The Medical Letter ® on Drugs and Therapeutics Objective Drug Reviews Since 1959 Volume 57 ISSUE ISSUE No 1433 1473 Volume 56 July 20, 2015 IN THIS ISSUE Aptensio XR – A Long-Acting Methylphenidate for ADHD p Prestalia – Another Combination for Hypertension p Namzaric – A Combination of Old Drugs for Alzheimer’s Disease p 101 103 105 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 57 ISSUE ISSUE No 1433 1473 Volume 56 ▶ July 20, 2015 Take CME Exams ALSO IN THIS ISSUE Prestalia – Another Combination for Hypertension p 103 Namzaric – A Combination of Old Drugs for Alzheimer’s Disease p 105 Aptensio XR – Another LongActing Methylphenidate for ADHD The FDA has approved Aptensio XR (Rhodes), an extended-release formulation of methylphenidate hydrochloride, for treatment of attention-deficit/ hyperactivity disorder (ADHD) The Aptensio XR capsules contain multilayer beads designed to provide both a rapid onset and a long duration of action This formulation of methylphenidate has been available in Canada as Biphentin since 2006 Pronunciation Key Methylphenidate: meth” il fen’ i date Aptensio: app ten’ see oh METHYLPHENIDATE — Methylphenidate is effective in reducing the symptoms of ADHD in both children and adults.1,2 The effects of immediate-release methylphenidate products on behavior begin within 30 minutes and last for 3-5 hours; repeat dosing at mid-day is usually required Long-acting methylphenidate products are dosed once daily Some generic formulations of Concerta, which has a duration of action of 10-12 hours, have been found to release the drug at a slower rate after hours and may have a shorter duration of action.3-5 Immediate-release tablets are sometimes given in addition to long-acting formulations to provide a boost early in the morning or to smooth withdrawal later in the day CLINICAL STUDIES — In a randomized, double-blind, placebo-controlled trial, 26 children 6-12 years old with ADHD were titrated to an optimal dose of Aptensio XR for 2-4 weeks, followed by crossover treatment for week each with placebo and the new methylphenidate formulation After each 1-week treatment period, the children were evaluated using the SKAMP-Total score, which measures ADHD symptoms in a laboratory school setting, at time points between and 12 hours post-dose SKAMP-Total scores were significantly better (lower) with the active drug than with placebo at each of the time points.6 In a double-blind trial, 230 children 6-17 years old with ADHD were randomized to receive Aptensio XR 10, 15, 20, or 40 mg or placebo for week ADHD symptoms, Table Pharmacology of Some Oral Long-Acting Methylphenidate Products Aptensio XR Concerta Ritalin LA Metadate CD Quillivant XR Generic Available No Yes1,2 Yes1 Yes1 No Formulation ER capsules ER tablets ER capsules ER capsules ER oral suspension Mechanism of drug delivery Multilayer beads 40% IR, 60% CR Osmotic-release delivery system 20% IR, 80% CR Beads 50% IR, 50% DR Beads 30% IR, 70% ER Powder 20% IR, 80% DR Tmax h and h h and 6-10 h h and 5.5-6.6 h 1.5 h and 4.5 h 5h Half-life ~5 h ~3.6 h ~3.5 h ~6.8 h ~5.6 h Onset of action ≤60 20-60 10-60 20-60 45 Duration of action 12 h 10-12 h 6-8 h 6-8 h 12 h ER = extended-release; IR = immediate-release; CR = controlled-release; DR = delayed-release Concerta, Ritalin LA, and Metadate CD have generic equivalents, which could have a different mechanism of drug delivery and somewhat different pharmacokinetic parameters The generic formulations manufactured by Mallinckrodt and UCB are not considered therapeutically equivalent to Concerta The only generic formulation currently considered therapeutically equivalent (AB-rated) is an authorized generic manufactured by Janssen and marketed by Actavis (http://www.fda.gov/drugs/drug safety/ucm422568.htm) 101 Published by The Medical Letter, Inc • A Nonprofit Organization The Medical Letter July 20, 2015 Vol 57 (1473) ® Table Some Long-Acting Methylphenidate Products for ADHD Some Available Formulations Drug Pediatric Dosage1 Initial/Usual Adult Dosage Initial/Usual Cost2 $195.00 Aptensio XR (Rhodes) 10, 15, 20, 30, 40, 50, 60 mg ER caps 10 mg qAM/30 mg qAM No data Concerta (Janssen) generic6 18, 27, 36, 54 mg ER tabs5 18 mg qAM/36 mg qAM 18 or 36 mg qAM/72 mg qAM 265.20 208.50 Daytrana7 (Noven) 10 mg/9 hrs, 15 mg/9 hrs, 20 mg/9 hrs, 10 mg patch on hrs, off 15 hrs/30 mg patch 30 mg/9 hrs transdermal patches8 on hrs, off 15 hrs9 30 mg patch on hrs, off 15 hrs/60 mg patch on hrs, off 15 hrs9 275.80 Metadate CD3 (UCB) generic 10, 20, 30, 40, 50, 60 mg ER caps4 20 mg qAM/30 mg qAM 20 mg qAM/80 mg qAM 206.70 136.50 Ritalin LA3,10 (Novartis) generic 10, 20, 30, 40, 60 mg ER caps4 20, 30, 40 mg ER caps4 10-20 mg qAM/30 mg qAM 10-20 mg qAM/80 mg qAM 212.70 130.20 Quillivant XR (Pfizer) 25 mg/5 mL ER susp11 20 mg qAM/30-40 mg qAM No data 204.50 ER = extended-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 July 5, 2015 Reprinted with permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy Alcohol consumption may increase the rate of release of methylphenidate and should be avoided The contents of the capsule may be sprinkled on a small amount of applesauce or ice cream and taken immediately Pharmacokinetics are identical whether the beads are swallowed whole inside a capsule or sprinkled on food Tablets must be swallowed whole, and should not be crushed or chewed The generic formulations manufactured by Mallinckrodt and UCB are not considered therapeutically equivalent to Concerta The only generic formulation currently considered therapeutically equivalent (AB-rated) is an authorized generic manufactured by Janssen and marketed by Actavis (http://www.fda.gov/ drugs/drug safety/ucm422568.htm) FDA-approved only for use in children 6-17 years old Daytrana is supplied in sealed trays containing 10 or 30 patches in individual pouches The patch should be applied hours before an effect is needed and removed hours after application The patch can be removed before hours if a shorter duration of action is desired 10 Should not be taken with antacids or other drugs that decrease gastric acidity 11 Available in bottles containing 60, 120, 150, or 180 mL Must be reconstituted before administration and is stable for up to months Each bottle is packaged with an adapter and dosing syringe as measured by the ADHD-RS-IV questionnaire, decreased from baseline with all doses of the active drug, but only the 20- and 40-mg doses resulted in significantly lower symptom scores compared to placebo.7 Patients who completed the double-blind trial and enrolled in an 11-week open-label phase were titrated to their optimal dose of Aptensio XR ADHDRS-IV scores continued to decline throughout the open-label phase Several large studies have found no evidence that stimulants used to treat ADHD increase the risk of serious cardiovascular events in children or adults Patients with no history or clinical signs of heart disease not need to undergo an electrocardiogram or consult with a cardiologist before starting treatment with a stimulant.8 Use of stimulants should be avoided in patients with structural cardiac abnormalities, cardiomyopathy, serious arrhythmias, or coronary artery disease No studies are available comparing Aptensio XR directly with other long-acting methylphenidate formulations PREGNANCY AND LACTATION — Methylphenidate did not cause any teratogenic effects in rats and rabbits when administered at and 11 times, respectively, the maximum recommended human dose Spina bifida occurred in rabbits and decreased body weight occurred in rats given methylphenidate at doses that were, respectively, 40 and times the maximum recommended human dose Small amounts of methylphenidate are present in breast milk; no adverse effects on infants have been reported, but long-term studies are lacking ADVERSE EFFECTS — The most common adverse effects reported with Aptensio XR (occurring in ˃5% of patients and at a higher rate than with placebo) were headache, insomnia, abdominal pain, and decreased appetite Adverse effects of stimulants generally include suppression of appetite, failure to gain weight, slowing of growth, tachycardia, irritability, insomnia, tics, and rarely priapism and peripheral vasculopathy 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 102 DRUG INTERACTIONS — Methylphenidate should not be administered concurrently with a monoamine oxidase inhibitor (MAOI), or within 14 days after stopping one Alcohol consumption can increase the rate of release of methylphenidate from the Aptensio XR capsule and should be avoided The Medical Letter ® DOSAGE AND ADMINISTRATION — The recommended starting dosage of Aptensio XR in patients ≥6 years old is 10 mg once daily in the morning with or without food The dose can be increased in weekly increments of 10 mg up to a maximum of 60 mg once daily The capsules may be swallowed whole or, alternatively, opened, sprinkled on applesauce, and taken immediately CONCLUSION — In the absence of comparative trials, Aptensio XR appears to offer no clinical advantage over older long-acting methylphenidate preparations ■ L Greenhill et al Efficacy and safety of immediate-release methylphenidate treatment for preschoolers with ADHD J Am Acad Child Adolesc Psychiatry 2006; 45:1284 T Epstein et al Immediate-release methylphenidate for attention deficit hyperactivity disorder (ADHD) in adults Cochrane Database Syst Rev 2014 Sept 18; 9:CD005041 WE Pelham et al Once-a-day Concerta methylphenidate versus three-times-daily methylphenidate in laboratory and natural settings Pediatrics 2001; 107:E105 FDA Methylphenidate hydrochloride extended release tablets (generic Concerta) made by Mallinckrodt and Kudco Available at: http://www.fda.gov/drugs/drugsafety/ucm422568.htm Accessed July 9, 2015 R Maldonado Comparison of the pharmacokinetics and clinical efficacy of new extended-release formulations of methylphenidate Expert Opin Drug Metab Toxicol 2013; 9:1001 SB Wigal et al A randomized placebo-controlled double-blind study evaluating the time course of response to methylphenidate hydrochloride extended-release capsules in children with attention-deficit/hyperactivity disorder J Child Adolesc Psychopharmacol 2014; 24:562 SB Wigal et al Efficacy of methylphenidate hydrochloride extended-release capsules (Aptensio XR™) in children and adolescents with attention-deficit/hyperactivity disorder: a phase III, randomized, double-blind study CNS Drugs 2015; 29:331 Drugs for ADHD Med Lett Drugs Ther 2015; 57:37 ▶ Prestalia — Another Combination for Hypertension The FDA has approved Prestalia (Symplmed), an oral fixed-dose combination of the dihydropyridine calcium channel blocker amlodipine (Norvasc, and generics) and a new salt form of the angiotensinconverting enzyme (ACE) inhibitor perindopril, for treatment of hypertension in patients not adequately controlled on monotherapy or already taking both drugs, and in those just starting therapy who are likely to need multiple drugs to control their blood pressure The new salt form (perindopril arginine) is more stable and has a longer shelf-life than perindopril erbumine (Aceon, and generics).1 Two other ACE inhibitor/calcium channel blocker combinations, benazepril/amlodipine (Lotrel, and generics) and trandolapril/verapamil ER (Tarka, and generics), have been available in the US for many years Vol 57 (1473) July 20, 2015 Pronunciation Key Perindopril: per in’ doe pril Prestalia: pres ta li a Amlodipine: am loe’ di peen STANDARD TREATMENT — Nearly all recent guidelines recommend a thiazide-type diuretic (chlorthalidone is preferred), a calcium channel blocker, an ACE inhibitor, or an angiotensin receptor blocker (ARB) as initial therapy for hypertension in most non-black patients For black patients, a thiazide-type diuretic or calcium channel blocker is preferred for initial therapy, except for those with chronic kidney disease or heart failure, who should receive an ACE inhibitor or an ARB Beta blockers generally are no longer recommended as initial therapy except for patients with another indication, such as coronary heart disease or left ventricular dysfunction Most guidelines recommend an ACE inhibitor or an ARB over other classes for initial treatment of hypertension in non-black patients with diabetes Table Initial Monotherapy for Hypertension General Population Non-black Black THZD, ACE inhibitor, ARB, or CCB THZD or CCB Chronic Kidney Disease (CKD) Non-black Black ACE inhibitor or ARB ACE inhibitor or ARB Diabetes Non-black Black ACE inhibitor or ARB THZD or CCB1 THZD = thiazide-type diuretic; ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker Black patients with both diabetes and CKD should receive an ACE inhibitor or an ARB Many patients with hypertension need more than one drug to control their blood pressure If monotherapy does not achieve blood pressure goals, adding a second drug with a different mechanism of action is generally more effective than increasing the dose of the first drug and often allows for use of lower, better tolerated doses of both drugs If an ACE inhibitor or an ARB was used initially, it would be reasonable to add a thiazide-type diuretic or a calcium channel blocker When baseline blood pressure is >20/10 mm Hg above goal, many experts would begin therapy with two drugs.2 CLINICAL STUDIES — Approval of Prestalia was based on a prospective, active-controlled trial (PATH) in 837 patients with a mean seated blood pressure of 158/101 mm Hg who were randomized to Prestalia 14/10 mg, perindopril erbumine 16 mg, or amlodipine 10 mg once daily for weeks The mean reduction in blood pressure with the combination was 10.1/6.3 mm Hg more than with perindopril and 103 The Medical Letter Vol 57 (1473) ® July 20, 2015 Table Prestalia and Some Other Combinations for Hypertension Drug Prestalia and Its Components Perindopril erbumine – generic Aceon (Symplmed) Amlodipine – generic Norvasc (Pfizer) Perindopril arginine/amlodipine – Prestalia (Symplmed) Some Available Formulations Usual Adult Maintenance Dosage1 Cost2 2, 4, mg tabs 4, mg tabs 4-8 mg once/d or divided bid $18.40 80.80 2.5, 5, 10 mg tabs 2.5-10 mg once/d 2.10 113.50 3.5/2.5, 7/5, 14/10 mg tabs 3.5/2.5 mg-14/10 mg once/d 146.703 10/2.5, 10/5, 20/5, 20/10, 40/5, 40/10 mg caps 10/2.5-40/10 mg once/d 23.30 190.60 1/240, 2/180, 2/240, 4/240 mg tabs 2/180-4/240 mg once/d 126.90 146.90 20/5, 20/10, 40/5, 40/10 mg tabs 20/5-40/10 mg once/d 40/5, 40/10, 80/5, 80/10 mg tabs 40/5-80/10 mg once/d 126.30 174.10 160/5, 160/10, 320/5, 320/10 mg tabs 160/5-320/10 mg once/d 51.20 181.50 Other ACE Inhibitor/Calcium Channel Blocker Combinations Benazepril/amlodipine – generic Lotrel (Novartis) Trandolapril/verapamil ER – generic Tarka (Abbvie) ARB/Calcium Channel Blocker Combinations Olmesartan/amlodipine – Azor (Daiichi Sankyo) Telmisartan/amlodipine – generic Twynsta (Boehringer Ingelheim) Valsartan/amlodipine – generic Exforge (Novartis) 165.00 Dosage adjustments may be needed for renal or hepatic impairment Approximate WAC for 30 days’ treatment at the lowest usual adult maintenance 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 July 5, 2015 Reprinted wwwith permission by First Databank, Inc All rights reserved ©2015 www.fdbhealth.com/policies/drug-pricing-policy WAC according to the manufacturer Prestalia is also available through a membership program sponsored by Symplmed (bpcareconnect.com) for $9.95/month or $19.95/3 months 3.9/2.5 mm Hg more than with amlodipine In black patients and in those with diabetes, reductions in blood pressure with the combination were similar to those with amlodipine alone.3 Another trial in 1581 patients with mild to moderate uncomplicated hypertension found that the mean reduction in blood pressure after weeks was 7.2/4.1 mm Hg more with Prestalia 3.5/2.5 mg than with placebo; the combination was noninferior to the individual components alone in decreasing blood pressure.4 ADVERSE EFFECTS — Common adverse effects of Prestalia include edema, cough, headache, and dizziness Angioedema and hyperkalemia can occur with ACE inhibitors The combination is contraindicated in patients with hereditary or idiopathic angioedema PREGNANCY — Prestalia is classified as category D (positive evidence of risk) for use during pregnancy Use of ACE inhibitors during the second and third trimester reduces fetal renal function and increases fetal and neonatal morbidity and death 104 DOSAGE AND ADMINISTRATION – The recommended starting dosage of Prestalia is 3.5/2.5 mg once daily The dose can be increased every 7-14 days up to a maximum of 14/10 mg daily Prestalia is not recommended for patients ≥65 years old, or for those with hepatic impairment or a creatinine clearance