ISSUE ISSUE No 1433 1447 Volume 56 July 21, 2014 Take CME Exams ALSO IN THIS ISSUE Oral Propranolol (Hemangeol) for Infantile Hemangioma p 61 Ceritinib (Zykadia) for Non-Small Cell Lung Cancer p 62 A Responsive Neurostimulator Device (RNS System) for Epilepsy p 63 In Brief: Esomeprazole Strontium p 64 In Brief: Low-Dose Indomethacin (Tivorbex) for Pain p 64 ▶ IN BRIEF Generic Celecoxib The FDA has authorized two manufacturers (Teva, Mylan) to market generic formulations of celecoxib (Celebrex – Pfizer), the only COX-2 selective inhibitor remaining on the US market Celecoxib is less likely than nonselective NSAIDs to cause gastric ulcers or other GI toxicity,1 and unlike traditional NSAIDs, it does not have an antiplatelet effect Celecoxib is much less COX-2 selective than rofecoxib (Vioxx), which was removed from the US market because of an increased risk of cardiovascular events One analysis of randomized clinical trials that included a total of about 26,000 patients taking celecoxib found no evidence of an increased risk of cardiovascular thrombotic events compared to nonselective NSAIDs or placebo.2 A review of controlled observational studies found an increased cardiovascular risk with celecoxib (RR 1.17) that was similar to the risk with ibuprofen (RR 1.18) and slightly higher than the risk with naproxen (RR 1.09).3 All NSAIDs can cause renal toxicity, especially in the elderly.4 ■ PL McCormack Celecoxib: a review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis Drugs 2011; 71:2457 WB White et al Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials Am J Cardiol 2007; 99:91 P McGettigan and D Henry Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies PLoS Med 2011; 8:e1001098 RL Barkin et al Should nonsteroidal anti-inflammatory drugs (NSAIDs) be prescribed to the older adult? Drugs Aging 2010; 27:775 Extended-Release Oxycodone and Acetaminophen (Xartemis XR) The FDA has approved a fixed-dose extended-release formulation of oxycodone and acetaminophen (Xartemis XR – Mallinckrodt) for oral treatment of acute pain severe enough to require an opioid Oxycodone is available in the US as a single entity in oral immediate-release (Oxecta, and others) and extendedrelease (OxyContin) formulations Immediate-release oxycodone is also available in combination with aspirin (Percodan, and others), acetaminophen (Percocet, and others), or ibuprofen (see Table 1).1 THE NEW FORMULATION — Xartemis XR tablets contain immediate- and extended-release layers designed to release the active ingredients at a steady rate over an extended period Oxycodone plasma concentrations reach a peak in 3-4 hours Acetaminophen levels peak in 0.75-1 hour The elimination half-life is 4.5 hours for oxycodone and 5.8 hours for acetaminophen Steadystate concentrations of both drugs are achieved within 24 hours after the first dose A CLINICAL STUDY — Approval of extended-release oxycodone/acetaminophen was based on the results of a randomized, double-blind trial in 303 adults with moderate to severe acute pain following bunionectomy Patients received tablets of the combination or placebo every 12 hours for 48 hours More patients treated with the combination had a ≥30% reduction in pain intensity scores within hours after the first dose (63.1% vs 27.2% with placebo) The mean time between a dose of the combination and first use of 59 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter July 21, 2014 Vol 56 (1447) ® Table Some Oral Opioid Combinations Drugs Some Available Formulations Usual Daily Dosage Cost1 5/325, 7.5/325, 10/325 mg tabs 2.5/325, 5/325, 7.5/325, 10/325 mg tabs 5/300, 7.5/300, 10/300 mg tabs 5/325 mg tabs2 tab q6h $57.70 419.70 593.10 14.00 7.5/325 mg tabs tabs q12h 128.80 2.5/325, 5/325, 7.5/325, 10/325 mg tabs2 5/325, 7.5/325, 10/325 mg tabs2 5/300, 7.5/300, 10/300 mg tabs 5/300, 7.5/300, 10/300 mg tabs tab q4-6h 17.90 113.70 101.00 374.30 5/400 mg tabs tab q6h 2.5/200, 5/200, 7.5/200, 10/200 mg tabs 2.5/200, 5/200, 10/200 mg tabs 7.5/200 mg tabs tab q4-6h3 Acetaminophen-Containing Combinations Oxycodone/acetaminophen generic Percocet Primlev Roxicet extended-release Xartemis XR Hydrocodone/acetaminophen generic Lortab Vicodin Xodol Ibuprofen-Containing Combinations Oxycodone/ibuprofen generic Hydrocodone/ibuprofen generic Reprexain Vicoprofen 59.40 138.90 177.70 196.00 Approximate wholesale acquisition cost (WAC) for 14 days' treatment with the lowest usual daily dosage for tablets containing 7.5 mg of oxycodone or hydrocodone or for the closest available formulation Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) July 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Also available as an oral solution Formulations containing 2.5 or mg of hydrocodone may be taken as two tablets q4-6h rescue medication increased from 6.2 hours during the first dosing interval to 9.6 hours during the last dosing interval (between 36 and 48 hours).2 ADVERSE EFFECTS — In clinical studies with the combination, the most common adverse effects were nausea, dizziness, headache, vomiting, constipation, and somnolence Like other opioids, oxycodone can cause confusion, pruritus, dry mouth and sweating, and overdose could result in hypotension, respiratory depression, cardiac arrest, and death Acetaminophen overdose can cause serious or fatal hepatotoxicity; the total dose of acetaminophen from all sources should not exceed g/day The combination is classified as category C (fetotoxicity with acetaminophen in animals; no adequate human studies) for use during pregnancy Prolonged use of opioids during pregnancy can result in neonatal withdrawal syndrome DEPENDENCE AND ABUSE — Like other oxycodone combinations, Xartemis XR is classified as a schedule II controlled substance Dependence and abuse have been reported with all oxycodone-containing products Increasing the dose of the combination when oxycodone tolerance develops could lead to acetaminophen toxicity Crushing the tablets and then chewing or snorting them, or injecting a solution made from the crushed formulation, could result in opioid overdose and death Oxecta and OxyContin are formulated to deter abuse of the drug by injection or snorting 60 DRUG INTERACTIONS — Drugs that inhibit CYP3A4 may increase plasma concentrations of oxycodone and CYP3A4 inducers can decrease them.3 Mixed agonist/antagonist opioid analgesics, such as butorphanol (Stadol, and generics), could decrease the analgesic effect of oxycodone and possibly precipitate withdrawal symptoms in opioiddependent patients Urinary retention and severe constipation could occur with concurrent use of an anticholinergic drug Xartemis XR should not be used with (or within 14 days of stopping) a monoamine oxidase inhibitor DOSAGE AND ADMINISTRATION — Xartemis XR is available as extended-release tablets containing 7.5 mg of oxycodone and 325 mg of acetaminophen The recommended dosage is tablets every 12 hours with or without food The tablets can become sticky when wet and may adhere to the wall of the esophagus; they should be taken one at a time with enough water to ensure complete swallowing A second dose may be taken, if needed, as soon as hours after the initial dose, but subsequent doses should be taken every 12 hours CONCLUSION — The new extended-release formulation of oxycodone and acetaminophen (Xartemis XR) offers a twice-daily option for treatment of moderate to severe acute pain It might provide more stable analgesia than immediate-release combinations, but no comparative studies are available ■ The Medical Letter ® Drugs for pain Treat Guidel Med Lett 2013; 11:31 N Singla et al A randomized, double-blind, placebo-controlled study of the efficacy and safety of MNK-795, a dual-layer, biphasic, immediate-release and extended-release combination analgesic for acute pain Curr Med Res Opin 2014; 30:349 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 ▶ Oral Propranolol (Hemangeol) for Infantile Hemangioma The FDA has approved an oral solution of the nonselective beta-adrenergic blocker propranolol (Hemangeol – Pierre Fabre) for treatment of proliferating infantile hemangiomas INFANTILE HEMANGIOMAS — These benign congenital vascular tumors eventually tend to regress spontaneously, but early in life they can grow rapidly and can ulcerate, bleed, cause disfigurement, interfere with respiration or vision, and cause heart failure Complicated infantile hemangiomas have been treated with systemic corticosteroids Interferon alfa and vincristine are alternatives BACKGROUND — In a report describing 11 children with complicated infantile hemangiomas treated with propranolol (the first child was being treated for an associated condition), the color of the tumor changed within 24 hours from intense red to purple and its texture softened Subsequently, the tumors continued to regress until they were nearly flat, with residual skin telangiectasias.1 This initial report was followed by widespread off-label use of propranolol, a large number of case reports, and a consensus conference.2 MECHANISM OF ACTION — How propranolol causes regression of hemangiomas is unknown Suggested mechanisms include vasoconstriction, blocking angiogenesis, and causing apoptosis of tumor endothelial cells PHARMACOLOGY — Propranolol is rapidly absorbed from the GI tract, but undergoes extensive first-pass metabolism in the liver, and only about 25% of an oral dose reaches the systemic circulation Trace amounts of the drug are excreted unchanged in urine It has a plasma half-life of 3-6 hours CLINICAL STUDIES — Only one randomized, doubleblind, placebo-controlled trial of propranolol use to treat infantile hemangiomas has been published Among 39 children 11 weeks to years old with facial or other potentially disfiguring infantile hemangiomas, use of propranolol oral solution mg/kg/day in Vol 56 (1447) July 21, 2014 divided doses, compared to placebo, resulted in significantly greater reductions in tumor volume (60% vs 14%), color, and elevation after months of treatment.3 FDA approval of Hemangeol was based on an unpublished double-blind study, summarized in the package insert, in 460 infants 35 days to months old with proliferating infantile hemangiomas The patients were randomized to 1.2 or 3.4 mg/kg/day of propranolol in divided doses for or months, or to placebo Complete or nearly complete resolution of the hemangioma at 24 weeks, the primary endpoint, was achieved in 61 of 101 infants (60%) on propranolol 3.4 mg/kg/day for months and in of 55 (4%) receiving a placebo The package insert does not mention the complete resolution rates among patients who took the lower dose or were only treated for months ADVERSE EFFECTS — Hypoglycemia, presumably related to adrenergic blockade, has been the most serious adverse effect of propranolol therapy for infantile hemangioma Hypoglycemic seizures have been reported Infants with poor oral intake or concomitant infection appear to be at greatest risk.2 Propranolol can cause bronchospasm; it is contraindicated in children with asthma Hyperkalemia has been reported with its use for infantile hemangioma, possibly related to breakdown of the tumor cells Bradycardia and hypotension can occur, but generally have been asymptomatic and infrequent Sleep disturbances and nightmares have been reported In children with PHACE syndrome, which is characterized by large facial hemangiomas accompanied by arterial anomalies of the head and neck, treatment with propranolol may increase the risk of stroke.4 No deaths have been reported with use of oral propranolol to treat infantile hemangioma DRUG INTERACTIONS — Patients receiving propranolol who are treated concurrently with corticosteroids may be at increased risk for hypoglycemia because of adrenal suppression Propranolol is a substrate of cytochrome P450 enzymes 2D6, 1A2, and 2C19 and of the efflux transporter P-glycoprotein (P-gp) Inhibitors of CYP2D6, 1A2, or 2C19 may increase serum concentrations of the drug; inducers of CYP1A2 or 2C19 may decrease them.5 DOSAGE AND COST — Hemangeol is formulated as an oral solution containing 4.28 mg/mL of propranolol hydrochloride The manufacturer recommends starting treatment in infants weeks to months of age with doses of 0.15 mL/kg (0.6 mg/kg) twice daily at least 61 The Medical Letter ® hours apart The dose should be increased after one week to 0.3 mL/kg (1.1 mg/kg) twice daily After the second week, the dosage should be increased to the maintenance dosage of 0.4 mL/kg (1.7 mg/kg) twice daily, which is given for months The dose should be administered during or just after a feeding to minimize the risk of hypoglycemia The drug should not be given to children who are not eating or are vomiting A 120mL bottle of Hemangeol costs $375.00.6 CONCLUSION — Oral propranolol is safe and effective for treatment of complicated infantile hemangiomas Hypoglycemia appears to be the most worrisome adverse effect ■ C Léauté-Labrèze et al Propranolol for severe hemangiomas of infancy N Engl J Med 2008; 358:2649 BA Drolet et al Initiation and use of propranolol for infantile hemangioma: report of a consensus conference Pediatrics 2013; 131:128 M Hogeling et al A randomized controlled trial of propranolol for infantile hemangiomas Pediatrics 2011; 128:e259 D Metry et al Propranolol use in PHACE syndrome with cervical and intracranial arterial anomalies: collective experience in 32 infants Pediatr Dermatol 2013; 30:71 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 Approximate wholesale acquisition cost (WAC) Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™) July 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricingpolicy Actual retail price may be higher ▶ Ceritinib (Zykadia) for Non-Small Cell Lung Cancer Ceritinib (Zykadia – Novartis), an oral tyrosine kinase inhibitor, has received accelerated approval from the FDA for treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib (Xalkori) It is the second tyrosine kinase inhibitor to be approved for ALK-positive metastatic NSCLC; crizotinib was the first.1 Translocations of the ALK gene are found in about 5% of lung cancers2; they occur predominantly in nonsmokers with adenocarcinoma Table Pharmacology Drug class ALK tyrosine kinase inhibitor Route Oral Formulation 150 mg capsules Tmax 4-6 hours Half-life 41 hours Metabolism Primarily by CYP3A Elimination Feces (~92%); urine (~1%) 62 Vol 56 (1447) July 21, 2014 MECHANISM OF ACTION — Translocations of ALK, a receptor tyrosine kinase, result in expression of oncogenic fusion proteins, which increase cell proliferation Ceritinib inhibits ALK and other receptor tyrosine kinases CLINICAL STUDIES — A single-arm, open-label trial, summarized in the package insert, in 163 patients with metastatic ALK-positive NSCLC who had progressed on or were intolerant to crizotinib found that 41.1% of patients taking ceritinib 750 mg/day had a partial response and 2.5% had a complete response The median duration of response was 7.1 months Single-arm trials of ceritinib in treatment-naive ALKpositive NSCLC patients and trials comparing it to chemotherapy in treatment-naive and previouslytreated patients are ongoing ADVERSE EFFECTS — According to the manufacturer, diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of patients (including severe cases in 14%) treated with ceritinib in the clinical trial, resulting in dose reductions in 38% of patients Elevated transaminases, fatigue, decreased appetite, and constipation were also common Ceritinib can cause hepatotoxicity, bradycardia, hyperglycemia, and prolongation of the QT interval Severe, sometimes fatal, pneumonitis has been reported DRUG INTERACTIONS — Ceritinib is a substrate of CYP3A4 and P-glycoprotein Inhibitors of 3A4 can increase serum concentrations of ceritinib and inducers of 3A4 can decrease them.3 Concurrent use of ceritinib with strong CYP3A inhibitors or inducers is not recommended Ceritinib itself may inhibit CYP3A and CYP2C9 DOSAGE, ADMINISTRATION, AND COST — The recommended dosage of ceritinib is 750 mg (5 capsules) once daily taken at least hours before or after a meal Treatment should be continued until disease progression or toxicity occurs The labeling specifies a number of dosage adjustments when adverse effects occur The dose of ceritinib should be reduced by about one-third if concurrent use of a strong CYP3A inhibitor is needed A 30-day supply of Zykadia costs about $13,500.4 CONCLUSION — Ceritinib (Zykadia), an oral tyrosine kinase inhibitor, has produced a partial response in patients with metastatic anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer who have progressed on or are intolerant to crizotinib (Xalkori) Ceritinib can cause severe gastrointestinal adverse The Medical Letter ® effects, and it is expensive The effectiveness of ceritinib on progression-free and overall survival remains to be determined ■ Crizotinib (Xalkori) for non-small cell lung cancer Med Lett Drugs Ther 2012; 54:11 AT Shaw et al Ceritinib in ALK-rearranged non-small-cell lung cancer N Engl J Med 2014; 370: 1189 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 Approximate wholesale acquisition cost (WAC) Source: Analy$ource® Monthly (Selected from FDB Medknowledge™) July 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricingpolicy Actual retail price may be higher ▶ A Responsive Neurostimulator Device (RNS System) for Epilepsy The FDA has approved the use of a responsive neurostimulator device (RNS System – NeuroPace) for adjunctive treatment of adults with partial-onset seizures that are not controlled with ≥2 antiepileptic drugs and who have frequent and disabling seizures and no more than epileptogenic foci TREATMENT OF EPILEPSY — Treatment of epilepsy should begin with a single drug, gradually increasing the dosage until seizures are controlled or adverse effects become unacceptable If seizures persist, expert clinicians generally prescribe at least one and sometimes a second alternative drug as monotherapy before considering use of two drugs at the same time.1 About 30-40% of patients with epilepsy continue to have seizures despite treatment with antiepileptic drugs or have intolerable side effects.2 Vagus nerve stimulation, which requires subcutaneous implantation of an electrical pulse generator in the left chest wall that is connected to an electrode wrapped around the left vagus nerve in the neck, delivers pre-programmed impulses to the brain through the vagus nerve It has been used for years with some success in patients refractory to treatment with antiepileptic drugs.3 THE NEW DEVICE — The RNS System consists of a neurostimulator that is implanted in the skull under the scalp and leads that are surgically implanted in the brain near the seizure focus or foci The neurostimulator is a programmable, battery-powered device that continuously monitors brain electrical activity and delivers electrical stimulation to the foci as needed to prevent seizures The device costs about $40,000, and the average battery life is about 2-3.5 years.4 Vol 56 (1447) July 21, 2014 A CLINICAL STUDY — Approval of the new device was based on the results of a double-blind trial in 191 adults with partial-onset seizures who had >3 seizures per month, or epileptogenic regions, and were refractory to treatment with ≥2 antiepileptic drugs Patients were randomized to responsive cortical stimulation with the implanted neurostimulator or to sham neurostimulation (stimulation turned off) for 12 weeks After the initial 12 weeks, all patients received open-label active responsive cortical neurostimulation for an additional 84 weeks During the initial 12 weeks, patients who received responsive cortical stimulation had a 38% reduction in mean seizure frequency from baseline, the primary endpoint, compared to a 17% reduction among those who had sham neurostimulation, a statistically significant difference.5 A follow-up study found that neurostimulation with the RNS System reduced mean seizure frequency by 44% after year and by 53% at years post-implant.6 ADVERSE EFFECTS — The most frequent adverse effects reported during the clinical trial were implant-site infections and premature battery depletion Implant-site pain and headache are common in the post-operative period Intracranial hemorrhage can also occur During the 2-year follow-up study, adverse effects included device lead damage, device lead division, and increased seizure frequency Patients with the device should avoid having an MRI, electroconvulsive therapy, transcranial magnetic stimulation, or diathermy procedures CONCLUSION — The responsive neurostimulator device (RNS System) is effective in reducing seizure frequency in adults with partial-onset seizures that are not controlled with >2 antiepileptic drugs and who have no more than epileptogenic foci Its long-term effects are unknown How use of this device compares to vagus nerve stimulation for this indication remains to be determined ■ Drugs for epilepsy Treat Guidel Med Lett 2013; 11:9 JA French and TA Pedley Clinical Practice Initial management of epilepsy N Engl J Med 2008; 359:166 RH Howland Vagus nerve stimulation Curr Behav Neurosci Rep 2014; 1:64 Cost according to the manufacturer MJ Morrell et al Responsive cortical stimulation for the treatment of medically intractable partial epilepsy Neurology 2011; 77:1295 CN Heck et al Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System pivotal trial Epilepsia 2014; 55:432 63 The Medical Letter Vol 56 (1447) ® July 21, 2014 IN BRIEF IN BRIEF Esomeprazole Strontium Low-Dose Indomethacin (Tivorbex) for Pain The FDA has approved the proton pump inhibitor (PPI) esomeprazole strontium for use in adults for the same indications as esomeprazole magnesium (Nexium) : treatment of gastroesophageal reflux disease (GERD), prevention of NSAID-induced gastric ulcers, eradication of Helicobacter pylori, and treatment of pathological hypersecretory conditions It was first marketed in December 2013 as a branded drug (Esomeprazole Strontium) and a month later as a generic drug Table Oral Proton Pump Inhibitors Drug Usual Dosage1,2 Cost3 Dexlansoprazole – Dexilant (Takeda) Esomeprazole magnesium – Nexium (AstraZeneca) Nexium 24HR (OTC) Esomeprazole strontium – generic5 Esomeprazole Strontium (Amneal)5 Lansoprazole – generic Prevacid (Takeda) Prevacid 24HR (OTC) Omeprazole8 – generic Prilosec (AstraZeneca) Prilosec OTC Pantoprazole – generic Protonix (Pfizer) Rabeprazole – generic Aciphex, Aciphex Sprinkle (Eisai) 30-60 mg once/d $183.90 20-40 mg once/d 236.70 16.404 24.65-49.3 mg once/d6 15-30 mg once/d 20-40 mg once/d 40 mg once/d 20 mg once/d 60.007 200.807 93.70 276.30 17.804 17.90 204.40 17.804 7.00 229.80 59.00 349.90 OTC = Over the counter The lower end of the range is generally used for initial treatment of GERD Higher doses and bid dosing may be needed for patients with peptic ulcers, hypersecretory states like Zollinger-Ellison Syndrome, or for treatment of H pylori infection PPIs are generally taken 30-60 minutes before the first meal of the day Taking one before the evening meal may be more effective for nocturnal acid control Approximate wholesale acquisition cost (WAC) for 30 days’ treatment with the lowest usual dosage Source: Analy$ource® Monthly (Selected from FDB MedKnowledgeTM) July 5, 2014 Reprinted with permission by FDB, Inc All rights reserved ©2014 www.fdbhealth.com/policies/drug-pricing-policy Actual retail prices may be higher Cost of 28 tablets or capsules Branded and generic formulations are marketed by Amneal under the same name Equivalent to 20-40 mg of esomeprazole Cost of 49.3-mg capsules The 24.65-mg capsules are not yet available Also available in combination with sodium bicarbonate (Zegerid and Zegerid OTC) Strontium is incorporated into bone It is not recommended for use in children or during pregnancy because of the absence of safety data in those populations Use of esomeprazole strontium is not recommended for patients with severe renal impairment Esomeprazole strontium is the seventh PPI to become available as a single agent in the US No new clinical trials were required for its approval, which was based on earlier clinical trials with esomeprazole magnesium All of the PPIs appear to be equally effective.1 ■ Drugs for peptic ulcer disease and GERD Treat Guidel Med Lett 2014; 12:25 64 The same pharmaceutical company (Iroko) that recently marketed low-dose diclofenac (Zorvolex) for treatment of mild to moderate acute pain1 has now received approval from the FDA to market a lowdose oral formulation of indomethacin (Tivorbex) for the same indication Tivorbex is available in 20- and 40-mg capsules; conventional immediate-release indomethacin capsules contain 25 mg and 50 mg of the drug The rationale for this new product is the same as the one offered for Zorvolex: the drug is formulated as submicron particles that increase surface area, leading to faster dissolution and absorption According to the package insert, the time to reach peak serum concentrations (Tmax) was 1.67 hours with a 40-mg capsule of Tivorbex, compared to 2.02 hours with a standard 50-mg capsule of indomethacin The problem with Tivorbex is the same as the problem with Zorvolex: there are no studies comparing its efficacy to that of standard doses of indomethacin or to any other NSAID In addition, indomethacin is generally considered one of the most potent NSAIDs and one of those most likely to cause GI bleeding, increase cardiovascular risk, and damage the kidneys There is no good reason to use indomethacin in any dosage for treatment of mild to moderate pain ■ Low-dose diclofenac (Zorvolex) for pain Med Lett Drugs Ther 2014; 56:19 Coming Soon in The Medical Letter: Drugs for Inflammatory Bowel Disease Dalbavancin (Dalvance) for Skin and Skin Structure Infections Sucroferric Oxyhydroxide (Velphoro) for Hyperphosphatemia A Transcutaneous Electrical Nerve Stimulation Device (Cefaly) for Migraine Drugs for Osteoarthritis Read Our Blog: More@MedLetter Each week we publish a short blog post containing comments on topics that were previously published in The Medical Letter or are of special interest to 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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 differences between celecoxib and nonselective NSAIDs Review the efficacy and safety of extended-release oxycodone and acetaminophen (Xartemis XR) for treatment of acute pain Review the efficacy and safety of oral propranolol (Hemangeol) for treatment of infantile hemangioma Review the efficacy and safety of ceritinib (Zykadia) for treatment of ALK-positive metastatic non-small cell lung cancer Review the efficacy and safety of the responsive neurostimulator device (RNS System) for treatment of refractory epilepsy Review the efficacy and safety of esomeprazole strontium compared to other available proton pump inhibitors 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 XP/Vista/7/8, Mac OS X+; current versions of Microsoft IE, Mozilla Firefox, Google Chrome, Safari or any other compatible web browser High-speed 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 1447 Questions (Correspond to questions #11-20 in Comprehensive Exam #71, available January 2015) Generic Celecoxib Ceritinib (Zykadia) for Non-Small Cell Lung Cancer Celecoxib is less likely than nonselective NSAIDs to cause: a renal toxicity b GI toxicity c cardiovascular thrombotic events d all of the above Ceritinib is FDA-approved for patients: a with metastatic non-small cell lung cancer b with the ALK translocation c who have not responded to crizotinib d all of the above Extended-Release Oxycodone and Acetaminophen (Xartemis XR) A 63-year-old man with metastatic non-small cell lung cancer being treated with ceritinib complains of severe abdominal pain The most likely cause is: a bowel perforation b pancreatitis c ceritinib toxicity d peptic ulcer Xartemis XR is approved by the FDA for use in patients with: a chronic pain b acute pain c acute pain severe enough to require an opioid d severe chronic pain One apparent advantage of Xartemis XR over other oral opioid combinations is: a fewer doses per day b less risk of abuse c less danger from overdosage d all of the above Oral Propranolol (Hemangeol) for Infantile Hemangioma Infantile hemangiomas can: a interfere with vision b interfere with respiration c cause heart failure d all of the above The most serious adverse effect of propranolol therapy for infantile hemangioma appears to be: a bradycardia b hypertension c hypoglycemia d hypokalemia A Responsive Neurostimulator Device (RNS System) for Epilepsy The neurostimulator in the RNS System is: a worn on a belt around the waist b implanted subcutaneously in the abdomen c implanted under the scalp d implanted in the brain A 23-year-old woman with partial-onset seizures and epileptogenic foci has been treated with carbamazepine, but continues to have frequent, disabling seizures She is not a candidate for the RNS System because: a it has only been approved for use in children b she has not been treated with at least antiepileptic drugs c she has more than one epileptic focus d all of the above Esomeprazole Strontium 10 Esomeprazole strontium is: a approved by the FDA for adults for the same indications as Nexium b available generically c not recommended for use in patients with severe renal impairment d all of the above ACPE UPN: Per Issue Exam: 0379-0000-14-447-H01-P; Release: July 21, 2014, Expire: July 21, 2015 Comprehensive Exam 71: 0379-0000-15-071-H01-P; Release: January 2015, Expire: January 2016 EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.; ASSISTANT EDITORS, DRUG INFORMATION: Susan M Daron, Pharm.D., Corinne Z Morrison, Pharm.D., Michael P Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M Shah, Pharm.D., F Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard 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; Jules Hirsch, M.D., Rockefeller University; David N Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital, Copenhagen; 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 & SYSTEMS MANAGER: Cristine Romatowski; DIRECTOR OF MARKETING 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 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 2014 ISSN 1523-2859 Subscriptions (US): year - $98; 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Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter July 21, 2014 Vol 56 (1447) ® Table Some Oral Opioid Combinations Drugs Some Available Formulations Usual Daily... 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. .. 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