UTAH MEDICAID DUR REPORT FEBRUARY 2020 SAFE AND ... · CNS stimulants will be referred to as...

UTAH MEDICAID DUR REPORT

FEBRUARY 2020

SAFE AND APPROPRIATE USE OF CENTRAL NERVOUS SYSTEM STIMULANTS IN CHILDREN AND

ADOLESCENTS

Report finalized: January 2020

Drug Regimen Review Center

Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Joanita Lake, B.Pharm., MSc EBHC (Oxon), Research Assistant Professor Jacob Crook, MStat, Data and Statistical Analyst Joanne LaFleur, PharmD, MSPH, Associate Professor

University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2020 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

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Contents Introduction ........................................................................................................................................... 2

Methods ................................................................................................................................................. 3

Disease Overview ................................................................................................................................... 4

Table 1. DSM-5 Diagnostic Criteria for ADHD ................................................................................ 5

CNS Stimulant Medication Characteristics ............................................................................................ 6

Pharmacology of CNS Stimulant Medication ......................................................................................... 7

Table 2. Pharmacokinetic Properties and Other Considerations for CNS Stimulants ................... 8

Clinical Practice Guideline Recommendations .................................................................................... 12

Table 3. Clinical Practice Guidelines for Attention-Deficit/Hyperactivity Disorder in the Pediatric Population .................................................................................................................... 14

ADHD Comorbidities and Treatment Recommendations .................................................................... 17

Foster Care Children With ADHD ......................................................................................................... 18

Age Limit Considerations for CNS Stimulants ...................................................................................... 18

Table 4. FDA Prescribing Information for CNS Stimulants and Guideline Recommendations by Pediatric Age ................................................................................................................................ 19

Treatment Strategies for Patients with ADHD ..................................................................................... 20

Titration, Follow-Up, and Stopping Considerations ..................................................................... 21

Considerations for Selecting Short-Acting or Long-Acting Stimulant Formulations .................... 21

Concomitant Use of Stimulants ................................................................................................... 23

Maximum Recommended Daily Doses and Monthly Quantity Limits of CNS Stimulant Medication . 24

Table 5. Maximum Daily Doses for FDA-Approved CNS Stimulants in Pediatric Patients........... 25

Safety Concerns Related to CNS Stimulant Use in Children ................................................................ 30

Table 6. Warnings and Precautions for CNS Stimulants .............................................................. 32

Table 7. CNS Stimulant Adverse Events and Recommended Management ............................... 33

Utah Medicaid Utilization Data ............................................................................................................ 34

Discussion Topics for Potential Prior Authorization Criteria and Safety Edits ..................................... 41

Summary .............................................................................................................................................. 43

References ........................................................................................................................................... 46

Appendix A – Prescribing Information for CNS Stimulants .................................................................. 52

Appendix B – Utah Medicaid Utilization Data for CNS Stimulants ...................................................... 58

Appendix C – ICD-10 Diagnosis Codes ................................................................................................. 62

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Introduction Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder characterized by symptoms of inattention and/or hyperactivity-impulsivity that impact normal functioning and development.1,2 Untreated or undertreated ADHD may result in serious problems in the child’s health and daily functioning (eg, family conflicts, repeated failure at school, and social challenges).3 In addition, rates of emergency room visits, self-injuries, and motor vehicle crashes are higher in children with untreated ADHD compared to those who receive treatment.4 Medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of ADHD include central nervous system (CNS) stimulants (amphetamines and methylphenidate) and non-stimulants (atomoxetine, guanfacine, and clonidine). CNS stimulants will be referred to as stimulants throughout the report. Some stimulants are additionally approved for the treatment of narcolepsy, exogenous obesity, and binge eating disorder (BED).5-34

The full pathophysiology of ADHD is not well understood; however, evidence suggests that ADHD may be due to inadequate production of catecholamines such as norepinephrine and dopamine in the prefrontal cortex.35-37 Stimulants are used to increase CNS catecholamine levels and alleviate ADHD symptoms (ie, improve motivation, attention, and movement).4,38 Stimulant medications are available as short-acting (SA) and long-acting (LA) formulations.39-41 Duration of action ranges from 3 to 6 hours with SA formulations to 6 to 16 hours with LA formulations. Treatment approaches in children with ADHD should be individualized and adjusted to the child´s age and needs.42 For instance, an SA formulation may be useful in very young children who need small doses of a stimulant; an LA formulation may be helpful in school-aged children to reduce ADHD symptoms during school hours; and an LA formulation in the morning followed by an SA formulation in the evening may be useful in adolescents to cover school hours and after school hours (eg, while studying, driving, or at extracurricular activities).3 Clinical practice guidelines mention dosing strategies may include an LA formulation in the morning followed by an SA formulation latter in the day for children requiring a longer duration of effect thorough the day. Considerations regarding concomitant use of 2 LA or 2 SA formulations are not described in guidelines.3,42-44

Concurrent with the increase in understanding, awareness, and acceptance of ADHD in the medical setting over the last decades, the number of people diagnosed and treated for ADHD has also increased.45,4 According to the 2003-2011 National Survey of Children’s Health (NSCH), the estimated percentage of school-aged children (4 to 17 years old) ever diagnosed with ADHD by a health care provider increased from 5.5% to 8.3% between 2003 and 2011 in Utah. Nationally, this percentage rose from 7.8% to 11% between 2003 and 2011.46-48 Among children 4 to 17 years diagnosed with ADHD, the percentage of patients taking ADHD medication increased from 66.3% to 69.0% between 2007 and 2011 in the US.49 In Utah, this percentage decreased from 65.2% in 2007 to 60.3% in 2011.49 Concerning stimulant medications, methylphenidate and amphetamine prescriptions rose by 35.5% from 2008 to 2012 in the US, and especially in adolescents and adults.50

All stimulants are FDA approved in patients 6 years of age and older, with the exception of a branded mixed amphetamine salt formulation (Mydayis), only approved for children 13 years of age or older. Some amphetamine-based formulations have additional FDA approved dosing recommendations for children 3 through 5 years of age (ie, Adderall, Evekeo, Dexedrine, ProCentra, and Zenzedi); these are all short-acting products.5-34 About a third of children with ADHD are diagnosed before the age of 6 years.43

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The 2019 American Academy of Pediatrics (AAP) guideline recommends behavior therapy as first-line for the very young population (4 to 5 years of age) followed by methylphenidate as second-line therapy if behavioral interventions are insufficient to ameliorate clear disturbances in function.43 The 2016 National Survey of Children’s Health (NSCH) data of parent-reported ADHD medication suggests that 18% of children 2 to 5 years old with ADHD received medication and 60% received behavior therapy.51

Stimulants are considered the most efficacious medications for the treatment of ADHD; however, they are associated with adverse events such as decreased appetite, abdominal pain, headaches, irritability, sleep disturbances, and slowed growth. Long-term effects of stimulants in young children (eg, growth and brain development) are unknown.3,43,52 Stimulants are Schedule II controlled substances due to their high potential for abuse and ability to produce severe physical or psychological dependence.53 The 2019 AAP guideline recommends adolescents be evaluated for symptoms of substance abuse and potential for diversion or misuse of stimulants. Detailed information regarding abuse and misuse potential of ADHD stimulants will be reviewed in the March Drug Utilization Review (DUR) Board meeting.

The purpose of this review is to provide evidence to assist the Medicaid DUR Board in assuring safe and appropriate use of stimulant medication in children and adolescents. This review will specifically address potential age restrictions, dose limits, considerations for monthly quantity limits, and concerns regarding certain combinations of stimulants. Prior authorization criteria and provider outreach ideas will be proposed for discussion. Relevant utilization data in the Utah Medicaid pediatric population will be presented.

Methods Prescribing information for stimulants was obtained from package inserts available on FDA and DailyMed websites. Additional product information was found in Micromedex and Lexicomp. Textbooks were consulted for background information on pediatric mental health diseases, pharmacology, and diagnostic criteria (ie, the Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5]). The Centers for Disease Control and Prevention (CDC) website was consulted for background information and statistics regarding ADHD diagnosis and use of stimulants in children.

Websites of known professional organizations relevant to this report were searched to identify pertinent clinical practice guidelines, parameters, or recommendations (eg, the American Academy of Pediatrics [AAP], the American Academy of Child and Adolescent Psychiatry [AACAP], the Canadian ADHD Resource Alliance [CADDRA], and the National Institute for Health and Care Excellence [NICE] websites).

Relevant information was extracted from the 2019 Utah Medicaid Pharmacy and Therapeutics (P&T) Committee drug class review, “Updated Report of Central Nervous System Stimulants for the Treatment of Attention-Deficit/Hyperactivity Disorder,” and the 2016 Texas report on Psychotropic Medication Utilization Parameters for Children and Youth in Foster Care, 5th edition.54

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Disease Overview The most frequently diagnosed mental disorder in American children is ADHD, followed by behavior disorders, anxiety, and depression.55 ADHD was initially named as ‘hyperkinetic reaction in childhood’ in 1968 by the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 2nd edition (DSM-II). The term evolved to Attention Deficit Disorder (ADD) in 1980 (DSM-III) and finally to ADHD in 1987 (DSM-III-revised).56 ADHD is defined by DSM-5 as a neurodevelopmental disorder characterized by “impairing levels of inattention, disorganization, and/or hyperactivity-impulsivity,” which produce difficulty functioning in social, academic, and occupational settings.2 Inattention and disorganization involve difficulty sustaining focus on tasks and organizing activities. Hyperactivity-impulsivity involves restlessness, fidgeting, excessive movement/talking, and hasty actions that interfere with other people’s tasks.2 These symptoms are typically not consistent with the behavior considered normal for that age and developmental stage.2 ADHD may be divided into 3 different types based on symptoms: 1) predominantly inattentive presentation with only symptoms of inattention over the last 6 months, 2) predominantly hyperactive-impulsive presentation with only symptoms of hyperactivity-impulsivity over the last 6 months, or 3) combined presentation with symptoms of both inattention and hyperactivity-impulsivity equally exhibited over the last 6 months.2,57

ADHD is most often diagnosed during childhood and may continue into adulthood.43,46 ADHD is diagnosed more frequently in school-aged boys (1 in 5) than girls (1 in 11) and the average age of first onset of the disease is 7 years.43,46 Approximately 33% of children were diagnosed before the age of 6 years according to a 2014 national survey; with more than 50% being diagnosed by a primary care clinician (most commonly a pediatrician).43

According to parent-report data from the third National Survey of Children’s Health (NSCH) conducted in 2011-2012, the estimated percentage of school-aged children (4 to 17 years old) ever diagnosed with ADHD was 11% (6.4 million) in the United States (US) and 8.3% in Utah.46-48 The US prevalence of ADHD rose by 42% between 2003 and 2011.46,47 A redesigned 2016 NSCH showed an estimated prevalence in the US of 9.4% (6.1 million) among children 2 to 17 years old based on parent report.51,58,59 The economic burden of childhood ADHD in the US health care system reaches more than $38 billion per year, including costs associated with the treatment of patients, healthcare of family members, education, juvenile justice, and lost productivity for family members.60,61 About 64% of children with ADHD have another mental, emotional, or behavioral disorder, including behavior or conduct problem (52%), anxiety (33%), depression (17%), autism spectrum disorder (14%), and Tourette syndrome (1%).51,58 This may further contribute to increased health-care costs and morbidity. Increasing mental health disorder education and screening for other disorders can help to improve patient outcomes and reduce overall costs.62

Etiology and Risk Factors

ADHD causes and risk factors are unknown.63 Evidence suggests that genetics, brain injury, exposure to environmental agents (eg, lead) in pregnancy or young age, alcohol and/or tobacco use in pregnancy, a premature birth, and low birth weight are associated with the development of ADHD.63

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Diagnosis

There is not a specific test to diagnose ADHD and other mental conditions (eg, anxiety, depression, and sleep disorders) may present with similar symptoms.57,63 According to DSM-5 diagnostic criteria for ADHD, diagnosis requires the presence of 6 or more symptoms of inattention and/or hyperactivity-impulsivity for children (≤ 16 years old) or 5 or more symptoms for adolescents and adults (≥ 17 years old) that have persisted for at least 6 months and are inconsistent with the stage of development.2,57 In addition, further requirements are necessary to confirm the diagnosis of ADHD.2,57 Table 1 includes DSM-5 diagnostic criteria for ADHD and the 18 ADHD symptoms. The 2019 AAP guideline concerning diagnosis and treatment of ADHD in children and adolescents recommends meeting all DSM-5 criteria for the diagnosis of ADHD.43 When evaluating a patient for ADHD, screening for comorbid conditions (eg, anxiety, depression, oppositional defiant disorder, conduct disorder, and substance use) is recommended by the AAP guideline.43 Treatment strategies for comorbid conditions are presented on page 17.

Table 1. DSM-5 Diagnostic Criteria for ADHD2 Age Range DSM-5 Diagnostic Criteria Symptoms listed in DSM-5 Children (≤ 16 years old)

1. Six or more symptoms of inattention and/or hyperactivity-impulsivity that have persisted for at least 6 months and are inconsistent with the stage of development

2. Several symptoms are present before age 12 in 2 or more settings (eg, at home and school)

3. Several symptoms reduce the quality of school/work and social functioning

4. Symptoms do not adequately define other mental disorders

Symptoms of inattention: • Failure to pay close attention to details. Make

careless mistakes • Trouble maintaining attention on a single task • Inability to listen • Failure to finish duties at school, home, or

work • Trouble organizing tasks • Avoids tasks that require mental effort over a

long period of time • Loses necessary things (eg, school material) • Easily distracted • Forgetful in daily activities Symptoms of hyperactivity-impulsivity: • Fidgets • Trouble remaining seated • Feels restless (may run or climb in

inappropriate circumstances) • Trouble participating in quiet activities • "On the go” • Talks excessively and speaks out of turn • Blurts out an answer before a question is

completed • Trouble waiting turn • Often interrupts or intrudes

Adolescents and adults (≥ 17 years old)

1. Five or more symptoms of inattention and/or hyperactivity-impulsivity that have persisted for at least 6 months and are inconsistent with the stage of development

2. Several symptoms are present before age 12 in 2 or more settings (eg, at home and school)

3. Several symptoms reduce the quality of school/work and social functioning

4. Symptoms do not adequately define other mental disorders

Abbreviations: DSM-5, Diagnostic and Statistical Manual of Mental Disorders (5th edition)

Common behavior rating scales are used for the initial screening of ADHD and evaluation of treatment response. These should be completed by the parents, teacher, or patient and include ADHD rating scale-IV (ADHD-RS-IV); Academic Performance Rating Scale (APRS); Swanson, Kotkin, Agler, M-Flynn, and

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Pelham Scale (SKAMP); or Conners Rating Scales, among others. These rating scales should not be used alone to diagnose ADHD.41

CNS Stimulant Medication Characteristics Currently, there are more than 30 stimulant-containing products approved by the FDA for the treatment of ADHD. Most products are available as single-ingredient products containing 1 of the 6 different stimulant agents (amphetamine, dexmethylphenidate, dextroamphetamine, lisdexamfetamine, methamphetamine, or methylphenidate) and some are available as a combination of mixed salts of amphetamine and dextroamphetamine at different strengths (commonly called mixed amphetamine salts [MAS]). Administration frequency for ADHD treatment varies from once to thrice daily depending on the formulation selected.5-34 Some of these medications are additionally approved for the treatment of narcolepsy in youth 6 years and older (Adderall, all dextroamphetamine products, Evekeo, Metadate ER, Methylin, and Ritalin) and exogenous obesity in youth 12 years and older (Evekeo).5-34

Each stimulant is available as an oral capsule or tablet formulation. Some of these agents are additionally available as oral solutions/suspensions (amphetamine, dextroamphetamine, and methylphenidate), orally disintegrating tablets (ODT; amphetamine and methylphenidate), chewable tablets (lisdexamfetamine and methylphenidate), and a transdermal patch formulation (methylphenidate). Stimulants are available as short-acting (SA) and long-acting (LA) preparations. Some formulations can be substituted for other formulations containing the same active ingredient on a mg per mg basis (eg, lisdexamfetamine capsules can be substituted for lisdexamfetamine chewable tablets). However, switching from one product to another containing a different active ingredient on a mg per mg basis (eg, from amphetamine extended release [ER] ODT to mixed amphetamine salts capsules) should be avoided because of the risk of overdose due to different amphetamine-base compositions and pharmacokinetic profiles. Some formulations should be taken as a single, intact entity (ie, should not be crushed or chewed; eg, Adzenys XR-ODT, Focalin XR, Dexedrine Spansule, Concerta, Metadate ER, and Relexxii). Some capsules can be opened and sprinkled into soft food or drink (eg, Adderall XR, Mydayis, Vyvanse, Adhansia XR, Aptensio XR, Jornay PM, Metadate CD, and Ritalin LA).5-34 Younger children with difficulty swallowing whole tables or capsules may benefit from formulations that can be administered with greater ease (ie, ODT, solution, or sprinkle capsule).3,64

All agents are approved in patients 6 years of age or older, with the exception of a mixed amphetamine salt formulation (Mydayis), only approved in children 13 years or older. In addition, some amphetamine-based products have FDA-approved dosing recommendations for children 3 through 5 years of age (ie, Adderall, Evekeo, Dexedrine, ProCentra, and Zenzedi); these are all short-acting products.5-34 Table 1 of Appendix A provides a list of the CNS stimulants approved in the United States (US) along with their corresponding FDA indications and dosing recommendations. Table 2 of Appendix A includes special population considerations for CNS stimulants. Age limit considerations per formulation are addressed on pages 18 and 19.

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Pharmacology of CNS Stimulant Medication The full pathophysiology of ADHD is not well understood; however, evidence suggests that ADHD may be due to inadequate production of catecholamines such as norepinephrine and dopamine in the prefrontal cortex.35-37 Stimulants are used to increase the availability of these catecholamines, which alleviate ADHD symptoms.38 Increased levels of catecholamines result in stimulation of the peripheral and CNS systems and increases in blood pressure and bronchodilation.5,6,12,16,17 There are 2 main classes of stimulants, amphetamine-based and methylphenidate-based. Products with similar chemical structure can be classified under these 2 main classes:

• Amphetamine-based compounds: amphetamine, dextroamphetamine, lisdexamphetamine, and methamphetamine

• Methylphenidate-based compounds: dexmethylphenidate and methylphenidate

Amphetamines belong to the class of β-phenethlylamines and are potent noncatecholamine sympathomimetic amines.38,39 They increase the availability of catecholamines such as dopamine or norepinephrine via increased release or reuptake inhibition.5,6,16,17 The alerting and anorectic effects of amphetamines are thought to be due to norepinephrine release in central noradrenergic neurons. Chemically, amphetamine is composed of 2 active isomers, dextro- or d-amphetamine and levo- or l-amphetamine, which have different actions in the body. High doses of dextro-amphetamine act mainly on dopamine and are approximately 3-4 times more potent than levo-amphetamine in producing CNS stimulation.65 Levo-amphetamine acts mainly on norepinephrine at low doses and has slightly more potent cardiovascular and peripheral effects compared to dextro-amphetamine.65 Amphetamine products and mixed amphetamine salts utilize higher ratios of dextro-amphetamine to levo-amphetamine (Adzenys 3:1, Dyanavel 3.2:1, and Adderall 3:1) to reduce the risk of unwanted cardiovascular effects. Dextroamphetamine (Dexedrine) and lisdexamfetamine (Vyvanse, an inactive prodrug hydrolyzed by red blood cells and converted to dextro-amphetamine) are not mixed-isomer agents and have pharmacological effects solely due to dextro-amphetamine.39,62,66

Methamphetamine (Desoxyn) or N-methylamphetamine has a chemical structure similar to amphetamine.67 It exists in 2 different active isomers, d-methamphetamine and l-methamphetamine. D-methamphetamine is 3 to 5 times more potent than l-methamphetamine. Methamphetamine works by increasing the availability of catecholamines (dopamine, noradrenaline, and serotonin), enhancing release from storage sites, inhibiting reuptake through monoamine transporters, and decreasing metabolism by inhibiting oxidases.67 The central effects of methamphetamine are more prominent than those of amphetamine due its lipophilic nature.68

Methylphenidate is also structurally related to amphetamines, with the addition of a piperidine group. Methylphenidate exists as 2 active isomers, d- and l-threo methylphenidate. Methylphenidate products may contain only the d-threo isomer (or dexmethylphenidate), or a racemic mixture of the 2 isomers.10,11,21-23 Dexmethylphenidate is more potent than l-methylphenidate. Methylphenidate works by decreasing dopamine and norepinephrine reuptake and, overall, exhibits similar pharmacological properties as amphetamines.39,69

Durations of action ranges from 3 to 6 hours with immediate-release (IR) formulations to 6 to 16 hours with extended-release (ER) formulations.40,41 Individual patient genetic variations can result in

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differences in efficacy and optimal dose between the agents; for example, patients with a 9/9 dopamine transporter gene (SLC6A3/DAT1) genotype may require higher doses of stimulant medications in order to achieve adequate symptom control.70

Regarding the mechanism of sustained action with long-acting formulations, some products use specific drug delivery systems to produce a fast onset of action followed by a gradual release of the active ingredient. For instance, some oral formulations combine immediate-release and extended-release beads. These allow a first peak of plasma concentration due to the content in immediate-release active ingredient and a second peak due to the content in extended-release active ingredient (eg, Focalin XR, Adhansia XR, Aptensio XR, Metadate CD, and Ritalin LA).11,21,22,27,34 Other formulations are designed as osmotic delivery systems with amounts of immediate release active ingredient and amounts of osmotic components to control the rate of drug delivery (eg, Concerta, Relexxii).23,32 Jornay PM uses a technology other than that of the long-acting formulations with immediate release and extended release profiles. It is administered in the evening and contains microbeads with a delayed release and an extended release layer. This allows a delayed effect of methylphenidate that is observed when the child wakes up the next morning and a controlled release of the active substance throughout the day.26 Lisdexamfetamine is a prodrug converted to dextro-amphetamine by hydrolysis.39,62,66 It provides a longer time to onset of action and prolonged duration of effects.71

Table 2 includes pharmacokinetic properties by formulation type, dosing frequency, and mode of administration for the stimulants.

Table 2. Pharmacokinetic Properties and Other Considerations for CNS Stimulants5-34,39 Brand Name Preparations Formulation

Content in Active Ingredients

Admin. Tmax DoA Half-life

Amphetamine Products Adzenys ER ER oral suspension

LA (contains equal amounts of IR and ER amp)

3 to 1 ratio of d- to l-amp

QD 5 h NR 11-13 h (d-amp); 14-15 h (l-amp)

Adzenys XR-ODT ER ODT

LA (contains 50% IR and 50% ER amp)

3 to 1 ratio of d- to l-amp

QD (ODT) 5-8 h 10-12 h 9-11 h (d-amp); 10-14 h (l-amp)

Dyanavel XR ER oral suspension

LA (amounts of IR and ER amp not specified)

3.2 to1 ratio of d- to l-amp

QD 4-4.5 h NR 10-12 h (d-amp); 12-15 h (l-amp)

Evekeo Oral tablet SA

Ratio of d- to l-amp sulfate not specified

QD or BIDa 4 h 4-6 h 12 h

Evekeo ODT ODT

SA 1 to 1 ratio of d- to l-amp sulfate

QD or BID (ODT) 3-3.5 h 4-6 h

10 h (d-amp); 12 h (l-amp)

Dexmethylphenidate Products

Focalin Oral tablet

SA Dexmph hydrochloride

BIDa 1-1.5 h 3-5 h 2-3 h

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Focalin XR ER oral capsule

LA (capsules with bi-modal release profile. Each capsule contains 50% of Dexmph dose as IR beads and 50% as enteric-coated, delayed-release beads

Dexmph hydrochloride

QD (swallow whole)

1.5 h (1st

peak) 6.5 h (2nd peak)

9-12 h NR

Dextroamphetamine Products Dexedrine Spansule SR oral capsule

LA Dexamp sulfate QD or BID (swallow whole)

8 h 8 h 12 h

Generic DEXAMP sulfate Oral tablet Oral solution SA Dexamp sulfate QD or BIDa 3 h 4-6 h 12 h ProCentra Oral solution Zenzedi Oral tablet Dextroamphetamine/Amphetamine Mixed Salt Products

Generic DEXAMP/ AMP 5, 7.5, 10, 12.5, 15, 20, 30 Oral tablet

SA

Equal amounts of amp aspartate, amp sulfate, dexamp saccharate, and dexamp sulfate (3 to 1 ratio of d- to l-AMP base equivalent)

QD or BIDa 3 h NR

10-11 h (d-amp) 12-14 h (l-amp)

Adderall XR 5, 10, 15, 20, 25, and 30 ER oral capsule

LA

Equal amounts of amp aspartate, amp sulfate, dexamp saccharate, and dexamp sulfate (3 to 1 ratio of d- to l-amp base equivalent)

QD (swallow whole or sprinkle contents)

7 h 8-12 h39

9-11 h (d-amp) 11-13 h (l-amp)

10




Mydayis ER oral capsule

LA

Amp aspartate, amp sulfate, dexamp saccharate, and dexamp sulfate (different strengths compared to Adderall XR)


7-10 h NR

10-11 h (d-amp) 10-13 h (l-amp)

Lisdexamfetamine Products

Vyvanse Capsule, chewable tablet

LA Lisdex dimesylate


1 h (Lisdex) 4 h (Dexamp)

8-13 h

<1 h (Lisdex) 10-13 h (Dexamp)

Metamphetmine Products

Desoxyn Oral tablet

SA Methamp hydrochloride

QD or BIDa NR NR 4-5 h

Methylphenidate Products

Adhansia XR ER oral capsule

LA (capsules containing multilayered beads, with one IR layer containing 20% of mph dose and an ER layer with 80% of mph dose)

Mph hydrochloride (racemic mixture of d- and l-isomers)


1.5 h (1st peak) 12 h (2nd peak)

NR 7 h

Aptensio XR ER oral capsule



2 h (1st peak) 8 h (2nd peak)

≤16 h 5 h

Concerta ER oral tablet

LA, OROS formulation (tablet with an IR drug overcoat and 3 additional layers: 2 drug layers and 1 layer containing osmotic components)


QD (swallow whole)

1 h (initial peak) 6-10 h (mean peak)

8-12 h 3.5 h

Cotempla XR-ODT ER ODT

LA (tablets containing 25% IR and 75% ER mph)

QD (ODT) 5 h NR 4 h

Daytrana ER transdermal patch

LA (adhesive-based matrix transdermal system)

Mph (racemic mixture of d- and l-isomers)

Apply 2 hours before the effect is needed and remove 9 hours after application

8-10 h 11-12 h 4-5 h (d-mph); 1-3 h (l-mph)

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Jornay PM ER oral capsule

LA (capsules containing beads with a delayed-release layer and an ER layer)



14 h (single peak)

NR 5.9 h

Metadate CD ER oral capsule



1.5 h (1st Tmax) 4.5 h (2nd Tmax)

6-8 h 6.8 h

Metadate ER ER oral tablet

LA BID or TID (swallow whole)

NR 8 h NR

Methylin Oral solution

SA BID or TID 1-2 h 3-5 h 2.7 h

Quillichew ER ER oral chewable tablet

LA (tablets containing 30% IR and 70% ER mph)


QD (chewable) 5 h NR 5.2 h

Quillivant XR ER oral suspension

LA (oral suspension containing 20% IR and 80% ER mph)

QD 5 h NR 5.6 h (d-mph)

Relexxii ER oral tablet

LA (tablets with an IR drug overcoat and an osmotic system that delivers mph gradually)

QD (swallow whole)

1 h (1st Tmax) 6-10 h (2nd Tmax)

12 h NR

Ritalin Oral tablet

SA BID or TID a 1.9 h (0.3 to 4.4 h) 3-5 h

2.5-3.5 h (1.3-7.7 h) Ritalin LA

ER oral capsule

LA (capsules with bi-modal release profile. Each capsule contains 50% of mph dose as IR beads and 50% as enteric-coated, delayed-release beads)


1-4 h (1st Tmax) 4-11 h (2nd Tmax)

6-8 h

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; Amp, amphetamine; BID, twice daily; Dexamp, dextroamphetamine; Dexmph, dexmethylphenidate; DoA, duration of action; ER, extended release; IR, immediate release; h, hour; LA, long acting; Lisdex, lisdexamfetamine; MoA, mode of administration; Mph, methylphenidate; NR, not reported; ODT, orally disintegrating tablet; OROS, osmotic release oral system; QD, once daily; SA, short acting; Tmax, time to maximum concentration; TID, three times daily; XR, extended release

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Clinical Practice Guideline Recommendations In October 2019, the American Academy of Pediatrics (AAP) published an updated guideline for the treatment of ADHD in children and adolescents (4 to 17 years).43 No recommendations are available for the diagnosis and treatment of children younger than 4 years due to limited evidence available.43 Parent training in behavior management (PTBM) may be considered for children below 4 years of age with ADHD-like symptoms causing significant impairments.43 The 2019 AAP guideline provides the following strong recommendations for children and adolescents 4 to 17 years43:

• For preschool-aged children (4 through 5 years old) with ADHD, evidence-based PTBM and/or behavioral classroom interventions is strongly recommended as first-line therapy, if available.

There is strong evidence supporting the use of PTBM in preschool children. Behavioral therapy and stimulant medication seem to have similar effects on ADHD symptoms but improvements tend to continue with behavioral therapy.43 In addition, ADHD medication causes more side effects in young children than older children and long-term effects in young children have not been established.72 Consequently, behavioral therapies are recommended as first-line; however, some areas may not have evidence-based behavioral therapies available or a lack of insurance coverage may limit access.3

Guideline authors state that methylphenidate may be offered if behavioral therapy does not provide significant improvements and if there is moderate-to-severe dysfunction. Severity criteria include “…symptoms that have persisted for at least 9 months; dysfunction that is manifested in both home and other settings, such as preschool or child care; and dysfunction that has not responded adequately to PTBM.”43 If behavioral therapy is unavailable, clinicians should weigh the risks (potential adverse events and lack of evidence regarding long-term effects on growth and brain development) versus the benefits of initiating methylphenidate in this age group. Among ADHD medications, guideline authors consider methylphenidate has the strongest evidence regarding efficacy and safety in children 4 to 5 years; however, there is still limited evidence and methylphenidate is not FDA-approved for this age group.3 Some amphetamine formulations are approved for children younger than 6 years; however, evidence is considered insufficiently robust by guideline authors to recommend them first-line medication.3 In addition, evidence for non-stimulant medications in this age group is inadequate.

The AAP guideline suggests consultation with a mental health specialist in treating preschool-aged children.43 In addition, guideline authors state that “…Given the nationwide problem of limited access to mental health clinicians, pediatricians and other PCCs are increasingly called on to provide services to patients with ADHD and to their families. In addition, the AAP holds that primary care pediatricians should be prepared to diagnose and manage mild-to-moderate ADHD, anxiety, depression, and problematic substance use, as well as co-manage patients who have more severe conditions with mental health professionals. Unfortunately, third party payers seldom pay appropriately for these time consuming services.”43

The main study supporting the efficacy and safety of methylphenidate in preschool children with ADHD was a large, multicenter randomized controlled trials (the Preschool ADHD Treatment Study – [PATS]).43,73 It included children 3 to 5.5 years with moderate to severe dysfunction.43 Immediate-release methylphenidate at dosages 2.5 mg, 5 mg, and 7.5 mg 3 times daily was significantly more efficacious compared to placebo at reducing ADHD symptoms.74 The effect size in this study was smaller than that

13

reported in the literature for older children (0.4 to 0.8 in preschoolers compared to 0.5 to 1.3 in older children).74 The incidence of emotional side effects in children 4 to 5 years was higher than that reported in the literature for older children.73

• For elementary and middle school-aged children (6 through 11 years old) with ADHD, treatment with FDA approved medications together with PTBM and/or behavioral classroom interventions (preferably both psychosocial treatments) is strongly recommended.43 “Educational interventions and individualized instructional supports” are required as part of any treatment plan.43

Guideline authors state that both stimulants and non-stimulants have demonstrated efficacy in children aged 6 to 11 years and adolescents with ADHD; however, evidence is less strong for non-stimulant medications (atomoxetine, guanfacine, and clonidine).43

• For adolescents (12 through 17 years) with ADHD, FDA approved medications are strongly recommended first-line. The utilization of evidence-based training interventions and behavioral therapy is encouraged, if available.

Adolescents should be evaluated for symptoms of substance use and referred to a subspecialist for additional guidance if active substance use is detected. The potential for diversion, misuse, or abuse of ADHD medications should be assessed by monitoring symptoms and prescription refill requests. Most states require the participation of prescribers in prescription drug monitoring programs that may help identify and prevent diversion activities. Utah´s Controlled Substance Database (CSD) Program was created in July 1995 to gather data on dispensing controlled substances (Schedule II-V drugs) from pharmacies (retail, institutional, outpatient hospital, and in-state/out-state mail order pharmacies) and to help identify potential drug overutilization, misuse, and overprescribing of controlled substances in Utah.75 Another measure to minimize the risk of misuse or abuse includes the administration of agents with no abuse potential (eg, non-stimulants).43 Stimulant formulations with less abuse or diversion potential (ie, methylphenidate osmotic release oral system (OROS), methylphenidate transdermal patch, or lisdexamfetamine) may be also considered because the active substance is more difficult to extract from this type of formulations.3

Regarding young children, the 2018 NICE guideline advises that ADHD medication prescribing for any child < 5 years should commence only if a second specialist opinion is obtained from a provider with expertise in managing young children. For children that are at least 5 years of age, the first-line medication specified is methylphenidate. Second-line stimulants include lisdexamphetamine if a 6-week trial of methylphenidate fails, or dexamphetamine if lisdexamphetamine is intolerable due to its long duration of action.44

In 2007, the AACAP Preschool Psychopharmacology Working Group (PPWG) evaluated literature evidence available for psychopharmacological treatment in very young children.73 Guideline authors recommended use of psychosocial treatment before initiating pharmacological therapy in preschoolers. In addition, ADHD medication was not recommended for preschoolers with mild symptoms or impairment.73 The developed treatment algorithm for preschoolers (< 6 years of age) with ADHD included methylphenidate formulations as first-line based on a well-controlled randomized trial and 10 smaller studies in preschoolers receiving IR methylphenidate. There was no data supporting the use of ER methylphenidate in preschool-aged children; however, these ER formulations were included in the algorithm as first-line to improve adherence. Amphetamine formulations were recommended as

14

second-line due to limited evidence available at that time (one prospective study in patients receiving mixed amphetamine salts and no randomized controlled trials). Non-stimulants (atomoxetine and alpha-agonists) were recommended as third-line therapies.73 Table 3 describes clinical practice guideline recommendations for the management of ADHD in the Pediatric Population.

Table 3. Clinical Practice Guidelines for Attention-Deficit/Hyperactivity Disorder in the Pediatric Population Organization/Guideline Recommendations

American Academy of Pediatrics

Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents; October 201943

Preschool-aged children (4–5 years of age) with ADHD • Evidence-based behavioral PTBM and/or behavioral classroom interventions

as the first line of treatment, if available (grade A: strong recommendation). • Methylphenidate may be considered if behavioral interventions do not

provide significant improvement and there is moderate-to-severe continued disturbance in functioning. In areas in which evidence-based behavioral treatments are not available, the clinician needs to weigh the risks of starting medication before the age of 6 years against the harm of delaying treatment (grade B: strong recommendation)” (grade B: strong recommendation)

Elementary and middle school-aged children (6–11 years of age) with ADHD • FDA–approved medications for ADHD should be prescribed along with

PTBM and/or behavioral classroom intervention (preferably both psychosocial treatments) (grade A: strong recommendation) o Evidence is strong for stimulant medications and sufficient but less

strong for atomoxetine, extended-release guanfacine, and extended-release clonidine (in that order)

Adolescents (12–17 years of age) with ADHD • FDA–approved medications for ADHDs should be prescribed (grade A:

strong recommendation) • Evidence-based training interventions and/or behavioral interventions are

encouraged, if available (grade A: strong recommendation). Combinations of stimulants Combination regimens (ie, LA plus SA formulations) are mentioned as acceptable strategies to adjust therapy to an individual’s needs

Canadian ADHD Resource Alliance (CADDRA) Canadian ADHD Practice Guidelines, Fourth Edition; 201842

Recommendations below are provided in the context of treatment for patients 6 years of age and older. Authors refer to the AAP guideline regarding treatment of children less than 6 years of age. First-line treatments • Long-acting psychostimulants: a trial of long-acting formulations of both

classes (methylphenidate and amphetamine) is recommended Second-line treatments • Atomoxetine, guanfacine, and short-/intermediate-acting psychostimulants Third-line treatments • Eg, buproprion, clonidine, imipramine, and modafinil Combinations of stimulants Combination regimens (ie, LA plus SA formulations) and split-dosing of the LA product are mentioned as acceptable strategies for tailoring the dosage and timing of effects according to patient-specific needs.

15


National Institute for Health and Care Excellence (NICE)

Attention deficit hyperactivity disorder: diagnosis and management (NG87; March 2018)44

General recommendations: • Drug treatment should only be initiated by an ADHD specialist Children < 5 years • An ADHD-focused group parent-training program to parents or caregivers of

children < 5 years with ADHD should be offered as first-line treatment • If ADHD symptoms still cause a significant impairment in the child, “do not

offer medication for ADHD for any child < 5 years without a second specialist opinion from an ADHD service with expertise in managing ADHD in young children (ideally a tertiary service)”

Children ≥ 5 years and young people with ADHD: • Offer ADHD-focused parent-training program to parents or carers • Offer medication therapy if ADHD symptoms still cause a significant

impairment in at least 1 domain after implementing and reviewing environmental modifications

• First line treatment: methylphenidate (either short or long acting) o Consider switching to lisdexamfetamine if patients had inadequate

response in terms of ADHD symptoms and associated impairment to a 6-week trial of methylphenidate

o Consider dexamfetamine if patients cannot tolerate the longer effect profile of lisdexamfetamine

• Offer atomoxetine or guanfacine if: o Patients cannot tolerate methylphenidate or lisdexamfetamine OR

symptoms “have not responded to separate 6-week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses”

• Consider a course of CBT for young people “who have benefited from medication but whose symptoms are still causing a significant impairment in at least one domain”

Combinations of stimulants Combination regimens (ie, LA plus SA formulations) are mentioned as acceptable strategies to adjust therapy to an individual’s needs

British Association for Psychopharmacology Evidence based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology; 201438

Children and adolescents: • Children with severe ADHD: offer pharmacological treatment • Children with moderate ADHD: consider pharmacological treatment if no

response to psychological interventions • Treatment of choice: psychostimulant medication • Atomoxetine may be used if “there is a risk of misuse of psychostimulants

by children or the adults supporting the child” • “Appropriate child and family-based psychological interventions should be

available to all children with ADHD” • Patient and parental preferences should be considered

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American Academy of Child and Adolescent Psychiatry (AACAP)

Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder; 200741

Initial medication therapy should be with a trial of an agent with a labeled indication for the treatment of ADHD by the FDA: dextroamphetamine, methylphenidate, mixed salts amphetamine, or atomoxetine: • Stimulants are highly efficacious and are first-line • Methylphenidate and amphetamine agents are equally efficacious in the

treatment of ADHD • Long-acting formulations are equally efficacious as immediate-release

agents but may be more convenient • In patients with treatment-refractory disease, behavior therapy and/or the

use of medications not approved by the FDA for the treatment of ADHD (bupropion or tricyclic antidepressants) should be considered

• All patient should be monitored for treatment-emergent side effects and assessed periodically for treatment efficacy

• Patients treated with medication for ADHD should have height and weight monitored throughout treatment

• Treatment of ADHD should continue as long as symptoms remain present and cause impairment

American Academy of Child and Adolescent Psychiatry (AACAP); Preschool Psychopharmacology Working Group (PPWG)

Psychopharmacological treatment for very young children: contexts and guidelines; 200773

Steps of the algorithm: • First-line: methylphenidate • Second-line: amphetamine • Third-line option: atomoxetine, alpha agonist

Institute for Clinical Systems Improvement (ICSI)

Diagnosis and Management of Attention Deficit Hyperactivity Disorder in Primary Care for School-Age Children and Adolescents; 201276

Medication therapy • Use FDA-approved treatments for ADHD in children, including

psychostimulants and/or non-stimulants • Decision to initiate medication therapy should be made in conjunction with

parents and discussion of expected benefits and potential risks • Age, disease severity, and presence of comorbidities should be considered • Optimal medication management alone is superior to other modalities for

the core symptoms of ADHD • If patient does not respond to initial medication choice, a second or third

trial with other stimulants is recommended • Atomoxetine is recommended in patients with comorbid anxiety, sleep

initiation disorder, substance abuse, or tics • Extended-release guanfacine and extended-release clonidine have a labeled

indication as adjunctive therapy with stimulant medications • Second-line medications for ADHD therapy include tricyclic antidepressants

(imipramine, desipramine), alpha adrenergic agonist (clonidine), a nontricyclic antidepressant (bupropion), or immediate-release guanfacine

Abbreviations: ADHD, attention deficit hyperactivity disorder; CADDRA, Canadian ADHD Resource Alliance; CBT, cognitive behavioral therapy; LA, long-acting; SA, short-acting

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ADHD Comorbidities and Treatment Recommendations Children with ADHD often have associated comorbidities (up to 90%). A thorough assessment is required to identify both ADHD and comorbid conditions. For complex patients, consultation with an expert may be appropriate. Initiation of pharmacotherapy for ADHD in the presence of comorbidities includes concurrent initiation of treatment, or treatment may be directed first to either address ADHD or the comorbidity.42 The 2019 AAP guideline recommends that clinicians, if experienced in diagnosing comorbid conditions (eg, anxiety, oppositional defiant disorder, and mood disorders), may start treatment of the comorbid condition or refer to a subspecialist for evaluation and management.43 Subspecialists may include “…child and adolescent psychiatrists, clinical child psychologists, developmental behavioral pediatricians, neurodevelopmental disability physicians, child neurologists, or child- or school-based evaluation teams.”43

Recommendations concerning treatment sequencing reflect that one disorder may be a precursor to another or a risk factor for the other, or may reflect shared risk factors for both disorders.77

According to the 2018 CADDRA guideline, the most common comorbidities in children 6-12 years of age are learning disabilities and oppositional defiant disorder (ODD) (>31% prevalence), followed by autism spectrum disorder, tic disorders, or anxiety (11-30% prevalence), with a lower prevalence (1-10%) of depression, bipolar disorder, substance use disorder (SUD), or obsessive-compulsive disorder.42 Guideline recommendations for each comorbid condition are listed below42:

• In the setting of autism-spectrum disorder, Tourette’s syndrome, tics, or ODD initiate ADHD therapy first. Autism-spectrum disorder may respond well to ADHD therapy resulting in improved functioning. Stimulant therapy is often effective, but should be monitored closely in Tourette’s syndrome and tic disorders as tics may worsen in some patients.

• Therapy for comorbid conduct disorder, anxiety disorder, or major depressive disorder in the presence of ADHD should be initiated for the more severe condition (ADHD or comorbidity) first. Targeting specific comorbidity symptoms could be appropriate.

• Therapy for comorbid conduct disorder, obsessive-compulsive disorder, antisocial personality disorder, and addiction includes efficacious treatment for both conditions (ADHD and comorbidity) concurrently.

• Comorbid bipolar disorder should be pharmacologically stabilized before the initiation of ADHD therapy.

• Therapy for disruptive mood dysregulation disorder requires a combination of medications and psychosocial intervention.42

• Treatment remains a challenge in the setting of ADHD and comorbid substance abuse disorder. Each disorder can exacerbate the symptoms of the other and interact to maintain the other.78 The 2018 CADDRA guideline supports concurrent treatment of both disorders.42 Optimally, treatment of ADHD and SUD should include pharmacotherapy and non-pharmacological therapies (eg, cognitive behavioral therapy).77

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Foster Care Children With ADHD Up to 2,700 children are in foster care in Utah.79 Foster care children are an extremely vulnerable pediatric subset with an increased risk of mental and behavioral disorders. National rates of ADHD diagnosis are 3 times higher in this population than for non-foster care children.80-82 In addition, foster care children are more likely than other children to be diagnosed with a comorbid condition, including oppositional defiant disorder, depression, or anxiety.82 A study including 2011 Medicaid claims from multiple states showed that foster care children with ADHD were as likely as other children in Medicaid to be prescribed ADHD medication; however, they were more likely to receive psychological care. Approximately 75% of foster kids with ADHD received psychosocial services in 2011.82

Age Limit Considerations for CNS Stimulants Table 4 summarizes recommendations for use according to age as referred to in FDA-approved labeling and clinical practice guidelines. There is some inconsistency between product labeling and the standard of care specified in guidelines. For example, the 2019 AAP guideline recommends use of methylphenidate first-line when a medication is necessary in preschool age children (4 through 5). Nonetheless, the labeling for methylphenidate products specify dosing for children 6 years old and above. Additionally, it is unclear but assumed that if guideline authors refer general only to 2 single stimulants, methylphenidate or amphetamine, they are referring to methylphenidate-based and amphetamine-based products without specifying particular formulations.

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Table 4. FDA Prescribing Information for CNS Stimulants and Guideline Recommendations by Pediatric Age

Agents Brand names

Pediatric Age based on FDA-Approved

Indication and Dosing Recommendations for

ADHD

Guideline Recommendations for ADHD

2019 AAP43 2018 CADDRA42 2018 NICE44 2007 PPWG73

Methylphenidate-Containing Products Dexmethylphenidate SA Focalin ≥6 y (from CT) 4-5 y (MPH is 1st

line) ≥6 y (MPH is 1st

line) <4 years (Insufficient evidence; no recommendation for or against use)

≥6 y (LA stimulants are 1st line; SA and IA stimulants are 2nd line)

<5 y (do not offer medication without a second specialist opinion) ≥ 5 y (MPH is 1st line)

< 6 years (MPH is 1st line)

Dexmethylphenidate LA Focalin XR ≥6 y (from CT) Methylphenidate SA Methylin, Ritalin ≥6 y (Dosing Rec.) Methylphenidate LA Adhansia XR, Aptensio

XR, Concerta, Cotempla XR-ODT, Daytrana, Jornay PM, Metadate CD, Metadate ER, QulliChew ER, Quillivant XR, Relexxii, Ritalin-SR, Ritalin LA

≥6 y (Indication or dosing rec.) Ritalin LA: 6-12 y (Indication) Metadate CD: 6-15 y (Indication)

Amphetamine-Containing Products Amphetamine SA Evekeo ≥3 y (Dosing Rec.) ≥6 y (AMP is 1st

line) <4 years (Insufficient evidence; no recommendation for or against use)

≥6 y (LA stimulants are 1st line; SA and IA stimulants are 2nd line)

<5 y (do not offer medication without a second specialist opinion) ≥ 5 y (LISDEX is 2nd line and DEXAMPH is 3rd line)

< 6 years (AMP is 2nd line)

Evekeo ODT ≥6 y (Indication) Amphetamine LA Adzenys ER, Adzenys XR-

ODT, Dyanavel XR ≥6 y (Indication)

Dextroamphetamine SA Dexedrine, ProCentra, Zenzedi

≥3 y (Indication)

Dextroamphetamine LA Dexedrine Spansule ≥6 y (Indication) Mixed amphetamine salts SA Adderall ≥3 y (Dosing Rec.) Mixed amphetamine salts LA Adderall XR ≥6 y (Indication)

Mydayis ≥13 y (Indication) Lisdexamfetamine LA Vyvanse ≥6 y (Indication) Methamphetamine SA Desoxyn ≥6 y (Indication) Abbreviations: AAP, American Academy of Pediatrics; AMP, amphetamine; CADDRA, Canadian ADHD Resource Alliance; CT, clinical trial; DEXAMPH, dextroamphetamine or dexamphetamine; IA, intermediate-acting; LA, long-acting; LISDEX, lisdexamfetamine; MPH, methylphenidate; NICE, National Institute for Health and Care Excellence; PPWG, Preschool Psychopharmacology Working Group; Rec., recommendation; SA, short-acting; y, years

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Treatment Strategies for Patients with ADHD Treatment objectives in patients diagnosed with ADHD are to reduce ADHD symptoms, increase functional performance, and eliminate behavioral problems. Treatment strategies depend on the patient’s age and may include behavior therapy alone or behavior therapy with medication therapy.62 Behavioral therapies should be provided by well-trained professionals and include teaching the child new behaviors to replace those causing disruptions to activities of daily living, as well as teaching the child’s parents new skills and enforcing their current skills to help the child manage negative behaviors.3,43,72 There is strong evidence supporting the efficacy of behavioral therapies such as parent training in behavior management (PTBM) and classroom behavioral interventions in preadolescent children.3,43,72 Stimulant and nonstimulant agents are considered the mainstay of ADHD pharmacological treatment.

Stimulants, including amphetamine and methylphenidate preparations, are the most widely used ADHD treatments, are fast-acting, and are more efficacious than non-stimulants in reducing ADHD symptoms.38,62,72,83 Non-stimulant agents, including atomoxetine, guanfacine, and clonidine, are not as fast-acting as stimulants but have longer duration of action (up to 24 hours) and may be associated with fewer adverse effects.38,72,84,85 Stimulants may be used in combination with nonstimulants (clonidine or guanfacine) if patients do not respond to stimulants alone.86 Some evidence suggests antidepressants alone or in addition to a stimulant agent may be used, off label, in children with ADHD.41,76,84 The risk of abuse, misuse, and diversion is higher with stimulants compared to non-stimulants.1 Overall, ADHD medication in children and adolescents usually includes a stimulant agent (either methylphenidate or amphetamine) as first-line.3,38,44,62,87 The non-stimulant, atomoxetine, is usually suggested as third-line if methylphenidate or amphetamine treatment fail; however, it may be the drug of choice in patients with underlying anxiety disorder, severe tics, sleep disorder, or risk of abuse, misuse, or diversion of stimulant agents.62,76,88

In 2016, National Survey of Children’s Health (NSCH) data of parent-reported ADHD medication and behavior therapy use showed that 62% of children 2 to 17 years old with ADHD received medication for ADHD and 47% received ADHD behavior therapy in the previous year.51,59 Among children 2 to 5 years old with ADHD, 18% received medication and 60% received behavior therapy.51 In Utah, a national parental-report survey conducted between 2009 and 2010 in children 4 to 17 years old with special health care needs indicated that 66% received medication for ADHD in the past week, 42% received behavior treatment in the previous 12 months, and 30% received both treatments.89 This survey showed similar numbers nationally (74%, 44%, and 31% for medication use, behavior therapy use, and both treatments, respectively).89 Based on healthcare claims data from Medicaid (2008-2011) or employer-sponsored insurance (2008-2014), 75% and less than 55% of insured children 2 to 5 years old in clinical care for ADHD received ADHD medication or psychological services, respectively.90

Choice of medication therapy should be individualized and depends on patient’s age, family or patient preferences, coexisting conditions, symptom profile, duration of drug effect, abuse or diversion potential, social stigma, convenience, compliance, and cost.38,40,62,87 At the population level, both methylphenidate and amphetamine have similar efficacy and safety profiles; however, individual treatment response varies among children with ADHD. A better response or higher rates of adverse events may be occasionally observed in children treated with 1 of the 2 stimulant types (amphetamine-

21

or methylphenidate-based). Approximately 50% of children who do not respond to 1 stimulant type have a positive response to the other type.3 Therefore, multiple trials of different medications at various doses are often required to find the optimal regimen in children with ADHD.72 Some meta-analyses in children suggested that amphetamine-based products were slightly more effective with respect to ADHD symptoms; however, adverse events such as sleep disturbances were more pronounced among patients receiving amphetamine-based products. If patients do not respond to any stimulant medication, a non-stimulant medication may be effective.3

Titration, Follow-Up, and Stopping Considerations

Effective treatment plans should include behavioral and/or medication therapy, close monitoring by doctors and parents, and frequent follow-ups to find the medications and doses that most benefit the patient.42,62,72,84

Once the medication has been selected for an individual patient, dose should be initiated at the lowest effective dose with the minimum adverse events.3 The 2018 Canadian guideline recommends “start low and go slow” but keep increasing the dose until optimum effects have been achieved, side effects appear, or until the maximum recommended dosage is achieved.42 Medication titration may require several weeks. Switching medications is considered on a weekly basis (3- to 7-day period). During the first month, medication may be adjusted with a follow-up assessment every week or every 2 weeks. Prescriptions can allow up-titration or include 1 formulation of the same strength with directions to increase the amount of the initial dose.3 The 2019 AAP guideline states that low doses of SA methylphenidate should be initiated in preschool-aged children as metabolism of medication is slower in this population. Preschool-aged children require lower optimal daily doses than older children and may be more prone to experience emotional adverse events (eg, irritability and crying).47

After the titration period, the first face-to-face follow-up visit with the clinician is usually at week 4 following treatment initiation. This visit will monitor the patient´s response to the administered doses, adverse events, pulse, blood pressure, and weight.3 During the first year of therapy, face-to-face visits with a clinician are recommended every month until an optimal response is reached. Then, visits are recommended every 3 months. Medication changes (eg, dose reduction, stop medication, or change to an alternative therapy) may be needed during treatment.3 Following several years of therapy and stable response, medication may be discontinued to determine if ADHD therapy is still necessary. Medication should be slowly off-titrated to avoid withdrawal syndrome.17,42

In very young children, the PPWG recommended discontinuation (off-titration) of ADHD medication after 6 months followed by reassessment of symptoms. Some children with ADHD may not meet ADHD diagnosis criteria after a 6-month effective treatment and continuation of therapy is not required.73

Considerations for Selecting Short-Acting or Long-Acting Stimulant Formulations

Each stimulant is available in both long-acting (LA) and short-acting (SA) formulations, except lisdexamfetamine, only available as an LA formulation, and methamphetamine, only available as an SA formulation. Use of an SA product, with more frequent dosing, may decrease adherence to therapy compared to use of an LA product.42,71,91 SA formulations have higher abuse potential by snorting or intravenous route than LA formulations due to their pharmacokinetic profile and easy crushability (especially for SA tablets).42 SA formulations offer some advantages compared to LA formulations such

22

as dosing flexibility, lower cost, less insomnia, and coverage for short periods of time.3,42,71,87 SA preparations comprise initial treatment for many children to allow flexibility for dose adjustment to the optimal dose. They are especially useful in children less than 16 kg who require doses lower than those available with LA formulations.41,87

LA formulations require less frequent administration due to their longer half-lives and duration of action (6 to >16 hours).71 They are more likely to reduce stigma among school-age children because they do not need to take medicines at school, facilitate family monitoring and convenience, increase adherence, improve driving performance in adolescents and young adults, and are less likely to be abused or diverted because of the slower absorption and delivery to the CNS system compared to SA formulations.3,38,40,41,87 Some of the LA formulations are difficult to crush (eg, extended release capsules), which may deter intranasal or intravenous administration.40 However, LA formulations may cause adverse events in the evening such as reduced appetite and sleep problems.87 Some formulations may be more suitable for younger children or patients unable to swallow pills such as capsules that can be opened and sprinkled into soft food or drink, orally disintegrating tablets, oral solutions, or transdermal patch.3

Considering all the above points, SA or LA formulations may be considered for the treatment of ADHD in order to have sustained coverage thorough the day or to cover specific times where the patient needs medication (eg, while driving, studying, meeting friends, or at extra-curricular activities). Use of stimulant medication in people with ADHD is associated with improved driving performance and less risk of motor vehicle accidents.3 Following are some examples of clinical scenarios where SA versus LA formulations may be considered:

• If a clinician is concerned about treatment tolerability or response to a certain dosage titration, an SA formulation may be more suitable.92 For instance, when a stimulant can potentially worsen a comorbid psychiatric or medical condition, an SA formulation trial may be optimal.92

• If stimulants are causing insomnia, initiating the medication as early as possible in the morning or using a shorter-acting formulation may be considered.42

• If abuse, misuse, or diversion is a concern or the family has a preference against a stimulant, non-stimulant medication may be considered first-line.3 Long-acting stimulant formulations may be additionally considered as they have less risk of abuse, misuse, or diversion.42

• If adherence is an issue, LA formulations may be more suitable.42

The 2018 Canadian guideline mentions specific dosing strategies with LA and SA formulations:

• Split dosing of LA medications: A dosing option to manage early wearing off of LA products consists of dividing the dose of the LA formulation into 2 doses separated by 20 to 30 minutes to extend the duration of action.42

• Use of SA and intermediate-acting (IA) stimulants on a ‘pro re nata’ (prn) basis: For certain activities, taking an SA or IA stimulant on an ‘as required’ or prn basis may be sufficient for some children 6 to 17 years of age.42,92

23

Concomitant Use of Stimulants

Guideline authors describe that “[t]he decision about when to administer treatment during the day and how long the effect of that treatment needs to last must be explored by the clinician in consultation with the patient and patient’s family… considering the context of the individual’s experience. The numerous ways ADHD symptoms can impact a person’s daily life - at home, at school, at work, at play - makes it important to not only optimize treatment for core symptoms and to minimize side effects but to consider WHEN treatment is required.”42

The 2019 American Academy of Pediatrics guideline, the 2018 Canadian guideline, the 2018 NICE guideline, and published articles mention possible scenarios where concomitant use of 2 stimulant products (eg, LA plus SA products) may be suitable for children with ADHD3,42-44:

A) A long-acting formulation plus a shorter-acting formulation (augmentation strategy)

The 2018 Canadian guideline highlights that the general effects from a medication, for example duration of action, are based on the population average. Since there is definitely a subset of patients that experience effects below the average (eg, shorter duration of action than the mean), dosing should be tailored to the individual’s response/experience.42

Adolescents may require coverage for a period longer than the duration of action afforded by the LA product in order to improve functioning during the latter half of the day while studying, in extracurricular activities, driving, or maintaining positive social relationships. Thus, adding an SA formulation when the effect of the LA formulation wears off can optimize the effect and is viewed as acceptable use.38,42-44,93 Other children on LA formulations may need the addition of an SA formulation in the morning to help with symptom control at the beginning of the day.94

According to the 2018 Canadian guideline, the 2018 NICE guideline, and the 2014 British guideline, it appears generally acceptable to augment an LA product with an shorter-acting product of the same stimulant class (amphetamine-based or methylphenidate-based)38,42,44 For example, LA amphetamine-based preparations such as Adderall XR or Vyvanse may be augmented with SA or intermediate-acting (IA) dextro-amphetamine products. Methylphenidate-based preparations such as Concerta may be augmented with SA methylphenidate products.42,44

B) Two short-acting formulations

An SA formulation followed by another SA formulation may be necessary to reduce ADHD symptoms for a few additional hours without compromising sleep.92

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Maximum Recommended Daily Doses and Monthly Quantity Limits of CNS Stimulant Medication

A) Maximum Daily Doses

FDA prescribing information for stimulants generally recommends using amphetamines and methylphenidate at the lowest effective dosage and adjusting therapy according to patient-specific needs and response to therapy.5-34 The 2019 AAP guideline strongly recommends titration from a low dose to a maximum dose that can control symptoms with no adverse effects.

Table 5 includes maximum recommended daily doses based on FDA approved prescribing information, Micromedex,95 the 2007 AACAP guideline,41 and the 2016 Texas report on Psychotropic Medication Utilization Parameters for Children and Youth in Foster Care, 5th edition.54 Classification of currently available stimulants as short-acting or long-acting formulations was developed based on the ADHD medication list available at www.adhdmedicationguide.com.96 Some methylphenidate formulations are classified as intermediate-acting (duration of action up to 8 hours) by the 2007 AACAP guideline (ie, Metadate CD, Metadate ER, Ritalin SR, and Ritalin LA).41

B) Monthly Quantity Limits

Monthly quantity limits may be determined based on the maximum recommended daily doses and with respect to age (see Table 5). Other considerations when calculating maximum quantity limits may include the following:

a) Potential differences in quantity needs during titration or maintenance periods

o Titration schedules may utilize higher quantities of the lower dosages for gradual up-titration using a single filled prescription. Quantity limits may be appropriate once a patient’s dosage is stabilized (eg, after 2 months).

b) Strengths available for a product and dosing frequency

o Patients may need multiple strengths of a product to achieve a certain mg dosage per day.

c) Potential advantage of a single prescription versus prescriptions for 2 different strengths

d) Flexibility in dosage regimen

o Slip-dosing of LA products as a treatment strategy to extend the stimulant effect (especially for products with labeled BID dosing or with durations of action that may be considered intermediate acting).

f) Abuse potential of stimulants, especially with short-acting formulations

A prior authorization may be used to determine if quantity overages are appropriate.

http://www.adhdmedicationguide.com/

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Table 5. Maximum Daily Doses for FDA-Approved CNS Stimulants in Pediatric Patients

Generic (Brand Name) Dosage

Form/Strength Frequency of

Administration

Duration of Action5-

34,39,71,93

FDA-Approved Maximum Dosage

Literature-Based Maximum Dosage for Children and Adolescents (per 2016

Texas Report, Micromedex, and 2007 AACAP guideline)41,54,95

Amphetamine-Containing Products: Short Acting Formulations (Duration of Action: 4-6 hours)

Amphetamine (Evekeo)

Tablet: 5 mg and 10 mg

Once or twice daily 4-6 h

Maximum dosage for pediatric patients not specified (children 6-17 years: dosages may exceed

40 mg/day in rare cases) (For narcolepsy, no maximum dose specified. For obesity, up

to 30 mg/day)

Patients 3-5 years: 30 mg/day

Patients ≥ 6 years and >50 kg: 60 mg/day

Amphetamine (Evekeo ODT)

ODT: 5 mg, 10 mg, 15 mg, 20 mg


Maximum dosage for pediatric patients not specified (children 6-17 years: dosages may exceed

40 mg/day in rare cases)

Unknowna

Generic dextroamphetamine

(Dexedrine - DSC)

Tablet: 5 mg, 10 mg

Oral solution: 5 mg/5 mL


Maximum dosage for patient 3-5 years not specified

Maximum dosage for pediatric patient ≥ 6 years not specified

(in rare cases dosages may exceed 40 mg/day)

(For narcolepsy, maximum dose not specified)



Dextroamphetamine (ProCentra)

Oral solution: 5 mg/5 mL

Dextroamphetamine tablet (Zenzedi)

Tablet: 2.5 mg, 5 mg, 7.5 mg, 10 mg,

15 mg, 20 mg, 30 mg Generic

dextroamphetamine/ amphetamine

(Adderall - DSC)

Tablet: 5 mg, 7.5 mg, 10 mg, 12.5 mg,

15 mg, 20 mg, 30 mg




Methamphetamine (Desoxyn) Tablet: 5 mg Once or twice

daily NR Maximum dosage unspecified Unknowna

Amphetamine-Containing Products: Long-Acting Formulations (Duration of Action: 6-16 hours)

Amphetamine (Adzenys ER)

ER suspension: 1.25 mg/mL Once daily 10-12 h

Maximum dosage: • 6-12 years: 18.8 mg/day • 13-17 years: 12.5 mg/day

Unknowna

26




Administration


34,39,71,93




Amphetamine (Adzenys XR-ODT)

ER ODT: 3.1 mg, 6.3 mg, 9.4 mg,

12.5 mg, 15.7 mg, 18.8 mg

Once daily 10-12 h

No maximum dosage reported for adults Patients 6-12 years: 18.8 mg/day

Patients 13-17 years: 12.5 mg/day

Amphetamine (Dyanavel XR)

ER suspension: 2.5 mg/mL Once daily 10-12 h71 Maximum dosage for children

≥6 years: 20 mg/day ≥6 years: 20 mg/day

Dextroamphetamine SR (Dexedrine

Spansule)

SR capsule: 5 mg, 10 mg, and 15 mg

Once or twice daily

8 h Maximum dosage not specified

(in rare cases dosages may exceed 40 mg/day)


Patients ≥ 6 years and >50 kg:

60 mg/day

Dextroamphetamine/amphetamine (Adderall XR)

ER capsule: 5 mg, 10 mg, 15 mg, 20 mg,

25 mg, 30 mg Once daily 8-12 h39

Maximum dosage for pediatric patients 6-12 years: 30 mg QD No maximum dosage specified

for adolescents and adults



Dextroamphetamine/amphetamine

(Mydayis)

ER capsule: 12.5 mg, 25 mg, 37.5 mg,

50 mg Once daily 12-16 h71

Maximum dose for pediatric patients (13-17 years):

25 mg/day Unknowna

Lisdexamfetamine (Vyvanse)

Capsule: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg

Chewable tablet: 10 mg, 20 mg, 30 mg,

40 mg, 50 mg, 60 mg

Once daily 8-13 h Adults and pediatric patients ≥6

years: Maximum dosage: 70 mg/day


Patients ≥ 6 years:

70 mg/day

27




Administration


34,39,71,93




Methylphenidate-Containing Products: Short Acting Formulations (Duration of Action: 3-5 hours)

Dexmethylphenidate (Focalin)

Tablet: 2.5 mg, 5 mg, 10 mg Twice daily 3-5 h Maximum dose for pediatric

patients: 20 mg/day (10 mg BID)


Patients ≥ 6 years: 50 mg/day

Methylphenidate (Methylin)

Solution: 5 mg/5 mL, 10 mg/5 mL

Chew tablets: 2.5 mg,

5 mg, 10 mg

2 or 3 times daily

3-5 h Maximum dosage for adults and pediatric patients ≥6 years:

60 mg/day



≤50 kg: 60 mg/day >50 kg: 100 mg/day

Methylphenidate (Ritalin)

Tablet: 5 mg, 10 mg, 20 mg

2 or 3 times daily

3-5 h

Methylphenidate-Containing Products: Long-Acting Formulations (Duration of Action: 6-16 hours)

Dexmethylphenidate (Focalin XR)

ER capsule: 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg,

40 mg

Once daily 9-12 h Maximum dose for pediatric patients: 30 mg/day


Patients ≥ 6 years: 50 mg/day

Methylphenidate (Adhansia XR)


70 mg, 85 mg Once daily NR

Maximum dosages for pediatric patients ≥ 6 years: 70-

85 mg/day Unknowna

Methylphenidate (Aptensio XR)

ER capsule: 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg

Once daily ≤16 h Maximum dosage for patients ≥ 6 years: 60 mg/day



≤50 kg: 60 mg/day >50 kg: 100 mg/day

28




Administration


34,39,71,93




Methylphenidate (Concerta)

ER tablet: 18 mg, 27 mg, 36 mg, 54 mg Once daily 8-12 h

Maximum dosage: 54 mg/day for children and 72 mg/day for

adolescents and adults



108 mg/day

Methylphenidate (Cotempla XR-ODT)

ER ODT: 8.6 mg, 17.3 mg, 25.9 mg Once daily 10-12 h71

Maximum dosage for pediatric patients 6 to 17 years:

51.8 mg/day Unknowna

Methylphenidate (Daytrana)

ER transdermal patch: 10 mg/9 hr,

15 mg/9 hr, 20 mg/9 hr, 30 mg/9 hr

Apply 2 hours before the

effect is needed and

remove 9 hours after application

11-12 h Unspecified



30 mg/day

Methylphenidate (Jornay PM)


100 mg Once daily NR Maximum dose for patients

≥ 6 years: 100 mg/day Unknowna

Methylphenidate (Metadate CD)


50 mg, 60 mg Once daily 6-8 h39 Maximum dosage (age not

specified): 60 mg/day


Patients ≥ 6 years: ≤50 kg: 60 mg/day

>50 kg: 100 mg/day

Methylphenidate (Metadate ER - DSC)

ER tablet: 10 mg and 20 mg

2 or 3 times daily

8 h39 Maximum dosage for adults and children ≥6 years: 60 mg/day



≤50 kg: 60 mg/day >50 kg: 100 mg/day

29




Administration


34,39,71,93




Methylphenidate (QuilliChew ER)

ER chewable tablet: 20 mg, 30 mg, 40 mg Once daily NR Maximum dosage for patients

≥ 6 years: 60 mg/day Patients 3-5 years:

20 mg/day

Patients ≥ 6 years: ≤50 kg: 60 mg/day

>50 kg: 100 mg/day

Methylphenidate (Quillivant XR)

ER suspension 25 mg/5 mL Once daily 10-12 h71 Maximum dosage for patients

≥ 6 years: 60 mg/day

Methylphenidate (Relexxii)

ER tablet: 72 mg Once daily 12 h Maximum dosage: 54 mg/day for children and 72 mg/day for

adolescents and adults Unknowna

Methylphenidate (Ritalin LA)


60 mg Once daily 6-8 h71 Maximum dosage: 60 mg/day



≤50 kg: 60 mg/day >50 kg: 100 mg/day

Methylphenidate (Ritalin-SR - DSC) ER tablet: 20 mg 1 to 3 times

daily39 8 h

Maximum dosage for adults and children ≥6 years: 60 mg/day



≤50 kg: 60 mg/day >50 kg: 100 mg/day

Abbreviations: AACAP, American Academy of Child and Adolescent Psychiatry; BID, twice daily; DSC, discontinued; ER, extended release; FDA, United States Food and Drug Administration; QD, once daily a Not included in the last version of the 2016 Texas report, Psychotropic Medication Utilization Parameters for Children and Youth in Foster Care. Maximum dosing information from the literature are unknown

30

Safety Concerns Related to CNS Stimulant Use in Children The most common short-term adverse events associated with stimulants are loss of appetite, abdominal pain, headaches, and sleep problems.43 Other adverse events include growth delay, hallucinations, and psychotic symptoms.43

With respect to use of stimulant treatment in preschool-aged children with ADHD, there is a lack of evidence and clinical experience regarding effects on growth and brain development in the long-term. In addition, occurrence of other adverse events in this population is unknown.43

Table 6 includes warnings and precautions for CNS stimulants. Table 7 describes CNS stimulant adverse events.

Potential for abuse and dependence

Stimulant medications are Schedule II controlled substances. FDA prescribing information for stimulants contains a black box warning regarding the high potential risk for abuse and dependence.5-34 Signs of abuse and dependence should be evaluated before prescribing a stimulant and monitored during treatment.17

Cardiovascular risks

Cases of sudden cardiac death are very rare in children and adolescents taking stimulants. Reported cases occurred at usual doses in children and adolescents with serious heart problems.17,43 In 2011, the FDA issued an FDA drug safety communication regarding cardiovascular events with the use of ADHD medications.97 An observational study including children and young adults did not find an increased risk of serious cardiovascular events (ie, stroke, myocardial infarction, and sudden cardiac death) with the use of ADHD medications (stimulants including amphetamine and methylphenidate formulations and non-stimulants). However, ADHD medications should not be used in patients with serious heart conditions.97 Before prescribing a stimulant, clinicians should evaluate the patient’s cardiac history and family history of sudden death, cardiovascular symptoms, Wolff-Parkinson-White syndrome, hypertrophic cardiomyopathy, and long QT syndrome.43

Patients receiving stimulant medication can experience an increase in blood pressure of 2 to 4 mmHg and an increase in heart rate of around 3 to 6 bpm. Some patients may experience larger increases that may be clinically significant.10,21,22 Blood pressure and heart rates should be monitored in all patients receiving stimulant therapy.10,21,22,43 Caution should be exercised in patients with underlying cardiovascular conditions such as pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.17

Psychiatric adverse reactions

Stimulant use may aggravate symptoms of behavior disturbance and thought disorder in patients with prior psychotic disorder.17

Stimulants may induce mixed/manic episodes in patients with ADHD and comorbid bipolar disorder. Assess patients for bipolar disorder before initiating stimulant therapy and monitor for aggressive behavior.25 In addition, stimulant use at usual doses can cause new psychotic or maniac symptoms (eg,

31

hallucinations, delusional thinking, or mania) in children and adolescents with no prior history of psychotic disease or mania.17 Aggressive behavior may occur with the use of stimulants.17

Long-term suppression of growth

Suppression of growth with the use of stimulants has been reported in several studies including the Multimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) study in school-age children. The 3-year follow-up phase of the MTA study showed a temporarily reduction in growth velocity by 2 cm in height and 2.7 kg in weight over 3 years in the newly medicated subgroup compared to the untreated subgroup.98 These effects were more pronounced in children treated with higher doses of stimulants and those consistently medicated with stimulants (7-day treatment per week throughout the year).17,43,98 By the third year of treatment, effects on growth were less pronounced; however, a growth-rebound phenomenon was not shown.17,43,98

Children receiving stimulant therapy should be monitored for height and weight and assessed using growth charts. Treatment may be discontinued if children are not growing as expected for their age.17

Peripheral vasculopathy

Peripheral vasculopathy (eg, Raynaud´s phenomenon) has been reported with the use of stimulants at therapeutic doses. Although signs and symptoms are generally mild, some rare cases of digital and soft tissue injuries can occur. Signs and symptoms usually diminish following dose reduction or drug discontinuation. Some patients may require an evaluation by a rheumatologist.17

Other Warnings

Other additional warnings related to stimulant use include seizures (eg, may reduce the convulsive threshold) and visual disturbances.

Warnings specifically associated with use of amphetamines include serotonin syndrome and exacerbation of tics. Serotonin syndrome is a potentially life-threatening condition occurring when amphetamines are combined with other serotonergic agents or CYP2D6 inhibitors, or from overdosage. Serotonin syndrome symptoms include mental status changes, autonomic instability, neuromuscular symptoms, seizures, and gastrointestinal symptoms.17

Warnings associated with use of methylphenidate include priapism, gastrointestinal obstruction (particularly with Concerta and Relexxii), and hematologic alterations during long-term therapy. Permanent skin depigmentation under and around the methylphenidate transdermal patch (Daytrana) can occur (also known as chemical leukoderma). This skin condition can appear in other areas of the body different from the drug application site, which can simulate vitiligo and may be emotionally distressing.99 Signs of loss of skin pigmentation should be monitored.25

Monitoring requirements

Clinicians should regularly monitor blood pressure, pulse, height, weight, and signs of abuse and dependence in patients treated with stimulants.5-34 In addition, patient’s cardiac history and family history of cardiovascular diseases should be assessed prior to stimulant treatment. Further cardiac evaluation should be performed if symptoms indicating cardiac disease occur during stimulant therapy. Patients should be monitored for aggressive behavior.17 Certain patients may require evaluation by a

32

rheumatologist if severe circulation problems in fingers and toes appear.34 Patients applying methylphenidate transdermal patch should be monitored for skin depigmentation.25,99 Table 6. Warnings and Precautions for CNS Stimulants5-34,39

Agent US Black Box Warnings Concerning ADHD Indication Other Warnings and Precautions

Amphetamine (Adzenys ER, Adzenys XR-ODT; Dyanavel XR; Evekeo, Evekeo ODT)

General black box warning for amphetamines and methylphenidate-containing products: CNS stimulants have a high potential for abuse and dependence. Assess the risk of abuse prior to prescribing and monitor for signs of abuse and dependence while on therapy Specific black box warnings in the labeling of some products: “Pay particular attention to the possibility of subjects obtaining amphetamines for non-therapeutic use or distribution to others; prescribe and dispense the drugs sparingly” (Dextroamphetamine-containing products, methamphetamine) “Misuse of amphetamine may cause sudden death and serious cardiovascular adverse events” (Evekeo, dextroamphetamine-containing products, Adderall, methamphetamine) “Stimulants should be given cautiously to patients with a history of drug dependence or alcoholism. Chronic abusive use can lead to marked tolerance and psychological dependence with varying degrees of abnormal behavior” (Concerta, Daytrana, Metadate CD and Metadate ER) “Frank psychotic episodes can occur, especially with parenteral abuse. Careful supervision is required during withdrawal from abusive use since severe depression may occur. Withdrawal following chronic therapeutic use may unmask symptoms of the underlying disorder that may require follow-up” (Metadate CD and Metadate ER)

General warnings for amphetamine- and methylphenidate-containing products: - Serious cardiovascular reactions (eg,

sudden death) - Blood pressure and heart rate increases - Psychiatric adverse reactions (eg,

psychotic or manic symptoms) - Long-term suppression of growth - Peripheral vasculopathy, including

Raynaud’s phenomenon Specific warnings in the labeling of some products: - Serotonin syndrome - Seizures: Stimulants may reduce the

convulsive threshold (Evekeo and Evekeo ODT, dextroamphetamine-containing products, MAS, Vyvanse, methamphetamine, Concerta, Metadate CD and Metadate ER, Methylin, Relexxii)

- Visual Disturbance (dextroamphetamine-containing products, Adderall, Adderall XR, methamphetamine, Concerta, Metadate CD, Metadate ER, Methylin, Relexxii)

- Tics: may exacerbate tics (Adderall and Adderall XR)

- Prolonged penile erections or priapism (methylphenidate products)

- Gastrointestinal (GI) obstruction with preexisting GI narrowing (Concerta, Relexxii)

- Hematologic monitoring during prolonged therapy (Concerta, Daytrana, Metadate CD, Metadate ER, Relexxii)

- Allergic-Type Reactions FD&C Yellow No. 5 (tartrazine) (Adhansia XR only)

- Risks in Phenylketonurics: QuilliChew ER extended-release chewable tablets contain phenylalanine, a component of aspartame (Quillichew ER)

- Skin Depigmentation (Chemical leukoderma) and Contact Sensitization (Daytrana transdermal patch)

Dextroamphetamine (Dexedrine Spansule, Dexedrine, ProCentra, Zenzedi)

Dextroamphetamine-Amphetamine Mixed Salts (Adderall, Adderall XR, Mydayis)


Methamphetamine (Desoxyn)

Dexmethylphenidate (Focalin, Focalin XR)

Methylphenidate (Adhansia XR, Aptensio XR, Concerta, Cotempla XR-ODT, Daytrana, Jornay PM, Metadate CD, Metadate ER, Methylin, QuilliChew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA)

33

Table 7. CNS Stimulant Adverse Events and Recommended Management71,76 Adverse Events Management of Adverse Events/Recommendations Common adverse events Appetite suppression, weight loss Provide high-calorie meal, administer dose with or after meals,

consider dietitian referral, or cyproheptadine at night Stomach ache Reduce dose, if possible. Administer with full stomach Insomnia Administer dose earlier, reduce the last dose of the day, switch to

short-acting formulation, or consider alternative therapy (eg, atomoxetine, clonidine, antidepressant)

Headache Evaluate administration timing. Administer drug in divided doses. Take with food. Try a long-acting formulation. Administer a pain reliever

Rebound symptoms Use a longer-acting stimulant; combination of a short and long-acting formulation; atomoxetine; or antidepressant

Irritability, jitteriness Evaluate administration timing. Evaluate for comorbid conditions. Reduce dose or switch to long-acting formulation. Consider alternative therapy (eg, another stimulant, antidepressant, mood stabilizer, or atypical antipsychotic)

Linear growth impairment ‘Limit stimulant to high-priority needs’ (eg, try drug holidays). If adverse event is relevant, consider alternative treatment

Uncommon to rare adverse events Dysphoria Decrease dosage. Re-evaluate diagnosis. Consider alternative

treatment Skin discoloration Provide counseling regarding skin depigmentation with

methylphenidate patch Zombie-like state Lower dosage or switch stimulant agent Tics or abnormal movements Lower dosage. Consider alternative treatment (eg, atomoxetine,

clonidine, guanfacine) Priapism Immediate assistance is required. Consider alternative therapy Hypertention Lower dosage. Switch medication Hallucinations Withdraw stimulant medication. Re-evaluate diagnosis. Consider a

mood stabilizer or antipsychotic

34

Utah Medicaid Utilization Data Utilization data of stimulant medications was accessed to determine prescribing patterns for Utah Medicaid providers in comparison with the prescribing information, literature evidence, and US clinical practice guidelines for use of stimulant medications.

On the Utah Medicaid Preferred Drug List published on January 2020, the following 11 ADHD stimulant products are listed as preferred:

• Short-Acting Stimulants: generic amphetamine/dextroamphetamine tablet, Focalin (dexmethylphenidate), Methylin (methylphenidate) solution, generic methylphenidate tablet.

• Long-Acting Stimulants: generic amphetamine/dextroamphetamine ER capsule, Concerta (methylphenidate), Dyanavel XR (amphetamine), Focalin XR (dexmethylphenidate), Quillichew ER (methylphenidate), Quillivant suspension (methylphenidate), and Vyvanse (lisdexamfetamine).

The remaining stimulants containing amphetamine, dextroamphetamine, methamphetamine, or methylphenidate are listed as non-preferred. Brand combination products of amphetamine with dextroamphetamine are additionally listed as non-preferred.

A) Pharmacy Fills for the Utah Medicaid Population

CNS stimulants are carved out drugs; therefore, utilization data includes both Accountable Care Organization (ACO) and fee-for-service (FFS) patients. In general, patients were extracted from the database according to their age at the time the prescription claim was filled. Tables 1, 2, and 3 of Appendix B display complete Utah Medicaid utilization data for stimulants in the FFS and ACO pediatric patients younger than 18 years of age, 6 to 17 years of age, and 3 to 5 years of age.

Figure 1 shows the 10 most commonly prescribed stimulants from 2017 through December 2019 for the Utah Medicaid pediatric population (ACO and FFS patients). Note that branded and generic products were represented separately.

In 2019, 8713 pediatric patients (< 18 years of age) had a prescription filled for a stimulant (amphetamine- or methylphenidate-based). The 5 most commonly utilized stimulants in 2019 for patients younger than 18 years were Concerta ER tablets (osmotic release formulation), Vyvanse (lisdexamfetamine), generic amphetamine/dextroamphetamine ER capsule, generic amphetamine/dextroamphetamine IR tablet, and generic methylphenidate IR tablet. Note that utilization in 2019 was generally not higher than in 2017 or 2018 for the aforementioned products. An escalation in the use of the most common stimulant products was not identified. The average number of prescriptions per patient/year was 7 in 2019.

Figure 2 and Figure 3 show the 10 most commonly prescribed stimulants in 2019 for patients 6 to 17 and 3 to 5 years of age, respectively. Note that branded and generic products were represented separately.

Among the pediatric population who had a prescription filled for a stimulant (amphetamine- or methylphenidate-based) in 2019, 8470 unique patients were 6 to 17 years of age and 373 were 3 to 5 years of age. Among very young children, 22 were 3 years of age at the time the prescription claim for a stimulant was filled.

35

Figure 1. FFS and ACO Pediatric Patients (< 18 years) with a Prescription Filled for a Stimulant from January 1, 2017 to December 31, 2019 (Figure Shows the 10 Most Utilized Stimulant Products Sorted by Number of 2019 Patients, From Highest to Lowest)

Figure 2. FFS and ACO Pediatric Patients 6 to 17 years with a Prescription Filled for a Stimulant from January 1, 2019 to December 31, 2019 (Figure shows the 10 Most Utilized Stimulant Products Sorted by Number of 2019 Patients, From Highest to Lowest)

36

Figure 3. FFS and ACO Pediatric Patients 3 to 5 years with a Prescription Filled for a Stimulant from January 1, 2019 to December 31, 2019 (Figure shows the 10 Most Utilized Stimulant Products Sorted by Number of 2019 Patients, From Highest to Lowest)

Figure 4. FFS and ACO Prescription Claims by Formulation Type in 2019 (left panel: patients 6 to 17 years of age; right panel: patients 3 to 5 years of age)

B) Pharmacy Fills for the FFS Patients in 2019 and ICD-10 Diagnosis Codes for FDA-Approved Indications

Table 8 includes the number of FFS patients with a prescription filled for a stimulant in 2019 whom had an ICD-10 diagnosis code submitted for any of the possible FDA-approved indications from 2017 onward. ICD-10 diagnosis codes are described in Appendix C.

Among FFS patients who filled a prescription for a stimulant, 74% had an ICD-10 diagnosis code submitted for an FDA-approved indication (ie, ADHD, narcolepsy, BED, or obesity). Of the 900 patients with at least one of these ICD-10 codes, the majority (99%) had an ADHD code. Approximately 26% of FFS patients did not have any of the ICD-10 diagnosis codes we explored. Data for ACO patients is not reported in this section because there is incomplete information regarding ICD-10 diagnosis codes due to a time-lag in the data. Table 4 of Appendix B contains ACO and FFS data regarding ICD-10 diagnosis codes.

37

Table 8. Fee-for-Service Pediatric Patients with a Diagnosis Code Submitted for an FDA-Approved Indication Number of FFS patients (< 18

years) who filled a prescription for any stimulant product (mph or amph) over

the last year

Number of FFS patients (< 18 years) who filled a prescription for any stimulant over the last year and had an ICD-10 diagnosis

code submitted for ADHD, narcolepsy, BED, or obesitya from 2017 onward

Number of FFS patients (< 18 years) who filled a prescription for any

stimulant over the last year and had an ICD-10 diagnosis code submitted

for ADHDa from 2017 onward 1220 900 889

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; Amph, amphetamine; BED, binge eating disorder; FDA, U.S. Food and Drug Administration; FFS, fee-for-service; mph, methylphenidate a ICD-10 diagnosis codes are described in Appendix C.

C) Maximum Daily Doses for CNS Stimulants

We attempted to explore the number of patients and prescription claims that exceeded the maximum recommended daily dose over the last year (January 1, 2019 to December 31, 2019). Maximum daily doses for stimulants were established based on patient´s age (3 through 5 or 6 through 17 years of age), stimulant formulation, FDA prescribing information, and evidence from Micromedex,95 the 2007 AACAP guideline,41 and the 2016 Texas report on Psychotropic Medication Utilization Parameters for Children and Youth in Foster Care, 5th edition.54 (see Tables 9 and Table 10)

We looked at each independent fill and asked whether individual fills exceeded the dosage threshold. This was done so as to not catch overlapping supplies from different fills of the same product where the refill occurred on time (eg, 5 days or less before running out).

Looking at prescription fills independently, utilization data show that 33 patients 3 to 5 years of age (8.8%) and 55 patients 6 to 17 years of age (0.65%) exceeded the maximum daily dose for either amphetamine- or methylphenidate-based stimulant therapy in 2019. Note that approximately 30% of patients 3 to 5 years of age who filled a prescription for Quillivant suspension or methylphenidate capsule (generic of Metadate CD) exceeded the maximum daily dose for each prescription. Among children 6 to 17 years of age, more than 50% of patients who filled a prescription for Mydayis capsule (amphetamine/dextroamphetamine) exceeded the maximum daily dose.

Table 9. ACO and FFS Patients 3-5 Years of Age That Exceeded the Maximum Daily Dose in 2019

Generic Product Patients (2019)

Claims (2019)

Maximum daily dose

Patients exceeding the

maximum daily dose

Claims exceeding the

maximum daily dose

Mph QUILLIVANT SUS 25MG/5ML 43 147 20 mg/day 13 50

Mph METHYLPHENID CAP (Generic of Metadate CD) 24 59 20 mg/day 7 19

Mph METHYLPHENID TAB 5, 10, or 20 mg (Generic of Ritalin) 66 196 20 mg/day 5 22

Mph QUILLICHEW CHW 15 46 20 mg/day 4 4

Mph METHLPHENIDA CHW (Generic of Methylin) 34 99 20 mg/day 2 14

Amph/ dexamph

AMPHET/DEXTR CAP (Generic of Adderall XR) 43 140 30 mg/day <5 <5

Mph DAYTRANA transdermal patch <5 <5 20 mg/day <5 <5

38



Claims (2019)

Maximum daily dose


maximum daily dose


maximum daily dose

Mph CONCERTA TAB 44 118 40 mg/day <5 <5

Mph METHYLPHENID SOL (Generic of Methylin) 8 23 20 mg/day <5 <5

Mph METHYLPHENID TAB 18, 27, 36, or 54 mg ER (Generic of Concerta)

11 37 40 mg/day <5 7

Amp ADZENYS XR TAB 7 26 20 mg/day 0 0

Amp DYANAVEL XR SUS 2.5MG/ML 14 22 20 mg/day 0 0

Amp EVEKEO ODT TAB 10MG <5 <5 40 mg/day 0 0

Amp EVEKEO TAB 5 10 30 mg/day 0 0 Amph/ dexamph

AMPHET/DEXTR TAB (Generic of Adderall) 81 206 30 mg/day 0 0

Dexmph DEXMETHYLPH CAP (Generic of Focalin XR) <5 <5 10 mg/day 0 0

Dexmph DEXMETHYLPH TAB (Generic of Focalin) <5 <5 10 mg/day 0 0

Dexmph FOCALIN TAB 6 12 10 mg/day 0 0

Dexmph FOCALIN XR CAP 12 31 30 mg/day 0 0

Dexamp DEXTROAMPHET TAB (Generic of Dexedrine) <5 5 30 mg/day 0 0

Lisdex VYVANSE CAP 35 88 30 mg/day 0 0

Lisdex VYVANSE CHW 17 34 30 mg/day 0 0

Mph COTEMPLA TAB <5 11 52 mg/day 0 0

Mph JORNAY PM CAP 5 10 100 mg/day 0 0

Mph METHYLIN SOL <5 5 20 mg/day 0 0

Mph METHYLPHENID CAP ER (Generic of Ritalin LA) 5 8 20 mg/day 0 0

Mph METHYLPHENID TAB 10 or 20mg ER (Generic of Metadate ER) 10 22 20 mg/day 0 0

Total unique patients and claims 373 1364 33 122 Abbreviations: Amph/dexamph, amphetamine/dextroamphetamine; CAP, capsule; CHW, chewable tablet; dexamph, dextroamphetamine; dexmph, dexmethylphenidate; ER, extended release; lisdex, lisdexamfetamine; SOL, solution; SUS, suspension; TAB, tablet

39



Claims (2019)

Maximum daily dose


maximum daily dose


maximum daily dose

Amph/ Dexamph MYDAYIS CAP 24 145 25 mg/day 13 68

Lisdex VYVANSE CAP 2018 12363 70 mg/day 12 46 Amph/ dexamph

AMPHET/DEXTR TAB (Generic of Adderall) 1134 5351 60 mg/day 10 18

Dexmph FOCALIN XR CAP 607 3514 50 mg/day 10 68

Dexmph FOCALIN TAB 157 840 50 mg/day <5 6

Amph ADZENYS XR TAB 74 390 20 mg/day <5 <5

Amph DYANAVEL XR SUS 2.5MG/ML 69 310 20 mg/day <5 <5 Amph/ dexamph

AMPHET/DEXTR CAP (Generic of Adderall XR) 1850 9796 60 mg/day <5 <5

Dexmph DEXMETHYLPH CAP (Generic of Focalin XR) 82 354 50 mg/day <5 5

Lisdex VYVANSE CHW 168 732 70 mg/day <5 <5

Mph DAYTRANA transdermal patch 43 204 30 mg/day <5 13

Mph QUILLIVANT SUS 25MG/5ML 193 784 100 mg/day <5 <5

Amp ADZENYS ER SUS 1.25MG <5 7 20 mg/day 0 0

Amp EVEKEO TAB 7 25 60 mg/day 0 0 Amph/ dexamph ADDERALL XR CAP 36 67 60 mg/day 0 0

Dexmph DEXMETHYLPH TAB (Generic of Focalin) 25 74 50 mg/day 0 0

Dexamph DEXTROAMPHET CAP (Generic of Dexedrine Spansule) 47 236 60 mg/day 0 0

Dexamph DEXTROAMPHET SOL 5MG/5ML (Generic of Dexedrine)

<5 5 60 mg/day 0 0

Dexamph DEXTROAMPHET TAB (Generic of Dexedrine) 41 226 60 mg/day 0 0

Dexamph ZENZEDI TAB <5 14 60 mg/day 0 0

Mph COTEMPLA TAB 87 510 52 mg/day 0 0

Mph ADHANSIA XR CAP 55MG <5 <5 85 mg/day 0 0

Mph APTENSIO XR 9 27 100 mg/day 0 0

Mph CONCERTA TAB 2094 11423 108 mg/day 0 0

Mph JORNAY PM CAP 94 257 100 mg/day 0 0

Mph METHLPHENIDA CHW (Generic of Methylin) 52 165 100 mg/day 0 0

Mph METHYLIN SOL 18 57 100 mg/day 0 0

Mph METHYLPHENID CAP (Generic of Metadate CD) 535 2680 100 mg/day 0 0

Mph METHYLPHENID CAP ER (Generic of Ritalin LA) 37 78 100 mg/day 0 0

40



Claims (2019)

Maximum daily dose


maximum daily dose


maximum daily dose

Mph METHYLPHENID SOL (Generic of Methylin) 32 80 100 mg/day 0 0

Mph METHYLPHENID TAB 18, 27, 36, or 54 mg ER (Generic of Concetrta)

783 3367 108 mg/day 0 0

Mph METHYLPHENID TAB 5, 10, or 20 mg (Generic of Ritalin) 935 4122 100 mg/day 0 0

Mph METHYLPHENID TAB 10 or 20 mg ER (Generic of Metadate ER)

258 1001 100 mg/day 0 0

Mph METHYLPHENID TAB 72MG ER (Generic of Relexxii) 11 36 72 mg/day 0 0

Mph QUILLICHEW CHW 142 688 100 mg/day 0 0 Total unique patients and claims 8470 59930 55 229 Abbreviations: Amph/dexamph, amphetamine/dextroamphetamine; CAP, capsule; CHW, chewable tablet; dexamph, dextroamphetamine; dexmph, dexmethylphenidate; ER, extended release; lisdex, lisdexamfetamine; SOL, solution; SUS, suspension; TAB, tablet

D) Combinations of Stimulants

- Ongoing combinations of 2 long-acting formulations

In 2019, there were 9 pediatric patients that received 2 different LA formulations overlapping by at least 25 days AND received a second prescription of each overlapping product within 35 days of the initial prescription fill date. We required a second occurrence within 35 days of the initial prescription in order to capture ongoing therapy rather than a switch to another LA formulation. For instance, 83 patients received 2 different LA formulations that overlapped by at least 25 days; however, this may represent a switch to a different LA product.

- Ongoing combinations of 2 stimulants from different classes

In 2019, there were 59 pediatric patients that received an amphetamine-based medication overlapping with a methylphenidate-based medication by at least 25 days AND received a second prescription of each overlapping product within 35 days of the initial prescription fill date. We required a second occurrence within 35 days of the initial prescription in order to capture ongoing therapy rather than a switch to another LA formulation. For instance, 132 patients received 2 stimulants from different classes that overlapped by at least 25 days; however, this may represent a switch to another stimulant class.

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Discussion Topics for Potential Prior Authorization Criteria and Safety Edits Prior Authorization (PA) Considerations

• Appropriate indication

o Regarding ADHD, patients should have a diagnosis of ADHD based on the DSM-5 (or most recent DSM) diagnostic criteria.43

o Prescriptions may be allowed for other FDA-approved indications in youth (narcolepsy, exogenous obesity, binge eating disorder).

• Appropriate initiation

o Clinicians should obtain baseline information before initiation of therapy

Cardiac history, heart rate, blood pressure, height, weight, and signs of abuse and dependence.

• Appropriate monitoring

o Clinicians should monitor treatment response and adverse effects at every visit.

o Clinician should regularly monitor heart rate, blood pressure, height, weight, and signs of abuse and dependence.

• Special requirements with respect to age

o Patients 5 years old or younger:

For therapy initiation in patients ≤ 5 years of age consider requiring consultation or second opinion from a mental health specialist. Limited availability of mental health practitioners may warrant prescription by pediatric providers.

The AAP guideline states that “it may be helpful to obtain consultation from a mental health specialist with specific experience with preschool-aged children, if possible. “…Given the nationwide problem of limited access to mental health clinicians, pediatricians and other PCCs are increasingly called on to provide services to patients with ADHD and to their families. In addition, the AAP holds that primary care pediatricians should be prepared to diagnose and manage mild-to-moderate ADHD, anxiety, depression, and problematic substance use, as well as co-manage patients who have more severe conditions with mental health professionals. Unfortunately, third party payers seldom pay appropriately for these time consuming services.”43

Provider attestation of moderate to severe ADHD symptoms where behavioral interventions have failed or are unavailable for trial.

Consider requiring trial and inadequate response to methylphenidate prior to the use of other stimulants for children 4 through 5 years of age. Methylphenidate is the recommended first-line medication for patients 4 through 5 years of age according to the AAP guideline (off-label use); however, note that 5 amphetamine-based products (Adderall, Evekeo, Dexedrine, ProCentra, and Zenzedi) are FDA approved for children 3 through 5 years of age.

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o Adolescents with a history of substance abuse

May be treated initially with a non-stimulant medication or stimulant formulations with less abuse potential compared to other stimulants.

Should be evaluated regularly for stimulant misuse, abuse, or diversion.

Long-acting formulations may be preferred for maintenance therapy.

• Consider requiring a PA for certain combination regimens to ensure coordination of care between potentially different prescribers, and presence of a rationale for more complex regimens. However, switches in therapy may be allowed without a PA (ie, a single occurrence where claims overlap)

o Confirm appropriate use of 2 long-acting stimulants (eg, Aptensio XR and Concerta). This statement does not apply to a combination of the same product that just differs by strength (eg, Adzenys XR-ODT 3.1 mg and Adzenys XR-ODT 6.3 mg).

o Confirm appropriate use of 2 short-acting stimulants (eg, Evekeo ODT and Zenzedi). This statement does not apply to a combination of the same product that just differs by strength (eg, Evekeo 5 mg and Evekeo 10 mg).

o Assess rationale for use of 2 stimulants from different classes (eg, a methylphenidate-based formulation and an amphetamine-based formulation) and verify the same class combination has already been tried.

Note: Ideally, multiple providers who practice at the same location or within the same health system have access to the full medical records; prescriptions from 2 different doctors in this scenario may be coordinated appropriately.

o Consider a total daily dosage threshold for each medication.

Point of Sale Restrictions

• Monthly quantity limits based on maximum daily doses by age groups (as proposed in Table 5). A prior authorization may be used to determine if quantity overages are appropriate.

Provider Outreach Ideas Provider report cards can be developed to address the following issues:

• Fills that exceed maximum recommended dosing per product

• Occurrences of use of 2 LA stimulants overlapping over 60 days or more.

• Occurrences of use of 2 stimulants from different classes overlapping over 60 days or more.

• Occurrences of use of 2 SA stimulants overlapping over 60 days or more.

• Occurrences of use of stimulant therapy in patients with a diagnosis of a substance abuse disorder.

• Occurrences of stimulant therapy with hypnotic therapy.

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Summary This review provides evidence to assure safe and appropriate use of stimulant medication in children and adolescents. Particularly, potential age restrictions, dose limits, considerations for monthly quantity limits, and concerns regarding certain combinations of stimulants are discussed. Considerations for prior authorization (PA) criteria and provider outreach ideas are included on pages 41 and 42.

Regarding age limits, there is some inconsistency between product labeling and guideline recommendations. All stimulants are approved in patients 6 years of age and older, with the exception of a branded mixed amphetamine salt formulation (Mydayis), only approved for children 13 years of age or older. Some amphetamine-based products have additional FDA-approved dosing recommendations for children 3 through 5 years of age (ie, Adderall, Evekeo, Dexedrine, ProCentra, and Zenzedi). Although methylphenidate-based products are FDA approved only for children 6 years of age and above, the 2019 AAP guideline recommends use of methylphenidate as a first-line medication for preschool-aged children (4 to 5 years of age). Concerning amphetamine-based formulations, guideline authors consider evidence insufficiently robust to recommend them first-line for preschoolers. In 2007, the Preschool Psychopharmacology Working Group (PPWG) algorithm included amphetamine-based products as second line medication options. The AAP guideline suggests consultation with a mental health specialist in treating preschool-aged children. This guideline does not make any recommendation regarding the use of stimulants in children younger than 4 years of age due to the limited available evidence. Prior authorization criteria are proposed for children 5 years of age and younger. Potential requirements include the following:

a) consultation or second opinion from a mental health specialist

b) presence of moderate to severe ADHD symptoms following failure of behavioral therapy (if available)

c) trial and inadequate response to methylphenidate-based products prior to use amphetamine-based products.

Utilization data for the Utah Medicaid pediatric population (ACO and FFS population) show that 97.8% (59930) prescription claims were filled by patients 6 to 17 years of age and 2.2% (1364) were filled by patients 3 to 5 years of age in 2019. There were 373 patients 3 to 5 years of age receiving a stimulant in 2019 and 22 of these were 3 years of age. Among children 3 to 5 years old, prescription claims for both amphetamine- and methylphenidate-based stimulants were identified. Among FFS patients who filled a prescription for a stimulant, 74% had an ICD-10 diagnosis code submitted for an FDA-approved indication (ie, ADHD, narcolepsy, BED, or obesity). The majority (99%) of patients with at least one of these ICD-10 codes had an ADHD code.

Maximum daily doses for each stimulant were established based on patient´s age (3-5 or 6-17 years of age), FDA prescribing information, and evidence from Micromedex,95 the 2007 AACAP guideline,41 and the 2016 Texas report on Psychotropic Medication Utilization Parameters for Children and Youth in Foster Care, 5th edition (see Table 5). Looking at 2019 Utah Medicaid prescription fills independently, 33 (8.8%) patients 3 to 5 years of age and 55 (0.65%) patients 6 to 17 years of age exceeded the maximum daily dose for a stimulant product in 2019. Note that approximately 30% of patients 3 to 5 years of age who filled a prescription for Quillivant (methylphenidate) suspension or methylphenidate capsule

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(generic of Metadate CD) exceeded the average maximum daily dose. Among children 6 to 17 years of age, more than 50% of patients who filled a prescription for Mydayis (amphetamine/ dextroamphetamine) exceeded the maximum daily dose. Point of sale restrictions may include monthly quantity limits based on maximum daily doses.

ADHD symptoms can affect the patent´s activities of daily living in different settings (eg, home, school, and work). Treatment strategies for patients with ADHD should be individualized and depend on patient’s age, family or patient preferences, coexisting conditions, symptom profile, duration of effect required, swallowing difficulties, abuse or diversion potential, social stigma, convenience, and cost. Short-acting, intermediate-acting, and long-acting formulations should be considered to allow therapy to be adjusted to an individual’s needs. For example, some patients may require an LA formulation in the morning followed by an SA formulation later in the day to accommodate a recurrence of symptoms as the LA formulation wears off. This can improve functioning during the latter half of the day (eg, while driving, studying, meeting friends, or at extra-curricular activities) without compromising sleep. According to the 2018 Canadian guideline and 2018 NICE guideline, it appears generally acceptable to augment an LA product with an SA product of the same stimulant class (amphetamine-based or methylphenidate-based). When certain combinations of stimulants are prescribed, PA criteria may be required to ensure coordination of care between different prescribers and the presence of a rationale for more complex regimens: combinations of 2 or more long-acting stimulants (eg, Aptensio XR and Concerta); 2 or more short-acting stimulants (eg, Evekeo ODT and Zenzedi); and 2 or more stimulants from different classes (eg, combination of a methylphenidate-based formulation and an amphetamine-based formulation). Combinations of different strengths of the same product are excluded from these PA criteria. Utilization data regarding combinations of stimulants suggested that 9 pediatric patients received consecutive prescriptions of 2 different LA formulations and 59 pediatric patients received consecutive prescriptions of 2 stimulants from different classes (ie, an amphetamine-based medication and a methylphenidate-based medication).

Stimulant medications are Schedule II controlled substances. FDA prescribing information for stimulants contains a black box warning regarding the high potential risk for abuse and dependence. The most commonly reported short-term adverse events associated with stimulants are loss of appetite, abdominal pain, headaches, and sleep problems. Other adverse events include growth delay, hallucinations, and psychotic symptoms. In preschoolers, there is a lack of evidence and clinical experience regarding effects on growth and brain development in the long-term. Sudden cardiac death has been rarely reported at usual doses of stimulants in children and adolescents with serious heart problems. Although an observational study reported no increased risk of serious cardiovascular events in children and young adults taking ADHD medication, prescribing information states that stimulants should not be used in patients with serious cardiac conditions. Patients should receive a thorough cardiovascular assessment (eg, cardiac personal and family history) before initiating stimulant therapy. Monitoring requirements specified in the product labelling of stimulants include heart rate, blood pressure, height, weight, aggressive behavior, and signs of abuse and dependence.

A provider report card can be developed to address the following issues with stimulant prescribing for ADHD:

a) fills that exceed maximum recommended dosing per product.

b) occurrences of use of 2 LA stimulants.

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c) occurrences of use of 2 stimulants from different classes.

d) Additional issues not evaluated in this report may include occurrences of use of 2 SA stimulants; use of stimulant therapy in patients with a diagnosis of a substance abuse disorder; and use of stimulant therapy with hypnotic therapy.

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82. American Academy of Pediatrics. News Room. Children in Foster Care Three Times More Likely to Have ADHD Diagnosis. https://www.aap.org/en-us/about-the-aap/aap-press-room/pages/Children-in-Foster-Care-Three-Times-More-Likely-to-Have-ADHD-Diagnosis.aspx. Accessed January 13, 2020.

83. Faraone SV. Using Meta-analysis to Compare the Efficacy of Medications for Attention-Deficit/Hyperactivity Disorder in Youths. P & T : a peer-reviewed journal for formulary management. 2009;34(12):678-694.

84. National Institute of Health. National Institute of Mental Health (NIMH). Mental Health Information. Health Topics. Attention-Deficit/Hyperactivity Disorder. Last revised: March 2016. https://www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml. Accessed March 27, 2019.

85. Canadian Attention Deficit Hyperactivity Disorder Resource Alliance (CADDRA): Canadian ADHD Practice Guidelines, Third Edition, Toronto ON; CADDRA, 2011.

86. Young JL, Goodman DW. Adult Attention-Deficit/Hyperactivity Disorder Diagnosis, Management, and Treatment in the DSM-5 Era. Prim Care Companion CNS Disord. 2016;18(6).

87. CADTH Rapid Response Reports. In: Guidelines and Recommendations for ADHD in Children and Adolescents. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health Copyright (c) 2011 CADTH.; 2011.

https://www.cdc.gov/ncbddd/adhd/treatment.html

https://dopl.utah.gov/programs/csdb/

http://bit.ly/ADHD0312

https://utahfostercare.org/wp-content/uploads/2013/04/ufc-factsheet-general.pdf

https://utahfostercare.org/wp-content/uploads/2013/04/ufc-factsheet-general.pdf

https://www.aap.org/en-us/about-the-aap/aap-press-room/pages/Children-in-Foster-Care-Three-Times-More-Likely-to-Have-ADHD-Diagnosis.aspx

https://www.aap.org/en-us/about-the-aap/aap-press-room/pages/Children-in-Foster-Care-Three-Times-More-Likely-to-Have-ADHD-Diagnosis.aspx

https://www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml

https://www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml

51

88. CADTH Rapid Response Reports. In: Pharmacologic Management of Patients with ADHD: A Review of Guidelines. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health Copyright (c) 2016 Canadian Agency for Drugs and Technologies in Health.; 2016.

89. Centers for Disease Control and Prevention (CDC). Attention-Deficit / Hyperactivity Disorder (ADHD). State Profiles - Medication Treatment and Behavior Therapy Among Children Ages 4-17 Years (Survey Data). State profile: ADHD treatment in Utah. Page last reviewed: September 5, 2017. https://www.cdc.gov/ncbddd/adhd/stateprofiles-behavioral/stateprofile-behavioral-utah.pdf. Accessed March 26, 2019.

90. Centers for Disease Control and Prevention. Vital Signs: National and State-Specific Patterns of Attention Deficit/Hyperactivity Disorder Treatment Among Insured Children Aged 2–5 Years — United States, 2008–2014. https://www.cdc.gov/mmwr/volumes/65/wr/mm6517e1.htm. Accessed January 13, 2020.

91. Lopez FA, Leroux JR. Long-acting stimulants for treatment of attention-deficit/hyperactivity disorder: a focus on extended-release formulations and the prodrug lisdexamfetamine dimesylate to address continuing clinical challenges. Atten Defic Hyperact Disord. 2013;5(3):249-265.

92. Cascade E, Kalali AH, Weisler RH. Short-acting versus Long-acting Medications for the Treatment of ADHD. Psychiatry (Edgmont). 2008;5(8):24-27.

93. Jain R, Jain S, Montano CB. Addressing Diagnosis and Treatment Gaps in Adults With Attention-Deficit/Hyperactivity Disorder. Prim Care Companion CNS Disord. 2017;19(5).

94. Banaschewski T, Coghill D, Santosh P, et al. Long-acting medications for the hyperkinetic disorders. A systematic review and European treatment guideline. Eur Child Adolesc Psychiatry. 2006;15(8):476-495.

95. Micromedex (electronic version). Truven Health Analytics; 2020. 96. Adesman, A. Cohen Children's Medical Center of New York, part of Northwell Health.

http://www.adhdmedicationguide.com/. Accessed January 14, 2020. 97. U.S Food and Drug Administration. FDA Drug Safety Communication: Safety Review Update of

Medications used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) in children and young adults. Content current as of: 02/09/2018. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-medications-used-treat-attention. Accessed January 17, 2020.

98. Swanson JM, Elliott GR, Greenhill LL, et al. Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. Journal of the American Academy of Child and Adolescent Psychiatry. 2007;46(8):1015-1027.

99. U.S. Food and Drug Administration. Drug safety and availability. FDA Drug Safety Communication: FDA reporting permanent skin color changes associated with use of Daytrana patch (methylphenidate transdermal system) for treating ADHD. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-reporting-permanent-skin-color-changes-associated-use-daytrana. Accessed January 17, 2020.

https://www.cdc.gov/ncbddd/adhd/stateprofiles-behavioral/stateprofile-behavioral-utah.pdf

https://www.cdc.gov/ncbddd/adhd/stateprofiles-behavioral/stateprofile-behavioral-utah.pdf

https://www.cdc.gov/mmwr/volumes/65/wr/mm6517e1.htm

http://www.adhdmedicationguide.com/

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-safety-review-update-medications-used-treat-attention



https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-reporting-permanent-skin-color-changes-associated-use-daytrana

https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-reporting-permanent-skin-color-changes-associated-use-daytrana

52

Appendix A – Prescribing Information for CNS Stimulants

Table 1. FDA-Approved CNS Stimulants5-34

Generic Name

Brand Name Preparations

(Approval date) (Availability of Generic)

Labeled Indication(s)

Recommended Dosage

Amph

etam

ine

Adzenys ER ER oral suspension 1.25 mg/mL (September 2017)

Treatment of ADHD in patients ≥ 6 years old

• Patients 6 to 17 years: - Initial dosage: 6.3 mg QD - Maximum dosage: o 6-12 years: 18.8 mg/day o 13-17 years: 12.5 mg/day

Adults: 12.5 mg/day (recommended dose); maximum dose not specified

Adzenys XR-ODT ER ODT 3.1 mg, 6.3 mg, 9.4 mg, 12.5 mg, 15.7 mg, 18.8 mg (January 2016) Dyanavel XR ER oral suspension 2.5 mg/mL (October 2015)

Children ≥ 6 years: • Initial dosage: 2.5 mg or 5 mg QD Maximum dosage: 20 mg/day

Amph

etam

ine

sulfa

te Evekeo

Oral tablet 5 mg and 10 mg (August 2012) (Generic available)

Treatment of ADHD * Other labeled indications: narcolepsy and exogenous obesity

ADHD dosage: • Not recommended in children < 3 years • Pediatric patient 3 to 5 years:

Initial dosage: 2.5 mg/day • Pediatric patient ≥6 years:

Initial dosage: 5 mg QD or BID • Maximum dosage for pediatric patients ≥3

years not specified (in rare cases dosages may exceed 40 mg/day)

Narcolepsy dosage: • Usual dose for ≥6 years: 5-60 mg/day.

Maximum dose not specified Exogenous obesity dosage for ≥12 years: Up to 30 mg/day

Evekeo ODT ODT 5 mg, 10 mg, 15 mg, 20 mg (January 2019)

Treatment of ADHD in pediatric patients 6 to 17 years of age

• Pediatric patient ≥6 years: Initial dosage: 5 mg QD or BID

Maximum dosage not specified (in rare cases dosages may exceed 40 mg/day)

Dexm

ethy

lphe

nida

te

hydr

ochl

orid

e Focalin Oral tablet 2.5 mg, 5 mg, 10 mg (November 2001) (Generic available)

Treatment of ADHD

• Patients new to methylphenidate: 2.5 mg BID • Patients currently on methylphenidate: use

half the total daily dose of methylphenidate • Maximum dose: 20 mg/day (10 mg BID)

53


Generic Name




Recommended Dosage

Focalin XR ER oral capsule 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 40 mg (May 2005) (Generic available)

Treatment of ADHD

• Patients new to methylphenidate: Pediatric patients: 5 mg QD Adult patients: 10 mg QD

• Patients currently on methylphenidate: use half the total daily dose of methylphenidate

Maximum dosage: 30 mg/day in pediatric patients and 40 mg/day in adults

Dext

roam

phet

amin

e su

lfate

Dexedrine Spansule SR oral capsule 5 mg, 10 mg, and 15 mg (August 1976) (Generic available)

Treatment of ADHD in patients 6 to 16 years * Other labeled indications: narcolepsy

ADHD dosage in pediatric patients ≥ 6 years: • Initial dosage: 5 mg QD or BID • Maximum dosage not specified (in rare cases

dosages may exceed 40 mg/day) Narcolepsy: Usual dose for ≥6 years: 5-60 mg/day. Maximum dose not specified

Dexedrine Oral tablet 5 mg, 10 mg (February 1976) (Brand DSC; generic available) Oral solution 5 mg/5 mL (February 1976) (Brand DSC; generic available only)

Treatment of ADHD in children 3 to 16 years * Other labeled indications: narcolepsy

ADHD: • Pediatric patient 3 to 5 years: Initial dosage:

2.5 mg/day; maximum dosage not specified • Pediatric patient ≥ 6 years: Initial dosage: 5 mg

QD or BID; maximum dosage not specified (in rare cases dosages may exceed 40 mg/day)

Narcolepsy: Usual dose for ≥6 years: 5-60 mg/day. Maximum dose not specified

ProCentra Oral solution 5 mg/5 mL Zenzedi Oral tablet 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, and 30 mg

Dext

roam

phet

amin

e/

Amph

etam

ine

mix

ed sa

lts

Adderall 5, 7.5, 10, 12.5, 15, 20, 30 Oral tablet 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 30 mg (January 1960) (Brand DSC; generic available) * Contains amphetamine aspartate; amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate

Treatment of ADHD * Other labeled indications: narcolepsy

ADHD: • Not recommended for children < 3 years of age • Patients 3-5 years: 2.5 mg/day; maximum

dosage not specified • Patient ≥6 years: 5 mg QD or BID; maximum

dosage not specified (in rare cases dosages may exceed 40 mg/day)

Narcolepsy: Usual dose for ≥6 years: 5-60 mg/day. Maximum dose not specified

54


Generic Name




Recommended Dosage

Dext

roam

phet

amin

e/

Amph

etam

ine

mix

ed sa

lts (c

ontin

ued)

Adderall XR 5, 10, 15, 20, 25, and 30 ER oral capsule 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg (October 2001) (Generic available) * Contains amphetamine aspartate; amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate

Treatment of ADHD (efficacy established in pediatric patients 6-17 years and adults)

• Pediatric patients (6-12 years): initial dosage: 10 mg QD; maximum dosage for children: 30 mg QD

• Pediatric patients (13-17 years): initial dosage: 10 mg QD; maximum dosage not specified

• Adults: the recommended dosage is 20 mg QD; maximum dosage not specified

* Dosage should be adjusted in patients with severe renal impairment

Mydayis ER oral capsule 12.5 mg, 25 mg, 37.5 mg, 50 mg (June 2017) * Contains amphetamine aspartate; amphetamine sulfate, dextroamphetamine saccharate, and dextroamphetamine sulfate (different strengths compared to Adderall XR)

Treatment of ADHD in patients ≥ 13 years

Pediatric patients (13-17 years) • Initial dosage: 12.5 mg QD • Maximum dose: 25 mg/day Adults: • Initial dosage: 12.5 mg QD • Maximum dosage: 50 mg/day * Dosage should be adjusted with severe renal impairment. Use in patients with ESRD is not recommended

Lisd

exam

feta

min

e Di

mes

ylat

e

Vyvanse Oral capsule: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg (February 2007) Oral chewable tablet: 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (January 2017)

Treatment of ADHD * Other labeled indications: moderate to severe binge eating disorder (BED) in adults

ADHD: Adult and pediatric patients ≥6 years: • Initial dosage: 30 mg QD • Maximum dosage: 70 mg/day * Dosage should be adjusted with severe renal impairment and ESRD BED: Maximum dose for adults: 70 mg/day

Met

ham

phet

amin

e

Desoxyn Oral tablet 5 mg (December 1943) (Generic available)

Treatment of ADHD in children > 6 years

Children ≥6 years: • Recommended dosage: 5 mg QD or BID • Usual effective dose: 20-25 mg/day Maximum dose not specified

55


Generic Name




Recommended Dosage

Met

hylp

heni

date

Adhansia XR ER oral capsule 25 mg, 35 mg, 45 mg, 55 mg, 70 mg, 85 mg (February 2019)


Patients ≥ 6 years: • Initial dosage: 25 mg QD Maximum dosages: 70-85 mg daily (in pediatric patients) or 85-100 mg daily (in adults)

Aptensio XR ER oral capsule 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (April 2015)


Pediatric patients ≥ 6 years: • Initial dosage: 10 mg QD

Maximum dosage: 60 mg/day

Concerta ER oral tablet 18 mg, 27 mg, 36 mg, 54 mg (August 2000) (Generic available)

Treatment of ADHD in children ≥ 6 years, adolescents, and adults ≤ 65 years

• Initial dosage for patients new to methylphenidate: - Children and adolescents: 18 mg QD - Adults: 18 to 36 mg QD

• Maximum dosage: 54 mg/day for children and 72 mg/day for adolescents and adults

Patients currently on methylphenidate: Dosing based on current dose regimen and clinical judgment

Cotempla XR-ODT ER ODT 8.6 mg, 17.3 mg, 25.9 mg (June 2017)

Treatment of ADHD in pediatric patients 6-17 years

Children 6-17 years: • Initial dosage: 17.3 mg QD Maximum dosage: 51.8 mg/day

Daytrana ER transdermal patch 10 mg/9 hr, 15 mg/9 hr, 20 mg/9 hr, 30 mg/9 hr (April 2006)

Treatment of ADHD (efficacy established in pediatric patients 6-17 years)

Apply Daytrana to the hip area • Initial dose: 10 mg QD Maximum dosage: unspecified

Jornay PM ER oral capsule 20 mg, 40 mg, 60 mg, 80 mg, 100 mg (August 2018)


Patients ≥ 6 years: • Initial dose: 20 mg daily in the evening Maximum dosage: 100 mg/day

Metadate CD ER oral capsule 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg (April 2001) (Generic available)

Treatment of ADHD (efficacy established in children 6 to 15 years)

• Initial dosage: 20 mg QD Maximum dosage: 60 mg/day (QD)

Metadate ER ER oral tablet 10 mg and 20 mg (June 1988) (Brand DSC; generic available for ER tablet 10 mg and 20 mg)


Adults and children ≥6 years: • Metadate ER can replace IR tablets when the

8-hour dosage corresponds to ER tablet size Maximum dosage: 60 mg/day

56


Generic Name




Recommended Dosage

Met

hylp

heni

date

(con

tinue

d)

Methylin Oral solution 5 mg/5 mL, 10 mg/5 mL (December 2002) (Generic available) Chewable tablet 2.5 mg, 5 mg, 10 mg (April 2003) (Brand DSC; generic available)


• Adults: Average dosage is 20 to 30 mg/day in 2 or 3 divided doses (range: 10 to 60 mg/day)

• Pediatric patients ≥ 6 years: initial dosage: 5 mg BID

• Maximum dosage: 60 mg/day

QuilliChew ER ER oral chewable tablet 20 mg, 30 mg, 40 mg (December 2015)

Treatment of ADHD

Patients ≥ 6 years: • Initial dosage: 20 mg QD Maximum dosage: 60 mg/day Quillivant XR

ER oral suspension 25 mg/5 mL (September 2012)

Treatment of ADHD

Relexxii ER oral tablet 72 mg (December 1955) (Generic available)

Treatment of ADHD in children ≥ 6 years, adolescents, and adults ≤ 65 years

• Initial dosage for patients new to methylphenidate: - Children and adolescents: 18 mg QD - Adults: 18 to 36 mg QD

• Maximum dosage: 54 mg/day for children and 72 mg/day for adolescents and adults

Patients currently on methylphenidate: Dosing based on current dose regimen and clinical judgment

Ritalin Oral tablet 5 mg, 10 mg, 20 mg (December 1955) (Generic available) Ritalin-SR ER tablet 20 mg (Brand DSC; generic available)

Treatment of ADHD in pediatric patients ≥ 6 years and adults * Other labeled indications: narcolepsy

Ritalin tablets: • Adults: Average daily dosage is 20 to 30 mg (in

2 or 3 divided doses) • Pediatric patients ≥ 6 years: 5 mg BID • Maximum dosage: 60 mg/day Ritalin-SR may be used in place of Ritalin when the 8-hour dosage of Ritalin-SR corresponds to the titrated 8-hour dosage of Ritalin

Ritalin LA ER oral capsule 10 mg, 20 mg, 30 mg, 40 mg, 60 mg (June 2002) (Brand DSC; generic available)

Treatment of ADHD in pediatric patients 6 to 12 years

• Initial dosage: 20 mg QD Maximum dosage: 60 mg/day

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; BID, twice daily; DSC, discontinued; ER, extended release; FDA, Food and Drug Administration; IR, immediate release; ODT, orally disintegrating tablet; QD, once daily; XR, extended release

57

Table 2. Special Population Considerations for CNS Stimulant Agents5-34,39

Agent Pediatrics Geriatrics Renal & Hepatic Impairment Pregnancy & Lactation Amphetamine-Containing Products

Amphetamine (Adzenys ER, Adzenys XR-ODT; Dyanavel XR; Evekeo, Evekeo ODT)

Efficacy and safety established in children ≥ 3 years old

(Dexedrine, Procentra, or Zenzedi)

Efficacy and safety established in

children ≥ 6 years old (all amphetamine products,

Dexedrine Spansule, Adderall, Adderall XR, Vyvanse, and

Desoxyn)

Efficacy and safety established in children ≥ 13 years old (Mydavis)

Evekeo and Adderall (generic)

labeling states: “Amphetamines are not recommended for use in

children < 3 years of age with ADHD”8

No studies in elderly patients

No renal or hepatic adjustment reported in the manufacturer’s

labeling

Pregnancy: May cause fetal harm

Lactation: Breastfeeding not recommended

Dextro-amphetamine (Dexedrine Spansule, Dexedrine, ProCentra, Zenzedi)

No renal or hepatic adjustment reported in the manufacturer’s

labeling Dextro-amphetamine-Amphetamine Mixed Salts (Adderall, Adderall XR, Mydayis)

Adderall XR: dosage adjustments in patients with severe renal

impairment. Not recommended in ESRD


Insufficient data on elderly patients

Renal: Severe renal impairment: max dose

(50 mg/day) ESRD: max dose (30 mg/day)

Hepatic: No hepatic adjustment reported in

the manufacturer’s labeling Methamphetamine (Desoxyn) No renal or hepatic adjustment

reported in the manufacturer’s labeling

Methylphenidate-Containing Products Dex-methylphenidate (Focalin, Focalin XR)

Efficacy and safety established in children ≥ 6 years old

No studies in elderly patients

No experience with the use of these agents in patients with renal or

hepatic impairment

Pregnancy: These agents should be used during pregnancy only if the

potential benefit justifies the potential risk to the

fetus Lactation: Caution should

be exercised

Methylphenidate (Adhansia XR, Aptensio XR, Concerta, Cotempla XR-ODT, Daytrana, Jornay PM, Metadate CD, Metadate ER, Methylin, QuilliChew ER, Quillivant XR, Relexxii, Ritalin, Ritalin LA)

No studies in patients > 72

years old

Abbreviations: ER, extended release; ESRD, end stage renal disease; ODT, orally disintegrating tablet; XR, extended release

58

Appendix B – Utah Medicaid Utilization Data for CNS Stimulants Table 1. FFS and ACO Utilization Data for Patients Younger than 18 Years of Age (from January 1, 2017 to December 31, 2019) (Stimulant Products are Sorted by Number of 2019 Patients, From Highest to Lowest)

2017 2018 2019 Generic Product Patients Claims Patients Claims Patients Claims

Methylphenidate HCl Concerta (mph) tablet ER (OROS) 2082 10540 2132 11489 2125 11541

Lisdexamfetamine Dimesylate

Vyvanse capsule (lisdexamph) 2460 14448 2351 13488 2044 12451

Amphetamine-Dextroamphetamine Amph/damph capsule ER 327 1372 1981 10433 1879 9936 Amphetamine-Dextroamphetamine Amph/damph tablet 1486 6939 1329 6238 1204 5557 Methylphenidate HCl Mph tablet (5, 10, or 20mg) 1145 5223 1032 4621 993 4318 Methylphenidate HCl Mph tablet ER (OROS) 1260 5443 961 3969 791 3404

Dexmethylphenidate HCl Focalin XR (dmph) capsule ER 622 3666 619 3670 617 3545

Methylphenidate HCl Mph capsule CD 504 2021 582 3071 554 2739 Methylphenidate HCl Mph tablet ER (10 or 20mg) 306 1206 298 1160 267 1023

Methylphenidate HCl Quillivant XR (mph) suspension 393 1965 168 508 228 931

Lisdexamfetamine Dimesylate

Vyvanse chewable tablet (lisdexamph) 42 98 143 451 180 766

Dexmethylphenidate HCl Focalin (dmph) tablet 171 815 170 877 161 852

Methylphenidate HCl Quillichew (mph) chewable tablet ER 38 130 131 588 152 734

Methylphenidate HCl Jornay PM (mph) capsule ER 0 0 0 0 98 267

Methylphenidate Cotempla XR-ODT (mph) ODT ER 7 13 155 518 91 521

Dexmethylphenidate HCl Dmph capsule ER 94 380 97 375 83 355 Methylphenidate HCl Mph chewable tablet 45 158 43 155 81 264

Amphetamine Dyanavel XR (Amph) suspension 59 162 96 389 80 332

Amphetamine Adzenys XR (amph) tablet 35 117 107 408 77 416 Dextroamphetamine Sulfate Damph capsule ER 64 303 62 236 47 236

Methylphenidate Daytrana (mph) transdermal patch 65 265 56 277 44 208

Dextroamphetamine Sulfate Damph tablet 124 543 71 296 43 231 Methylphenidate HCl Mph capsule ER/LA 0 0 15 22 40 86 Methylphenidate HCl Mph solution 59 204 57 249 38 103 Amphetamine-Dextroamphetamine

Adderall XR (amph/damph) capsule 1896 10557 47 127 36 67

Dexmethylphenidate HCl Dmph tablet 34 98 24 80 26 75

59

Table 1. FFS and ACO Utilization Data for Patients Younger than 18 Years of Age (from January 1, 2017 to December 31, 2019) (Stimulant Products are Sorted by Number of 2019 Patients, From Highest to Lowest)

2017 2018 2019 Generic Product Patients Claims Patients Claims Patients Claims Amphetamine-Dextroamphetamine

Mydayis (amph/damph) capsule <5 6 23 89 24 145

Methylphenidate HCl Methylin (mph) solution 0 0 7 17 21 62 Amphetamine Sulfate Evekeo (amph) tablet 18 60 26 67 11 35 Methylphenidate HCl Mph tablet 72mg ER 0 0 <5 <5 11 36

Methylphenidate HCl Aptensio XR (mph) capsule ER 0 0 7 13 9 27

Amphetamine Adzenys XR (amph) suspension 0 0 <5 6 <5 7

Dextroamphetamine Sulfate Zenzedi (damph) tablet <5 6 <5 10

<5 14

Methylphenidate HCl Adhandia XR capsule 0 0 0 0 <5 <5

Amphetamine Sulfate Evekeo ODT tablet 0 0 0 0 <5 <5 Dextroamphetamine Sulfate Damph solution <5 15 0 0 <5 5 Amphetamine-Dextroamphetamine Adderall tablet <5 <5 0 0 0 0 Dextroamphetamine Sulfate Procentra solution 0 0 <5 12 0 0 Methylphenidate HCl Metadate ER (mph) tablet 37 87 9 16 0 0

Methylphenidate HCl Metadate CD (mph) capsule ER 369 1437 21 33 0 0

Methylphenidate HCl Ritalin LA (mph) capsule ER 25 62 0 0 0 0 Total Total 9522 68340 9110 63960 8713 61294

Abbreviations: Amph, amphetamine; damph, dextroamphetamine; dmph, dexmethylphenidate; ER, extended release; lisdexamph, lisdexamphetamine; mph, methylphenidate; ODT, orally disintegrating tablet; OROS, osmotic-release oral system

Table 2. FFS and ACO Utilization Data for Patients 6 to 17 Years of Age (from January 1, 2019 to December 31, 2019) (Stimulant Products are Sorted by Number of 2019 Patients, From Highest to Lowest) 2019 Generic Product Patients Claims Methylphenidate HCl Concerta (mph) tablet ER (OROS) 2094 11423 Lisdexamfetamine Dimesylate Vyvanse (lisdexamph) capsule 2018 12363 Amphetamine-Dextroamphetamine Amph/damph capsule ER 1850 9796 Amphetamine-Dextroamphetamine Amph/damph tablet 1134 5351 Methylphenidate HCl Mph tablet 5, 10, or 20mg 935 4122 Methylphenidate HCl Mph tablet ER (OROS) 783 3367 Dexmethylphenidate HCl Focalin XR (dmph) capsule ER 607 3514 Methylphenidate HCl Mph capsule CD 535 2680 Methylphenidate HCl Mph tablet ER (10 or 20mg) 258 1001 Methylphenidate HCl Quillivant XR (mph) suspension 193 784

60

Table 2. FFS and ACO Utilization Data for Patients 6 to 17 Years of Age (from January 1, 2019 to December 31, 2019) (Stimulant Products are Sorted by Number of 2019 Patients, From Highest to Lowest) 2019 Generic Product Patients Claims Lisdexamfetamine Dimesylate Vyvanse (lisdexamph) chewable tablet 168 732 Dexmethylphenidate HCl Focalin (dmph) tablet 157 840 Methylphenidate HCl Quillichew (mph) chewable tablet ER 142 688 Methylphenidate HCl Jornay PM (mph) capsule ER 94 257 Methylphenidate Cotempla XR-ODT (mph) ODT ER 87 510 Dexmethylphenidate HCl Dmph capsule ER 82 354 Amphetamine Adzenys XR (amph) tablet 74 390 Amphetamine Dyanavel XR (amph) suspension 69 310 Methylphenidate HCl Mph chewable tablet 52 165 Dextroamphetamine Sulfate Damp capsule ER 47 236 Methylphenidate Daytrana (mph) transdermal patch 43 204 Dextroamphetamine Sulfate Damph tablet 41 226 Methylphenidate HCl Mph capsule ER/LA 37 78 Amphetamine-Dextroamphetamine Adderall XR (amph/damph) capsule 36 67 Methylphenidate HCl Mph solution 32 80 Dexmethylphenidate HCl Dmph tablet 25 74 Amphetamine-Dextroamphetamine Mydayis (Amph/damph) capsule 24 145 Methylphenidate HCl Methylin (mph) solution 18 57 Methylphenidate HCl Mph tablet 72mg ER 11 36 Methylphenidate HCl Aptensio XR (mph) capsule ER 9 27 Amphetamine Sulfate Evekeo (amph) tablet 7 25 Amphetamine Adzenys XR (amph) suspension <5 7 Dextroamphetamine Sulfate Zenzedi (damph) tablet <5 14 Methylphenidate HCl Adhandia XR capsule <5 <5 Dextroamphetamine Sulfate Damph solution <5 5 Total Total 8470 59930

Abbreviations: Amph, amphetamine; damph, dextroamphetamine; dmph, dexmethylphenidate; ER, extended release; lisdexamph, lisdexamphetamine; mph, methylphenidate; ODT, orally disintegrating tablet; OROS, osmotic-release oral system

Table 3. FFS and ACO Utilization Data for Patients 3 to 5 Years of Age (from January 1, 2019 to December 31, 2019) (Stimulant Products are Sorted by Number of 2019 Patients, From Highest to Lowest)

2019 Generic Product Patients Claims Amphetamine-Dextroamphetamine Amph/damph tablet 81 206 Methylphenidate HCl Mph tablet (5, 10, or 20mg) 66 196 Methylphenidate HCl Concerta (mph) tablet ER (OROS) 44 118 Amphetamine-Dextroamphetamine Amph/damph capsule ER 43 140 Methylphenidate HCl Quillivant XR (mph) suspension 43 147

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Table 3. FFS and ACO Utilization Data for Patients 3 to 5 Years of Age (from January 1, 2019 to December 31, 2019) (Stimulant Products are Sorted by Number of 2019 Patients, From Highest to Lowest)

2019 Generic Product Patients Claims Lisdexamfetamine Dimesylate Vyvanse capsule (lisdexamph) 35 88 Methylphenidate HCl Mph chewable tablet 34 99 Methylphenidate HCl Mph capsule CD 24 59 Lisdexamfetamine Dimesylate Vyvanse chewable tablet (lisdexamph) 17 34 Methylphenidate HCl Quillichew (mph) chewable tablet ER 15 46 Amphetamine Dyanavel XR (Amph) suspension 14 22 Dexmethylphenidate HCl Focalin XR (dmph) capsule ER 12 31 Methylphenidate HCl Mph tablet ER (OROS) 11 37 Methylphenidate HCl Mph tablet ER (10 or 20mg) 10 22 Methylphenidate HCl Mph solution 8 23 Amphetamine Adzenys XR (amph) tablet 7 26 Dexmethylphenidate HCl Focalin (dmph) tablet 6 12 Amphetamine Sulfate Evekeo (amph) tablet 5 10 Methylphenidate HCl Jornay PM (mph) capsule ER 5 10 Methylphenidate HCl Mph capsule ER/LA 5 8 Methylphenidate Cotempla XR-ODT (mph) ODT ER <5 11 Methylphenidate HCl Methylin (mph) solution <5 5 Dextroamphetamine Sulfate Dmph tablet <5 5 Methylphenidate Daytrana (mph) transdermal patch <5 <5

Amphetamine Sulfate Evekeo ODT tablet <5 <5

Dexmethylphenidate HCl Dmph capsule ER <5 <5

Dexmethylphenidate HCl Dmph tablet <5 <5

Total Total 373 1364 Abbreviations: Amph, amphetamine; damph, dextroamphetamine; dmph, dexmethylphenidate; ER, extended release; lisdexamph, lisdexamphetamine; mph, methylphenidate; ODT, orally disintegrating tablet; OROS, osmotic-release oral system

Table 4. Pediatric Patients (FFS and ACO) with a Diagnosis Code Submitted for an FDA-Approved Indication

Number of patients (< 18 years) who filled a

prescription for any stimulant product (mph or amph) over

the last year

Number of patients (< 18 years) who filled a prescription for any stimulant over the

last year and had an ICD-10 diagnosis code submitted for ADHD, narcolepsy, BED, or

obesitya from 2017 onward

Number of patients (< 18 years) who filled a prescription for any stimulant over the last year and had an ICD-10 diagnosis code submitted for ADHDa

from 2017 onward ALL (ACO+FFS) FSS ALL (ACO+FFS) FSS ALL (ACO+FFS) FSS

8713 1220 3400b 900 3369b 889 Abbreviations: ACO, Accountable Care Organization; ADHD, attention-deficit/hyperactivity disorder; Amph, amphetamine; BED, binge eating disorder; FDA, U.S. Food and Drug Administration; FFS, fee-for-service; Mph, methylphenidate a ICD-10 diagnosis codes are described in Appendix C. b For the ACO population, there is incomplete information regarding ICD-10 diagnosis codes due to a time-lag in the data.

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Appendix C – ICD-10 Diagnosis Codes ADHD

ICD Diagnosis

F900 ATTN-DEFCT HYPERACTIVITY DISORDER, PREDOM INATTENT F901 ATTN-DEFCT HYPERACTIVITY DISORDER, PREDOM HYPERACT F902 ATTENTION-DEFICIT HYPERACTIVITY DISORDER, COMBINED F908 ATTENTION-DEFICIT HYPERACTIVITY DISORDER, OTHER TY F909 ATTENTION-DEFICIT HYPERACTIVITY DISORDER, UNSPECIF Note: The ICD-10 diagnosis code R41840 (ATTENTION AND CONCENTRATION DEFICIT) was not included in this list Narcolepsy

ICD Diagnosis G47411 NARCOLEPSY WITH CATAPLEXY G47419 NARCOLEPSY WITHOUT CATAPLEXY G47421 NARCOLEPSY IN CONDITIONS CLASSIFIED ELSEWHERE WITH G47429 NARCOLEPSY IN CONDITIONS CLASSIFIED ELSEWHERE W/O

Binge eating disorder (BED)

ICD Diagnosis F5081 BINGE EATING DISORDER

Obesity

ICD Diagnosis E6601 MORBID (SEVERE) OBESITY DUE TO EXCESS CALORIES E6609 OTHER OBESITY DUE TO EXCESS CALORIES E662 MORBID (SEVERE) OBESITY WITH ALVEOLAR HYPOVENTILAT E668 OTHER OBESITY E669 OBESITY, UNSPECIFIED

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