The Medical Letter ® on Drugs and Therapeutics Volume 58 ISSUE ISSUE No 1433 1497 Volume 56 June 20, 2016 IN THIS ISSUE A New Abuse-Deterrent Opioid — Xtampza ER p 77 Spritam – A New Formulation of Levetiracetam for Epilepsy p 78 Two New Amphetamines for ADHD p 80 Reslizumab (Cinqair) for Severe Eosinophilic Asthma p 81 Addendum: Doxycycline for Young Children? p 82 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 June 20, 2016 Take CME Exams ISSUE ISSUE No 1433 1497 Volume 56 ▶ ALSO IN THIS ISSUE Spritam – A New Formulation of Levetiracetam for Epilepsy p 78 Two New Amphetamines for ADHD p 80 Reslizumab (Cinqair) for Severe Eosinophilic Asthma p 81 Addendum: Doxycycline for Young Children? p 82 A New Abuse-Deterrent Opioid – Xtampza ER The FDA has approved Xtampza ER (Collegium), a new extended-release, abuse-deterrent capsule formulation of oxycodone, for management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate Pronunciation Key Xtampza : ex tamp’ zah ABUSE-DETERRENT OPIOIDS — Five other abusedeterrent opioid formulations were approved earlier, three as single-drug products and two in combinations with opioid antagonists.1 Two of these products, Morphabond (morphine ER) and Targiniq ER (oxycodone ER/naloxone), have not yet been marketed Zohydro ER (hydrocodone ER) was reformulated in 2015 to make abuse more difficult, but it has not received FDA approval as an abusedeterrent opioid No studies are available comparing the relative safety of these products No opioid formulation prevents consumption of a large number of intact dosage units, the most common method of abuse Abuse-deterrent formulations have one or more properties that make their intentional nontherapeutic use more difficult, less attractive, or less rewarding THE NEW FORMULATION — Xtampza ER is available in capsules containing microspheres formulated with oxycodone base and inactive ingredients that make the formulation more difficult to manipulate for the purpose of abuse Each capsule contains 9, 13.5, 18, 27, or 36 mg of oxycodone (equivalent to 10, 15, 20, 30 or 40 mg of oxycodone HCl, respectively) PHARMACOKINETICS — The oral bioavailability of Xtampza ER is greater when taken with food (Cmax Table Pharmacology Formulation 9, 13.5, 18, 27, 36 mg capsules1 Route Oral Tmax 4.5 hours2 Metabolism Hepatic mainly by CYP3A4 and to a lesser extent by CYP2D6 Elimination Primarily in urine as metabolites Half-life 5.6 hours3 Of oxycodone base Equivalent to 10, 15, 20, 30, 40 mg of oxycodone HCl With food; hours later than with immediate-release oxycodone With food; half-life of immediate-release oxycodone is 3.2 hours increased by 100-150% and AUC by 50-60% with a high-fat meal) In one pharmacokinetic study, crushing Xtampza ER capsules did not increase the Cmax or the AUC of oxycodone compared to intact capsules when both were taken with a high-fat meal Crushing the capsules also did not compromise the extended-release properties of Xtampza ER, unlike OxyContin abuse-deterrent tablets, which lost their extended-release properties when crushed.2 In another study, crushing and snorting Xtampza ER capsules following a high-fat meal resulted in lower peak serum concentrations of oxycodone than taking intact capsules.3 CLINICAL STUDIES — A 12-week, randomized, double-blind trial in 740 patients with moderate to severe chronic low back pain compared Xtampza ER with placebo The maximum dose was 144 mg/day (equivalent to 160 mg of oxycodone HCl) Patients treated with the active drug had significantly lower pain scores from week 2-12 than those who received placebo.4 ADVERSE EFFECTS — Nausea, headache, constipation, somnolence, pruritus, vomiting, and dizziness, all typical opioid side effects, occurred commonly in the clinical trial in patients treated with Xtampza ER PREGNANCY — As with other opioid analgesics, prolonged use of Xtampza ER during pregnancy can cause neonatal opioid withdrawal syndrome 77 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter Vol 58 (1497) ® Table Some Abuse-Deterrent Opioid Formulations Drug Hydrocodone ER Hysingla ER (Purdue) Zohydro ER2 (Pernix) Morphine ER/ naltrexone Embeda (Pfizer) Oxycodone ER OxyContin (Purdue) Xtampza ER (Collegium) Abuse-Deterrent Mechanism Cost $215.80 Resists crushing and breaking; tablets form a viscous gel when dissolved Contains excipients that form a 404.90 viscous gel when capsules are crushed or dissolved Contains sequestered opioid antagonist, which is released if capsules are crushed or dissolved 178.50 Resists crushing and breaking; tablets form a viscous gel when dissolved Microspheres resist effects of crushing and chewing; melted or dissolved contents of capsules are difficult to inject 188.80 202.20 ER = extended-release Approximate WAC for 30 days’ treatment at the recommended starting dosage for patients who are not opioid tolerant 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 June 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www fdbhealth.com/policies/drug-pricing-policy Not FDA-approved as having abuse-deterrent properties Oxycodone is excreted in breast milk and can cause opioid effects in breastfed newborns DRUG INTERACTIONS — Oxycodone is metabolized mainly by CYP3A4 and to a lesser extent by CYP2D6 Administration of Xtampza ER concurrently with drugs that inhibit CYP3A4 (or discontinuation of CYP3A4 inducers) can increase serum concentrations of oxycodone and could be fatal Concurrent use of CYP3A4 inducers could decrease oxycodone serum concentrations and the analgesic effect of the drug.5 DOSAGE AND ADMINISTRATION — The recommended starting dosage of Xtampza ER for opioid-naive patients is mg every 12 hours The capsules must be taken with food; patients should consume the same amount of food with every dose in order to ensure consistent plasma levels For patients who have difficulty swallowing the capsules, their contents can be sprinkled on soft foods or into a cup, and then given orally or through a gastrostomy or nasogastric tube The maximum daily dose of Xtampza ER is 288 mg (equivalent to 320 mg oxycodone HCl) The package insert contains dosing instructions for conversion from other oxycodone formulations or other opioids Patients with hepatic impairment starting Xtampza ER should take one-third to onehalf the usual dosage; they should not take the drug if the required dose is 40 kg; the dosage can be increased by 500 mg twice daily every weeks, up to a maximum of 1500 mg twice daily For children ≥4 years old who weigh 20-40 kg, the starting dosage is 250 mg twice daily; the dosage can be increased by 250 mg twice daily every weeks, up to a maximum of 750 mg twice daily Spritam disintegrates when taken with a sip of liquid The patient should place the tablet on the tongue with a dry hand, take a sip of liquid, and then swallow after the tablet disintegrates The tablets should not be broken, chewed, or swallowed whole Patients should peel the blister foil off the package rather than push the tablet through the foil Spritam tablets can also be dispersed in a small volume of liquid and taken immediately CONCLUSION – Patients with epilepsy who have trouble taking oral levetiracetam tablets may find the new rapidly disintegrating formulation (Spritam) easier to swallow Generic levetiracetam oral solution is a much cheaper alternative ■ Drugs for epilepsy Treat Guidel Med Lett 2013; 11:9 S Boudriau et al Randomized comparative bioavailability of a novel three-dimensional printed fast-melt formulation of levetiracetam following the administration of a single 1000-mg dose to healthy human volunteers under fasting and fed conditions Drugs R D 2016; 16:229 JJ Cereghino et al Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial Neurology 2000; 55:236 SD Shorvon et al Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures European Levetiracetam Study Group Epilepsia 2000; 41:1179 E Ben-Menachem and U Falter Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy European Levetiracetam Study Group Epilepsia 2000; 41:1276 TA Glauser et al Double-blind, placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures Neurology 2006; 66:1654 S Noachtar et al Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures Neurology 2008; 70:607 SF Berkovic et al Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy Neurology 2007; 69:1751 E Halma et al Behavioral side-effects of levetiracetam in children with epilepsy: a systematic review Seizure 2014; 23:685 79 The Medical Letter ▶ Vol 58 (1497) ® Adzenys XR-ODT is the first extended-release orally disintegrating tablet formulation of amphetamine to become available in the US It contains a 3:1 ratio of dto l-amphetamine in 50% immediate-release and 50% delayed-release particles Approval of Adzenys XRODT was based on pharmacokinetic studies that found that the serum concentration/time curves of d- and l-amphetamine with Adzenys XR-ODT were virtually identical to those with Adderall XR Two New Amphetamines for ADHD Two new extended-release amphetamine products have been approved by the FDA for once-daily treatment of attention-deficit/hyperactivity disorder (ADHD) in patients ≥6 years old: Adzenys XR-ODT (Neos Therapeutics), an orally distintegrating tablet, and Dyanavel XR (Tris Pharma), an oral suspension Adzenys : add zen’ iss June 20, 2016 Pronunciation Key Dyanavel : die an uh vel Dyanavel XR extended-release oral suspension contains a 3.2:1 ratio of d- to l-amphetamine in a mixture of immediate-release and extended-release particles Approval of Dyanavel XR was based on the results of an unpublished trial (summarized in the package insert) in 108 children 6-12 years old with ADHD who were titrated to an optimal dose (max 20 mg/day) of the new suspension over weeks, followed by week of treatment with either the active drug or placebo After the 1-week treatment period, the children were evaluated using the SKAMP-Combined score, which measures ADHD symptoms in a laboratory school setting, at time points between and 13 hours post-dose SKAMP-Combined scores improved significantly more with Dyanavel XR than with placebo at all time points AMPHETAMINES FOR ADHD — Amphetamines generally have been as effective as methylphenidate in decreasing overactivity, impulsivity, and inattention in children with ADHD Some children who have not responded to methylphenidate may respond to an amphetamine, and vice versa Racemic amphetamine sulfate, mixed amphetamine salts, dextroamphetamine, and lisdexamfetamine dimesylate, an oral prodrug of dextroamphetamine, vary in duration of action, but appear to be similar in efficacy.1,2 All stimulants used for treatment of ADHD are classified as Schedule II controlled substances by the DEA Table Some Amphetamines for ADHD Drug Pediatric Dosage1 Initial/Usual Cost2 3.1, 6.3, 9.4, 12.5, 15.7, 18.8 mg ER ODT4,5 10-12 h 6.3 mg qAM/6.3-18.8 mg qAM6 $270.00 2.5 mg/mL ER susp7 13 h 2.5-5 mg qAM/2.5-20 mg qAM 59.00 5, 10 mg tabs 10 h8 mg qAM or bid9/2.5-5 mg bid 324.4010 5, 7.5, 10, 12.5, 15, 20, 30 mg tabs 4-6 h mg qAM or bid9/10 mg bid 5, 10, 15, 20, 25, 30 mg ER caps 10-12 h 5-10 mg qAM/30 mg qAM 61.10 322.30 154.80 213.70 5, 10 mg tabs 4-6 h mg qAM or bid9/10 mg bid 2.5, 5, 7.5, 10, 15, 20, 30 mg tabs 5, 10, 15 mg SR caps13 6-8 h mg qAM or bid/15 mg qAM 10, 20, 30, 40, 50, 60, 70 mg caps11 13-14 h14 30 mg qAM/30-70 mg qAM Some Available Formulations Amphetamines Amphetamine – Adzenys XR-ODT (Neos Therapeutics) Dyanavel XR (Tris) Racemic amphetamine sulfate – Evekeo (Arbor) Mixed amphetamine salts – short-acting – generic Adderall (Teva) long-acting – generic Adderall XR (Shire) Dextroamphetamines3 Dextroamphetamine12 – short-acting – generic Dexedrine (Amedra) Zenzedi (Arbor) long-acting – generic Dexedrine Spansule (Amedra) Lisdexamfetamine dimesylate – Vyvanse (Shire) Duration of Action 11 118.50 342.00 346.80 148.80 504.60 248.30 ER = extended-release; ODT = orally disintegrating tablets; susp = suspension; SR = sustained-release Dosage for children ≥6 years old Approximate WAC for 30 days’ treatment with the lowest usual pediatric 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 June 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www.fdbhealth.com/policies/drug-pricing-policy Taking the drug with gastrointestinal acidifying agents such as ascorbic acid or fruit juice decreases its absorption and use of alkalinizing agents such as sodium bicarbonate increases its absorption Drugs that acidify the urine can increase amphetamine excretion and those that alkalinize the urine can decrease its excretion Equivalent to 5, 10, 15, 20, 25, and 30 mg strengths of Adderall XR The tablet should be placed on the tongue and swallowed after it disintegrates It should not be crushed or chewed The maximum recommended daily dose is 18.8 mg for patients 6-12 years old and 12.5 mg for patients 13-17 years old 2.5 mg of amphetamine base is equivalent to mg of mixed amphetamine salts products AC Childress et al J Child Adolesc Psychopharmacol 2015; 25:402 Initial dosage for children 3-5 years old is 2.5 mg once daily 10 Cost for mg bid 11 The contents of the capsule may be sprinkled on a small amount of applesauce and given immediately 12 FDA-approved only for use in children 3-16 years old (short-acting) or 6-16 years old (long-acting) 13 Must be swallowed whole, and not be crushed or chewed 14 According to the manufacturer 80 The Medical Letter ® ADVERSE EFFECTS ― Adverse effects of amphetamines in children with ADHD include anorexia, failure to gain weight, tachycardia, irritability, insomnia, motor or vocal tics and, rarely, priapism and peripheral vasculopathy Stimulants can slow growth; the effect on final adult height is unclear Some children, especially teenagers, say that stimulants make them feel less spontaneous and less comfortable in their social interactions Stimulants can induce or exacerbate symptoms in patients with psychiatric disorders; these drugs should be used with caution in patients with a history of mania, psychosis, drug dependence, or alcoholism CONCLUSION — The two new amphetamine products, Adzenys XR-ODT and Dyanavel XR, offer once-daily alternatives for children with ADHD who are unable to swallow tablets or capsules ■ Drugs for ADHD Med Lett Drugs Ther 2015; 57:37 Racemic amphetamine sulfate (Evekeo) for ADHD Med Lett Drugs Ther 2015; 57:137 ▶ Reslizumab (Cinqair) for Severe Eosinophilic Asthma The FDA has approved reslizumab (Cinqair – Teva), a humanized interleukin-5 (IL-5) antagonist monoclonal antibody, for add-on maintenance treatment of severe asthma in adults who have an eosinophilic phenotype It is the second IL-5 antagonist to be approved in the US; mepolizumab (Nucala) was approved for the same indication in 2015.1 Pronunciation Key Reslizumab : res liz' ue mab Cinqair: sink ayr' EOSINOPHILIC PHENOTYPE — What constitutes an eosinophilic phenotype is not well defined, but patients with this phenotype generally have severe disease with high eosinophil levels in blood and/or sputum despite treatment with a corticosteroid.2 OTHER MONOCLONAL ANTIBODIES — In clinical trials, mepolizumab reduced exacerbations and the need for maintenance oral corticosteroids in patients with severe asthma and high eosinophil counts The recombinant humanized anti-IgE monoclonal antibody omalizumab (Xolair), which is FDA-approved for treatment of patients with moderate to severe persistent allergic asthma not well controlled on an inhaled corticosteroid, may be effective in patients with allergic asthma who have high blood eosinophil counts.3 No studies are available directly comparing mepolizumab, reslizumab, and omalizumab with each other MECHANISM OF ACTION — IL-5 is the major cytokine responsible for the growth, differentiation, recruitment, Vol 58 (1497) June 20, 2016 and activation of eosinophils Reslizumab binds to IL-5, blocking its binding to IL-5 receptors on the surface of eosinophils, thereby reducing the production and survival of eosinophils and decreasing airway inflammation CLINICAL STUDIES — Approval of reslizumab was based on the results of four randomized, double-blind, placebo-controlled trials Two of the studies enrolled a total of 953 patients 12-75 years old with moderate to severe asthma inadequately controlled on at least a medium-dose inhaled corticosteroid who had blood eosinophil counts of ≥400 cells/mcL and ≥1 exacerbation in the previous year Patients were randomized to receive reslizumab mg/kg or placebo every weeks for year Reslizumab significantly reduced the frequency of clinically significant asthma exacerbations, the primary endpoint, by 54% compared to placebo One or more asthma exacerbations occurred in 32% of patients receiving reslizumab compared to 50% of those receiving placebo The mean increase from baseline in forced expiratory volume in second (FEV1) was also significantly greater among patients treated with reslizumab (110 mL vs placebo).4 Among patients 12-17 years old included in the oneyear studies (n=25), the annual asthma exacerbation rate in those treated with reslizumab was twice as high as the rate in the placebo group (2.86 vs 1.37) In the third study, 315 patients 12-75 years old with asthma inadequately controlled on at least a mediumdose inhaled corticosteroid and blood eosinophil counts of ≥400 cells/mcL were randomized to reslizumab 0.3 or mg/kg or placebo once every weeks for 16 weeks The mean increase in FEV1 from baseline was 115 mL with the lower dose of reslizumab and 160 mL with the higher dose, compared to placebo; both Table Reslizumab and Mepolizumab Formulation Route Metabolism Half-life Reslizumab (Cinqair) 100 mg/10 mL singleuse vials IV Mepolizumab (Nucala) 100 mg single-dose vials SC Degradation by proteolytic enzymes ~24 days Degradation by proteolytic enzymes 16-22 days Dosage mg/kg IV q4 wks 100 mg SC q4 wks Approved ages ≥18 years ≥12 years Cost1 $2,5052 $2,500 Approximate WAC for a single treatment 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 June 5, 2016 Reprinted with permission by First Databank, Inc All rights reserved ©2016 www fdbhealth.com/policies/drug-pricing-policy Cost for a 70-kg patient (3 vials) 81 The Medical Letter ® differences were statistically significant Reslizumab mg/kg significantly improved asthma quality of life.5 The fourth study included patients 18-65 years old with asthma inadequately controlled on at least a mediumdose inhaled corticosteroid An elevated blood eosinophil count was not a requirement for study entry; 80% of the 492 enrolled patients had counts of