The Medical Letter ® On Drugs and Therapeutics Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication IN THIS ISSUE (starts on next page) Apremilast (Otezla) for Psoriatic Arthritis p 41 Eslicarbazepine Acetate (Aptiom) for Epilepsy p 42 Sorafenib (Nexavar) for Thyroid Cancer p 43 In Brief: Heptavalent Botulism Antitoxin p 44 Important Copyright Message The Medical Letter® publications are protected by US 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 US 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 FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 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 Published by The Medical Letter, Inc • 145 Huguenot Street, New Rochelle, NY 10801 • A Nonprofit Publication Volume 56 (Issue 1443) May 26, 2014 www.medicalletter.org Take CME Exams ALSO IN THIS ISSUE Table Pharmacology Eslicarbazepine Acetate (Aptiom) for Epilepsy p 42 Sorafenib (Nexavar) for Thyroid Cancer p 43 In Brief: Heptavalent Botulism Antitoxin p 44 Drug class PDE4 inhibitor Route Oral Formulation 10, 20, 30 mg tablets1 Apremilast (Otezla) for Psoriatic Arthritis Apremilast (Otezla – Celgene), an oral phosphodiesterase type-4 (PDE4) inhibitor, has been approved by the FDA for treatment of active psoriatic arthritis in adults It is the first PDE4 inhibitor to be approved for this indication STANDARD TREATMENT — Up to 40% of patients with psoriasis develop psoriatic arthritis.1 Nonsteroidal anti-inflammatory drugs (NSAIDs) may be tried first for treatment of mild disease The disease-modifying antirheumatic drug (DMARD) methotrexate is generally used for treatment of moderate to severe disease If there is minimal improvement after 12-16 weeks of methotrexate treatment, a tumor necrosis factor (TNF) inhibitor is often added or substituted.2 Ustekinumab (Stelara), a human interleukin-12 and -23 antagonist, has also been approved by the FDA for treatment of active psoriatic arthritis; how it compares in efficacy to TNF inhibitors remains to be determined.3 MECHANISM OF ACTION — PDE4 degrades cyclic adenosine monophosphate (cAMP) into AMP Apremilast inhibits PDE4, resulting in downregulation of the inflammatory response CLINICAL STUDIES — Approval of apremilast was based on randomized, double-blind, placebocontrolled trials in a total of 1493 adults with active psoriatic arthritis refractory to treatment with DMARDs Only one of these trials has been published4; the others are summarized in the package insert After 16 weeks, Tmax ~2.5 hours Half-life (terminal) 6-9 hours Metabolism Primarily by CYP3A4, to a minor extent by CYP1A2 and 2A6, then glucuronidation and hydrolysis Urine (58%); feces (39%) Elimination The 10- and 20-mg tablets are only available in a 2-week titration pack significantly higher percentages of patients achieved an American College of Rheumatology (ACR20) response, indicating >20% improvement from baseline in at least of measures of disease activity, with apremilast 30 mg twice daily (32-41%) than with placebo (18-19%) In the published trial, which enrolled 504 patients, 31% of patients taking 20 mg of apremilast twice daily and 40% of those taking 30 mg twice daily achieved an ACR20 response at week 16, both significant differences from placebo (19%) The percentages of patients who achieved an ACR50 or ACR70 response in the trials with apremilast were not significantly different from placebo No studies are available directly comparing apremilast with a TNF inhibitor In cross-study comparisons, response rates appear to be lower with apremilast In patients with moderate to severe plaque psoriasis without arthritis (not an FDA-approved indication), apremilast has improved symptoms and reduced lesions significantly more than placebo.5-7 ADVERSE EFFECTS — The most common adverse effects of apremilast in clinical trials were diarrhea, nausea, and headache These effects occurred most frequently during the first two weeks of treatment and tended to resolve with continued use of the drug No increased risk of malignancy or serious infection, including reactivation of tuberculosis, has been reported to date Apremilast can increase the risk of depression Loss of 5-10% of body weight has been reported FORWARDING OR COPYING IS A VIOLATION OF U.S AND INTERNATIONAL COPYRIGHT LAWS 41 Apremilast is classified as category C (developmental toxicity in animals; no adequate human studies) for use during pregnancy DRUG INTERACTIONS — Apremilast is metabolized primarily by CYP3A4 Coadministration with the strong CYP3A4 inducer rifampin reduced the area under the plasma concentration-time curve (AUC) of apremilast by 72% Concomitant use of apremilast with strong CYP450 enzyme inducers such as rifampin or carbamazepine is not recommended.8 DOSAGE, ADMINISTRATION, AND COST — To reduce gastrointestinal adverse effects, apremilast should be titrated over days from 10 mg twice daily to a final recommended dosage of 30 mg twice daily The final dose should be reduced to 30 mg once daily in patients with severe renal impairment (CrCl 18 years old with refractory partial-onset seizures Two of these trials have been published,3,4 and the third is summarized in the package insert At 12 weeks, the mean number of seizures per 28 days was significantly lower with eslicarbazepine 800 mg/day (in of the studies) and 1200 mg/day than with placebo ADVERSE EFFECTS — Dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, tremor, asthenia, rash, and dysarthria have occurred with use of Table Clinical Trials with Eslicarbazepine Acetate1 Placebo 800 mg 1200 mg Study (n = 270) No of seizures (mean) per 28 days 6.6 5.0 4.3 Study (n = 267) No of seizures (mean) per 28 days 8.6 6.2 6.6 Study (n = 596) No of seizures (mean) per 28 days 7.9 6.5 (NS) 6.0 NS = Not statistically significant compared to placebo Data from the manufacturer’s package insert The FDA required some revisions to the data from the published trials The Medical Letter • Volume 56 • Issue 1443 • May 26, 2014 eslicarbazepine acetate The percentages of patients who discontinued the drug as a result of an adverse reaction were 14% with the 800-mg dose and 25% with the 1200-mg dose, compared to 7% with placebo Hyponatremia (which has been problematic with oxcarbazepine), serious dermatologic reactions (including Stevens-Johnson syndrome), DRESS syndrome (eosinophilia and hepatic toxicity), angioedema, and anaphylactic reactions have been reported with use of eslicarbazepine acetate Eslicarbazepine acetate is classified as category C (developmental toxicity in animals; no adequate human studies) for use during pregnancy DRUG INTERACTIONS — Eslicarbazepine can inhibit CYP2C19 and induce CYP3A4 It can increase serum concentrations of drugs metabolized by CYP2C19, such as clobazam and omeprazole, and decrease serum concentrations of drugs metabolized by CYP3A4, such as simvastatin and oral contraceptives.5,6 Enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital, and primidone can reduce serum concentrations of eslicarbazepine Table Eslicarbazepine Acetate and Oxcarbazepine Drug Eslicarbazepine acetate – Aptiom (Sunovion) Available Formulations Usual Adult Dosage 200, 400, 600, 800 mg tabs 800 mg once daily Oxcarbazepine – 150, 300, 600 mg generic tabs; 300 mg/5 mL Trileptal (Novartis) susp extended-release 150, 300, 600 mg Oxtellar XR ER tabs (Supernus) 1200-2400 mg divided bid 1200-2400 mg once daily Cost1 CONCLUSION — Eslicarbazepine acetate (Aptiom), which is a prodrug for an active metabolite of oxcarbazepine, is modestly effective for once-daily adjunctive treatment of partial-onset seizures in adults with epilepsy Whether it offers any advantage over oxcarbazepine, which costs less, remains to be established Drugs for epilepsy Treat Guidel Med Lett 2013; 11:9 A Verrotti et al Eslicarbazepine acetate: an update on efficacy and safety in epilepsy Epilepsy Res 2014; 108:1 E Ben-Menachem et al Eslicarbazepine acetate as adjunctive therapy in adult patients with partial epilepsy Epilepsy Res 2010; 89:278 C Elger et al Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial-onset seizures: a randomized, double-blind, placebo-controlled, parallel group phase III study Epilepsia 2009; 50:454 Inhibitors and inducers of CYP enzymes and P-glycoprotein Med Lett Drugs Ther 2013; 55:e44 A Falcão et al Effect of eslicarbazepine acetate on the pharmacokinetics of a combined ethinylestradiol/levonorgestrel oral contraceptive in healthy women Epilepsy Res 2013; 105:368 Sorafenib (Nexavar) for Thyroid Cancer The FDA has approved the use of the oral multikinase inhibitor sorafenib (Nexavar – Bayer) for treatment of locally recurrent or metastatic, progressive, differentiated thyroid cancer (papillary or follicular) refractory to radioactive iodine treatment Sorafenib was approved earlier for treatment of advanced renal cell and unresectable hepatocellular cancer.1 $599.40 114.60 551.30 495.00 Approximate wholesale acquisition cost (WAC) for 30 days’ treatment at the lowest usual dosage Source: Analy$ource® Monthly (Selected from FDB MedKnowledge™ May 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 DOSAGE AND ADMINISTRATION — The recommended starting dosage of eslicarbazepine acetate is 400 mg once daily, which should be increased after week to 800 mg once daily, up to a maximum dosage of 1200 mg/day Patients with renal impairment (CrCl 70% Which of the following are among the most common side effects of apremilast? a an increased risk of serious infection b rash c diarrhea d all of the above Eslicarbazepine Acetate (Aptiom) for Epilepsy Eslicarbazepine is an active metabolite of: a carbamazepine b oxcarbazepine c neither d both A 23-year-old woman with poorly controlled partial-onset seizures and no health insurance has heard that Aptiom is the newest treatment for this disorder and would like to try it You could tell her that: a the drug would probably cost more than $500 per month b it would probably reduce the number of her seizures by 50% c it has been shown to be superior to carbamazepine and oxcarbazepine d all of the above Sorafenib (Nexavar) for Thyroid Cancer The FDA has approved sorafenib for which of the following: a advanced renal cell cancer b unresectable hepatocellular cancer c locally recurrent or metastatic, progressive, differentiated thyroid cancer d all of the above The most common adverse effect of sorafenib in patients with thyroid cancer has been: a gastrointestinal perforation b bleeding c generalized rash or desquamation d palmar-plantar erythrodysesthesia ACPE UPN: Per Issue Exam: 0379-0000-14-443-H01-P; 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