Stimulants and Related Agents Therapeutic Class Review (TCR) May 14, 2020 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland 21046 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. 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FDA-APPROVED INDICATIONS ADHD Narcolepsy Drug Manufacturer Age 3–5 Age ≥ 6 Other Indications Adults (Age ≥ 6 years) years years Stimulants: Immediate-Release amphetamine sulfate tablet generic, Exogenous obesity age ≥ 12 X X -- X (Evekeo®)1 Arbor years amphetamine sulfate orally disintegrating tablet (ODT) Arbor -- X -- -- -- (Evekeo ODT™)2 Excessive sleepiness armodafinil* generic, associated with narcolepsy, -- -- -- -- (Nuvigil®)3 Cephalon OSA, and SWD for age ≥ 17 years dexmethylphenidate IR generic, Novartis -- X -- -- -- (Focalin®)4 X dextroamphetamine IR generic, Arbor X (≤ 16 -- X -- (Zenzedi®)5 years) X dextroamphetamine generic, X (≤ 16 -- X -- solution (Procentra®)6 Independence years) methamphetamine generic, Exogenous obesity in adults -- X -- -- (Desoxyn®)7 Recordati and adolescents ≥ 12 years methylphenidate IR generic, -- X -- X -- (Methylin®†, Ritalin®)8,9 Shionogi mixed amphetamine salts IR generic, Teva X X -- X -- (Adderall®)10 Excessive sleepiness modafinil* generic, associated with narcolepsy, -- -- -- -- (Provigil®)11 Cephalon OSA, and SWD for age ≥ 17 years OSA – obstructive sleep apnea; SWD – shift work disorder * In OSA, modafinil and armodafinil are indicated as an adjunct to standard treatment(s) (e.g., continuous positive airway pressure [CPAP]) for the underlying obstruction. † Shionogi discontinued Methylin chewable tablets; the oral suspension remains available. Stimulants and Related Agents Review – May 2020 Page 2 | Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2020 Magellan Rx Management. All Rights Reserved. FDA-Approved Indications (continued) ADHD Narcolepsy Other Drug Manufacturer Age 3–5 Age ≥ 6 (age ≥ 6 Adults Indications years years years) Stimulants: Extended-Release (continued) amphetamine ER (Adzenys generic‡, Neos -- X X -- -- ER®, Adzenys XR-ODT®)12,13 amphetamine ER Tris -- X X -- -- (Dyanavel® XR)14 dexmethylphenidate ER generic, Novartis -- X X -- -- (Focalin XR®)15 dextroamphetamine ER X generic, Amedra -- -- X -- (Dexedrine®)16 (≤ 16 years) Moderate to severe lisdexamfetamine dimesylate Shire -- X X -- binge eating (Vyvanse®)17 disorder in adults methylphenidate ER§18 generic -- X -- -- -- methylphenidate ER Purdue/Adlon -- X X -- -- (Adhansia XR™)19 methylphenidate ER generic, Rhodes -- X X -- -- (Aptensio XR®)20 methylphenidate ER Neos -- X -- -- -- (Cotempla XR-ODT®)21 methylphenidate ER Ironshore -- X X -- -- (Jornay PM®)22 methylphenidate ER generic, Upstate -- X X X -- (Metadate ER®, Ritalin SR®)23,24 methylphenidate ER Pfizer -- X X -- -- (Quillichew ER®)25 methylphenidate ER Pfizer -- X X -- -- (Quillivant XR®)26 methylphenidate ER generic, Novartis -- X -- -- -- (Ritalin LA®)27 methylphenidate ER OROS generic, Janssen -- X X -- -- (Concerta®)28 methylphenidate transdermal Noven -- X -- -- -- (Daytrana®)29 mixed amphetamine salts ER generic, Shire -- X X -- -- (Adderall XR®)30 mixed amphetamine salts ER X Shire -- -- -- -- (Mydayis®)31 (≥ 13 years) OSA – obstructive sleep apnea; SWD – shift work disorder ‡ Authorized generic is available for Adzenys ER oral suspension Stimulants and Related Agents Review – May 2020 Page 3 | Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2020 Magellan Rx Management. All Rights Reserved. FDA-Approved Indications (continued) ADHD Narcolepsy Other Drug Manufacturer Age 3–5 Age ≥ 6 (age ≥ 6 Adults Indications years years years) Non-Stimulants atomoxetine (Strattera®)32 generic, Eli Lilly -- X X -- -- generic, Treatment of ADHD as clonidine ER (Kapvay®)33 -- X -- -- Concordia adjunct to stimulants generic, Treatment of ADHD as guanfacine ER (Intuniv®)34 -- X -- -- Shire adjunct to stimulants X pitolisant (Wakix®)35 Harmony -- -- -- -- (adults only) X solriamfetol (Sunosi®)¶36 Jazz -- -- -- OSA (adults)§ (adults only) OSA – obstructive sleep apnea; SWD – shift work disorder ¶ Solriamfetol is not indicated to treat underlying airway obstruction in OSA. The underlying airway obstruction must be treated (e.g., with continuous positive airway pressure [CPAP]) for ≥ 1 month before initiating solriamfetol for EDS. Any treatment used for the underlying airway obstruction should be continued throughout treatment with solriamfetol. Stimulant agents amphetamine, dexmethylphenidate, dextroamphetamine, lisdexamfetamine, methamphetamine, methylphenidate, and mixed amphetamine salts are Scheduled II controlled substances, and armodafinil, modafinil, and solriamfetol are Scheduled IV controlled substances. OVERVIEW Attention Deficit Hyperactivity Disorder (ADHD) The most common use of stimulants is for the treatment of ADHD, for which they are considered first- line therapy.37,38,39,40,41,42 ADHD, which has been diagnosed in approximately 15% of children 4 to 17 years of age and about 4% of adults, is a chronic condition with core symptoms of inattention, hyperactivity, and difficulty controlling behavior.43,44 It may also be accompanied by internalized disorders, such as sadness and anxiety, as well as aggressive and oppositional disorders.45,46,47 The 3 main types of ADHD are primary hyperactive, primary inattentive, and mixed. Children with ADHD may experience academic underachievement, difficulties in personal relationships, and low self-esteem.48,49 Early recognition of the signs and symptoms of ADHD, assessment, and treatment can help redirect the educational and social development of most children with ADHD. According to the 2019 ADHD guidelines developed by a subcommittee of the American Academy of Pediatrics (AAP), the primary care clinician should initiate an evaluation for ADHD for any child 4 through 18 years of age who presents with academic or behavioral problems and symptoms of inattention, hyperactivity, or impulsivity.50 The AAP guidelines now include a recommendation to screen patients for comorbidities such as depression, anxiety and substance use. The treatment of patients with ADHD should maximize function to improve relationships and performance at school, decrease disruptive behaviors, promote safety, increase independence, and improve self-esteem. Stimulants and Related Agents Review – May 2020 Page 4 | Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2020 Magellan Rx Management. All Rights Reserved. The AAP recommends parent- and/or teacher-administered behavior therapy as first-line treatment for children 4 to 5 years of age.51 Methylphenidate (MPH) may be prescribed if the behavior interventions do not provide significant improvement and there continues to be moderate to severe disturbance in the child’s function. For children 6 to 11 years of age, the evidence is particularly strong for FDA- approved stimulant use for ADHD, and sufficient, but less compelling for non-stimulants in the following order: atomoxetine (Strattera), guanfacine ER (Intuniv) and clonidine ER (Kapvay). Medication therapy in addition to behavioral therapy is recommended. For patients 12 to 18 years of age, the AAP recommends FDA-approved medications, with the adolescent’s assent, and behavior therapy as treatment for ADHD, preferably both. The Medical Letter suggests that school-age children, adolescents, and adults begin with an oral stimulant, noting that none of the agents have shown to be more effective than another; however, some patients may respond better to amphetamines than to methylphenidate and vice versa52 They advised that use of long-acting formulations, which generally contain both immediate- and extended- release components, has become standard clinical practice and the addition of a short-acting stimulants may improve symptom control early in the morning or to prolong the duration of action in the afternoon. They also indicate that short-acting stimulants may be useful in small children to demonstrate