utah medicaid dur report march 2020 safe and …

UTAH MEDICAID DUR REPORT

MARCH 2020

SAFE AND APPROPRIATE USE OF CENTRAL NERVOUS SYSTEM STIMULANTS IN ADULTS

Report finalized: February 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 .................................................................................................................................................. 3

Methods ........................................................................................................................................................ 5

Disease Overview .......................................................................................................................................... 6

Overview of Stimulant Medication Characteristics ...................................................................................... 8

Short-Acting Versus Long-Acting Stimulant Formulations ....................................................................... 9

Table 1. Advantages and Disadvantages of Short-Acting Versus Long-Acting Stimulant Formulations ............................................................................................................................................................ 10

Titration and Maximum Recommended Daily Doses of CNS Stimulant Medication .................................. 11

Table 2. Maximum Daily Doses for FDA-Approved CNS Stimulants in Children, Adolescents, and Adults, with Focus on Adults .............................................................................................................. 12

Abuse, Misuse, and Diversion of CNS Stimulants ....................................................................................... 17

Table 3. Clinical Practice Guideline Recommendations on Abuse, Misuse, and Diversion of Stimulants ........................................................................................................................................... 20

Table 4. Stimulant Medications and Suspected Relative Abuse Potential ......................................... 22

Concomitant Use of Two or More Stimulants ............................................................................................ 26

Concomitant Use of Stimulants With Benzodiazepine/Non-benzodiazepine Hypnotics ........................... 27

Table 5. Duration of Action of Benzodiazepines ................................................................................ 29

Table 6. Non-benzodiazepine, Non-barbiturate Hypnotics ............................................................... 30

Table 7. Clinical Practice Guideline Recommendations for the Management of Insomnia in Patients with ADHD .......................................................................................................................................... 33

Safety Concerns Related to CNS Stimulant Use in Adults ........................................................................... 35

Table 8. CNS Stimulant Adverse Events and Recommended Management ...................................... 37

Utah Medicaid Utilization Data ................................................................................................................... 38

Table 9. ACO and FFS Patients Who Received a Stimulant in the Past Year (February 2019 Through January 2020) and Had an ICD-10 Code Submitted Between February 2018 and February 2020 for Stimulant Dependence, Abuse, or Poisoning ..................................................................................... 39

Table 10. FFS Patients Who Received a Stimulant in the Past Year (February 2019 Through January 2020) and Had an ICD-10 Code Submitted Between February 2018 and February 2020 for Stimulant Dependence, Abuse, or Poisoning ..................................................................................................... 39

Table 11. ACO and FFS Patients with Concurrent Use of Stimulants and Hypnotics ......................... 40

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

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

References .................................................................................................................................................. 45

Appendix A - Literature Search Strategies .................................................................................................. 53

Appendix B – Diagnosis of ADHD ................................................................................................................ 55

Appendix C – Prescribing Information for CNS Stimulants ......................................................................... 56

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Table 1. FDA-Approved CNS Stimulants ............................................................................................. 56

Table 2. Pharmacokinetic Properties and Other Considerations for CNS Stimulants ........................ 62

Table 3. Special Population Considerations for Central Nervous System Stimulant Agents ............. 66

Table 4. Warnings and Precautions for CNS Stimulants..................................................................... 67

Appendix D: Comparison of Benzodiazepines and Non-Benzodiazepine Hypnotics .................................. 68

Appendix E: Utilization Data for Stimulant Abuse, Dependence, and Poisoning ....................................... 71

Appendix F: ICD-10 Diagnosis Codes ........................................................................................................... 76

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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 in social, academic, and occupational settings.1,2 Medications 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).3-32

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.33-35 Stimulants are used to increase CNS catecholamine levels and alleviate ADHD symptoms (ie, improve motivation, attention, and movement).36,37 Stimulant medications are categorized as short-acting (SA), intermediate-acting (IA), and long-acting (LA) formulations.38-40 Duration of action ranges from 3 to 6 hours with SA formulations to up to 16 hours with LA formulations; intermediate-acting formulations last 6 to 8 hours. Treatment approaches in patients with ADHD should be individualized and adjusted to the patient´s age and needs.41 For example, clinical practice guidelines mention that some patients may require an LA formulation in the morning followed by an SA formulation later in the day to prolong the duration of effect thorough the day. The short-acting afternoon dose can improve functioning during the latter half of the day (eg, at work, college, or social activities) without compromising sleep.42 Considerations regarding concomitant use of 2 LA formulations, 2 SA formulations, or 2 stimulants from different classes are not described in guidelines.41-44

All stimulants are FDA approved in the pediatric population with ADHD. Some are additionally approved in adults with ADHD. The average age of first onset of the disease is 7 years,43,45 but more than 50% of children with ADHD continue experiencing symptoms into adulthood.41,46

Concurrent with the increase in understanding and awareness of ADHD in the medical setting over the last decades, the number of people diagnosed and treated for ADHD has also increased.47,37 The prevalence of ADHD in US adults is estimated to be 4.4% according to a National Comorbidity Survey Replication (NCS-R) conducted between 2001 and 2003.48-50 The prevalence in older adults is approximately 3%.41 The rise in patients diagnosed with ADHD is evidenced by an increase in stimulant medication prescribing; methylphenidate and amphetamine prescriptions rose by 35.5% from 2008 to 2012 in the US, especially in adolescents and adults.51

Greater accessibility to prescription stimulants raises concerns regarding misuse and diversion potential in the general population.47,52 In 2016, the Centers for Disease Control and Prevention (CDC) reported that 2.1% of the US population aged 12 years and older misused prescription stimulants in the previous year, with highest rates of misuse reported in adults between 18 and 25 years old. Overdose deaths involving psychostimulants with abuse potential (illicit drugs or prescription stimulants) increased by 37% from 2016 to 2017.53

Stimulants are considered the most efficacious medications for the treatment of ADHD; however, they are associated with adverse events such as loss of appetite, increased heart rate and blood pressure, and reduced sleep.42,43,46 Stimulants are Schedule II controlled substances due to their high potential for

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abuse and ability to produce severe physical or psychological dependence.54 Abuse and dependence cautions are included in the FDA black box warning in the prescribing information for all stimulants. People with or without a diagnosis of ADHD may abuse stimulants because of their euphoric effects, self-esteem enhancement effects, improvement in mental and physical performance, increase in activity, loss of appetite, wakefulness for longer periods, and recreational effects (ie, to “get high”).55 In general, drug effects depend on the dose and route of administration.55 A person abusing stimulants can swallow, snort, smoke, or intravenously inject the drug.55 Non-oral administration may produce an immediate sensation known as a “rush or flash.” In addition, use of stimulants in larger amounts, more frequently, or for longer periods of time than prescribed constitutes drug misuse.55 The abuse, misuse, and diversion of stimulants are worrying because of their associated cardiovascular and psychiatric adverse effects and legal penalties. Negative effects associated with misuse or abuse of stimulants include agitation, hostility, panic, aggression, suicidal thoughts, paranoia, hallucinations, tolerance, both physical and psychological dependence, and physical side effects (eg, dizziness, tremors, headache, palpitations, sweating, and vomiting).55 People with specific pre-existing medical conditions (eg, structural cardiac abnormalities or other serious heart problems, psychosis, and tic disorder) are more likely to experience these side effects. Legal consequences of stimulant diversion may include a fine or incarceration.52

Sleep problems are very frequently reported in patients with ADHD.41 Patients with ADHD can experience sleep disturbances due to inadequate sleep hygiene, stimulant treatment, untreated ADHD, a comorbid psychiatric condition (eg, anxiety and depression), or a comorbid sleep disorder (eg, insomnia, restless leg syndrome, periodic limb movements of sleep, or circadian-based phase delay in sleep-wake patterns). Changing the dosage, timing, and formulation of stimulant may improve sleep problems. The majority of patients with ADHD present with a diagnosis for another psychiatric disorder. In adults, common comorbid conditions include anxiety, mood disorders, behavioral disorders, and substance use disorders.43 Patients with ADHD should be screened for comorbid conditions and receive treatment accordingly. If sleep problems are caused by an underlying disorder (eg, a psychiatric condition such as anxiety), treatment of that disorder may not fully attenuate the patient’s insomnia.56 Consequently, some patients with ADHD and comorbidities may require pharmacotherapy for insomnia (eg, benzodiazepine or non-benzodiazepine hypnotics) in addition to stimulant therapy. Stimulants, benzodiazepines, and most non-benzodiazepine hypnotics (ie, eszopiclone, suvorexant, zaleplon, and zolpidem) are controlled substances with the potential for misuse, abuse, and dependence.

The purpose of this review is to provide evidence that can assist the Medicaid Drug Utilization Review (DUR) Board in assuring safe and appropriate use of stimulant medications in adults. This review will specifically address concerns related to abuse, misuse, and diversion of stimulant medications. In addition, potential safety edits or prior authorization criteria for stimulants regarding dose limits, concurrent use of more than 1 stimulant, and concurrent use of stimulants with medications approved for insomnia in adults (benzodiazepine or non-benzodiazepine hypnotics) will be evaluated. Utilization data will be presented to explore abuse potential of stimulant medications and concomitant hypnotic use in adults.

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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 and UpToDate were consulted for background information on 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 abuse, misuse, and overdose of stimulants in children, adolescents, and adults.

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], the National Institute for Health and Care Excellence [NICE] websites, the European Network for Hyperkinetic Disorders, and the European Network Adult ADHD [ENAA]).

A literature search for systematic reviews and meta-analyses addressing abuse, misuse, and diversion of stimulants was conducted in Ovid Medline and Epistemonikos in November 2019. Another literature search addressing ADHD and comorbid insomnia or use of stimulants in combination with hypnotics (benzodiazepine and non-benzodiazepine hypnotics) was conducted in Ovid Medline in January 2020. Reference lists of relevant systematic reviews were additionally screened. Complete search strategies are provided in Appendix A.

Relevant information was additionally extracted from the 2017 Utah Medicaid DUR report on concurrent use of benzodiazepines and stimulants, the 2019 Utah Medicaid Pharmacy and Therapeutics (P&T) Committee drug class review on Central Nervous System Stimulants for the Treatment of Attention-Deficit/Hyperactivity Disorder, and the 2020 Utah Medicaid DUR report on safe and appropriate use of CNS stimulants in children and adolescents.

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Disease Overview

Attention-deficit/hyperactivity disorder and Clinical Practice Guideline Recommendations

According to parent-report data from the National Survey of Children’s Health (NSCH) conducted in 2016, the estimated percentage of American children 2 to 17 years old ever diagnosed with ADHD by a health care provider was 9.4% (6.1 million).57-59 In US adults, the prevalence of ADHD is estimated to be 4.4% according to a National Comorbidity Survey Replication (NCS-R) conducted between 2001 and 2003.48-50 The prevalence in older adults is approximately 3%.41

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 Functional impairments differ by age groups. In adults with ADHD, the most frequently observed functional impairments include academic problems, occupational failure, relationship difficulties, self-esteem problems, substance abuse, injury/accidents, and risky sexual behavior.41 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.2,60

The causes and risk factors for ADHD are unknown.61 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.61

ADHD is most often diagnosed during childhood.43,45 Diagnosis is more frequently in school-aged boys (1 in 5) than girls (1 in 11). The average age of first onset of the disease is 7 years.43,45 More than 50% of children with ADHD continue experiencing symptoms into adulthood.41,46 Older adults can also experience ADHD symptoms.41 In adults with ADHD, epidemiological and clinical studies have suggested a sex ratio of 1:1.46

There is not a specific test to diagnose ADHD and other mental conditions (eg, anxiety, depression, and sleep disorders) may present with symptoms similar to ADHD.41,60,61 According to the DSM-5 diagnostic criteria for ADHD, a diagnosis of ADHD 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.2,60 In addition, the following requirements are necessary to confirm the diagnosis of ADHD: a) several symptoms should be present before age 12 in 2 or more settings (eg, at home and school). Many adults do not recall early symptoms and this information may be obtained from a parent or a family member who remembers the patient´s early history, b) several symptoms should reduce the quality of school/work and social functioning; and c) symptoms are not consistent with other mental disorders.2,41,60 Table 1 of Appendix B includes DSM-5 diagnostic criteria for ADHD and the 18 symptoms

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considered for diagnosis. Standardized screening scales are useful to gather information from patients or people who know the patient with suspected ADHD. For adults with suspected ADHD, these tools may include the World Health Organization “Adult ADHD Self-Report Scale (ASRS)” and the Wender Utah Rating Scale.41,46 For diagnostic evaluation, the use of structured diagnostic interviews is recommended, including the Diagnostic Interview for ADHD in adults, second edition (DIVA 2.0).41,46 These tools should not be used alone to diagnose ADHD but used in conjunction with the DSM-5 diagnostic criteria.

Some adults without a previous diagnosis of ADHD may seek an ADHD evaluation if they are parents of children with ADHD or have heard or read about ADHD in adults and have some symptoms. Other adults who were diagnosed during childhood and stopped taking medication during adolescence may seek re-evaluation of ADHD if they begin having symptoms. Clinicians may treat adults with ADHD for a comorbid condition (eg, anxiety or mood disorder) without being aware of the underlying ADHD. There is very limited data concerning ADHD in older adults compared to younger patients; however, undiagnosed ADHD in older adults can result in functional and psychosocial disturbances. Comorbidities such as depression and cognitive impairment may confound diagnosis of ADHD in older adults.41 The 2018 Canadian guideline highlights the importance of raising awareness among clinicians regarding ADHD in older adults.41

An ADHD evaluation should include comorbidity screening.41 Approximately 85% of adults with ADHD also have a comorbid mental health condition.41 A study by Fayyad et al showed 23% of adults with ADHD had 1 comorbidity, 14% had 2 comorbidities, and 14% had 3 comorbidities. The most common comorbid conditions were anxiety disorders (34%), mood disorders (22%), behavioral disorders (15%), and substance use disorders (11%).41,46 Before treatment initiation, comorbidities should be evaluated to determine the most appropriate order of treatment. Generally, therapy should be initiated for the more severe condition first (ADHD or comorbidity).46 Psychosis, bipolar disorder, substance abuse, severe depression, and severe anxiety are most commonly treated before ADHD. Comorbid milder mood disorders, anxiety disorders, and emotional instability can be treated concurrent with ADHD therapy. Drug and alcohol abuse problems should be stabilized before the initiation of ADHD therapy.46

Criminality is associated with ADHD. Around 25% of adult male prisoners have ADHD. Use of medication for ADHD seems to minimize the risk of criminality.36

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, medication therapy alone, or behavior therapy with medication therapy.62 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.36,62-64 Non-stimulant agents, including atomoxetine, guanfacine, and clonidine, have a slower onset, a longer duration of action (up to 24 hours), and may be associated with fewer adverse effects.36,63,65,66 Stimulants may be used in combination with nonstimulants (clonidine or guanfacine) if patients do not respond to stimulants alone.67 The risk of abuse, misuse, and diversion is higher with stimulant compared to non-stimulant therapy.1 Overall, ADHD therapy usually includes a stimulant agent (either methylphenidate or amphetamine) first-line.36,42,44,62,68 The non-stimulant, atomoxetine, is usually recommended third-line if methylphenidate or amphetamine treatments fail;

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however, it may be the drug of choice in patients with underlying anxiety disorders, severe tics, sleep disorders, or in patients with risk of abuse, misuse, or diversion of stimulant agents.62,69,70

Choice of medication therapy should be individualized based on patient’s age, family or patient preferences, comorbid conditions, symptom profile, duration of drug effect required, abuse or diversion potential, social stigma, convenience, compliance, and cost.36,39,62,68

There are no US clinical practice guidelines specific for adults with ADHD. Guidelines from the Canadian ADHD Resource Alliance (CADDRA), the European Network Adult ADHD (ENAA), and the National Institute for Health and Care Excellence (NICE) do provide specific recommendations for the adult population with ADHD.41 ENAA recommends psychoeducation first-line for adults with ADHD. When pharmacotherapy is necessary, stimulants are endorsed first-line. Long-acting formulations are preferred due to better adherence, less abuse potential, lower rebound symptoms, safer driving, and higher coverage throughout the day than short-acting formulations.46 The 2018 CADDRA guideline positions long-acting stimulant formulations as first-line agents in adults with ADHD due to reasons similar to those presented in the ENAA guideline. Short-acting/intermediate-acting stimulant formulations and long-acting non-stimulants are recommended as second-line agents.41 The 2018 NICE guideline specifies lisdexamfetamine or methylphenidate as firs-line therapy for adults with ADHD. Second-line stimulants include dexamphetamine if lisdexamphetamine is intolerable due to its long duration of action.44 For adolescents (12 through 17 years of age), the 2019 American Academy of Pediatrics (AAP) guideline recommends pharmacotherapy as first-line and behavioral therapy is encouraged, if available.43

Overview of Stimulant Medication Characteristics Stimulant products are classified according to their chemical structure as amphetamine-based or methylphenidate-based stimulants:

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

• Methylphenidate-based compounds: dexmethylphenidate and methylphenidate.

Currently, there are more than 30 amphetamine- or methylphenidate-based products approved by the FDA for the treatment of ADHD. All formulations are FDA approved for use in the pediatric population with ADHD. Some medications are additionally approved for use in adults with ADHD (Adzenys ER, Adzenys XR-ODT, Adderall XR, Mydayis, Vyvanse, Methylin, Ritalin, Focalin XR, Adhansia XR, Concerta, Metadate ER, Relexxii, and Ritalin-SR). Aptensio XR, Dyanavel XR, Jornay PM, QuilliChew ER, and Quillivant XR are approved in patients 6 years and older. There are no clinical trials conducted in adults for these 5 agents; however, FDA clinical pharmacology reviews state that pharmacokinetic data together with clinical practice and previous experience with methylphenidate and amphetamine appear to support the extension of the indication from pediatric patients to adults.71,72 See Table 1 of Appendix C for a specific product availability. A subset of stimulants are approved for other indications, including treatment of narcolepsy in youth 6 years and older (Adderall, all dextroamphetamine products, Evekeo, Metadate ER, Methylin, and Ritalin), exogenous obesity in patients 12 years and older (Evekeo), and binge eating disorder in adults (Vyvanse).3-32

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Stimulants are available as oral formulations (capsule, tablet, solution, suspension, chewable tablet, and orally disintegrating tablet) and transdermal patch. Durations of action ranges from 3 to 6 hours with immediate-release (IR) formulations to up to 16 hours with extended-release (ER) formulations.39,40,73 Products differ in the pharmacokinetic profile and content of isomers, which are combined in varying ratios to increase desired pharmacologic effects and reduce adverse effects. Some formulations may be more suitable for younger children or patients with difficulties swallowing whole pills, such as capsules that can be opened and sprinkled into soft food or drink, orally disintegrating tablets, oral solutions, or transdermal patch.42

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).9,19,20,25,32 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 extended drug delivery (eg, Concerta, Relexxii).21,30 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 onset of methylphenidate that is observed when the child wakes up the next morning and a controlled release of the active substance throughout the day.24 Lisdexamfetamine is a prodrug converted to dextro-amphetamine by hydrolysis.38,62,74 It provides a longer time to onset of action with prolonged duration of effect.75

Table 1 of Appendix C 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 C contains pharmacokinetic properties and other characteristics for CNS stimulants. Table 3 of Appendix C includes special population considerations for CNS stimulants.

Short-Acting Versus 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. Table 1 describes key characteristics of LA and SA formulations together with advantages and disadvantages associated with use of these formulations.

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Table 1. Advantages and Disadvantages of Short-Acting Versus Long-Acting Stimulant Formulations Short-Acting Formulations Long-Acting Formulations

More frequent dosing, which may decrease adherence to therapy41,75,76

Less frequent administration due to their longer half-lives and duration of action (6 to >16 hours); may increase adherence compared to SA formulations75 Onset of action may be delayed

Higher abuse potential by snorting or intravenous administration than LA formulations due to their pharmacokinetic profile and easy crushability (especially for tablets)41

Less likely to be abused or diverted because of the slower absorption and delivery to the CNS system compared to SA formulations36,39,40,42,68 Some of the LA formulations are difficult to crush (eg, extended release capsules), which may deter intranasal or intravenous administration.39

Dosing flexibility41,42,68,75 SA formulations are useful for: - Initial treatment to allow flexibility for dose

adjustment to the optimal dose - Children less than 16 kg who require doses lower

than those available with LA formulations40,68

More likely to reduce stigma among school-age children because they do not need to take medicines at school and facilitate family monitoring and convenience36,39,40,42,68

Less insomnia41,42,68,75 More likely to impact sleep and produce sleep problems68

Less likely to interfere with appetite More likely to interfere with appetite, especially the evening meal

Coverage for short periods of time41,42,68,75 Improve driving performance in adolescents and young adults36,39,40,42,68

Lower cost41,42,68,75 Abbreviations: LA, long-acting; SA, short-acting

Considering 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 young adult 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.42 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 (eg, when a stimulant can potentially worsen a comorbid psychiatric or medical condition, an SA formulation trial may be optimal).77

• If stimulants are causing sleep disturbances, initiating the medication as early as possible in the morning or using a shorter-acting formulation may be preferred.41

• 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.42 Long-acting stimulant formulations may also be considered as they have less abuse, misuse, or diversion potential.41

• If adherence is an issue, LA formulations may be more suitable.41

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Titration and Maximum Recommended Daily Doses of CNS Stimulant Medication Titration, Follow-Up, and Discontinuation Considerations

Once the appropriate stimulant has been selected for an individual patient, the 2018 Canadian guideline recommends “start low and go slow” with continued dosage increases until optimum effects have been achieved, side effects appear, or until the maximum recommended dosage is achieved.41 FDA prescribing information for stimulants recommends adjusting therapy according to patient-specific needs and response to therapy.3-32 Switching medications is considered on a weekly basis (3- to 7-day period). Medication titration may require several weeks. During the first month, medication may be adjusted with a follow-up assessment every 1-2 weeks. Clinicians can prescribe different strengths of the same medication that allow up-titration or prescribe 1 strength with directions to gradually increase (eg, doubling or tripling) the initial daily dosage.42

After the titration period, the first face-to-face follow-up visit with the clinician is usually at week 4 following treatment initiation. During the first visit, the provider will monitor the patient´s response to the administered doses, adverse events, pulse, blood pressure, and weight.42 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, discontinuation, or change to an alternative therapy) may be needed during treatment.42 Following several years of therapy with stable response, a trial discontinuation of medication may be considered to determine if ADHD therapy is still necessary. Medication discontinuation should follow a slow taper to avoid a withdrawal syndrome.15,41

Maximum Recommended Daily Doses for CNS Stimulants in Adults

Table 2 includes maximum recommended daily doses for stimulants in children, adolescents, and adults (with focus on adults) based on FDA approved prescribing information, Micromedex,78 and Lexicomp.38 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.79 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).40 Among the stimulant formulations included in Table 2 with a pediatric indication for ADHD, some are additionally approved for the treatment of ADHD in adults based on the labeled indication or dosing recommendations. Prescribing information specifically includes maximum daily doses for adults, with the exception of 3 LA amphetamine-based products (Adzenys ER, Adzenys XR-ODT, and Adderall XR).

http://www.adhdmedicationguide.com/

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Table 2. Maximum Daily Doses for FDA-Approved CNS Stimulants in Children, Adolescents, and Adults, with Focus on Adults

Generic (Brand Name) Dosage

Form/Strength Frequency of

Administration

Duration of Action3-

32,38,75,80

FDA-Approved Maximum Dosage in Children, Adolescents and Adults (with

Focus in Adults)

Maximum Dosage for Adults per Micromedex and Lexicomp38,78

Amphetamine-Containing Products: Short Acting Formulations

Amphetamine (Evekeo)

Tablet: 5 mg and 10 mg

Once or twice daily 4-6 h

- ADHD: Only approved in children ≥3 years of age (children 6-17 years: dosages may exceed 40 mg/day in rare cases).

- Narcolepsy: no maximum dose specified in patients ≥ 6 years (usual dose: 5-60 mg/day)

- Obesity: up to 30 mg/day. Not

recommended in < 12 years old

Information matches prescribing information (Adult dosing recommendations are for narcolepsy and obesity. No adult ADHD dosing recommendations)

Amphetamine (Evekeo ODT)

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


Only approved in children 6-17 years of age (dosages may exceed 40 mg/day in rare cases)

Information matches prescribing information (only approved in pediatric patients with ADHD)

Generic dextroamphetamine (Dexedrine - DSC)

Tablet: 5 mg, 10 mg Oral solution: 5 mg/5 mL


- ADHD: Only approved in children ≥3 years of age (children 6-17 years: dosages may exceed 40 mg/day in rare cases).


Information matches prescribing information (Adult dosing recommendations are for narcolepsy. No adult ADHD dosing recommendations)

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


Dosing recommendations in adults with ADHD (maximum dose: 60 mg/day) and narcolepsy

Methamphetamine (Desoxyn) Tablet: 5 mg Once or twice

daily NR Children ≥ 6 years old: maximum dosage unspecified


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Administration


32,38,75,80


Focus in Adults)


Amphetamine-Containing Products: Long-Acting Formulations

Amphetamine (Adzenys ER)

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

Approved in children ≥ 6 years old, adolescents, and adults Maximum dosage: • 6-12 years: 18.8 mg/day • 13-17 years: 12.5 mg/day • No maximum dosage specified for

adults (“there was not adequate evidence that doses greater than 20 mg/day conferred additional benefit”)

Maximum dose in adults is unspecified. Doses above 20 mg/day may not confer additional benefit 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

Amphetamine (Dyanavel XR)

ER suspension: 2.5 mg/mL Once daily 10-12 h75

Maximum dosage for patients ≥6 years: 20 mg/day. Clinical trials in children 6 to 12 years of age. PK studies in adults

Maximum dose in adults: 20 mg/day

Dextroamphetamine SR (Dexedrine Spansule)

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

Once or twice daily

8 h

- Children 6-16 years old: maximum dosage unspecified (in rare cases dosages may exceed 40 mg/day).


Information matches prescribing information (Adult dosing recommendations are for narcolepsy only. No adult ADHD dosing recommendations)

Dextroamphetamine/amphetamine (Adderall XR)

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

Once daily 8-12 h38

Approved in children ≥ 6 years old, adolescents, and adults - No maximum dosage specified for

adolescents and adults (“there was not adequate evidence that doses greater than 20 mg/day conferred additional benefit”)

Maximum dose for adults is unspecified. Doses above 20 mg/day may not confer additional benefit

14




Administration


32,38,75,80


Focus in Adults)


Dextroamphetamine/amphetamine (Mydayis)

ER capsule: 12.5 mg, 25 mg, 37.5 mg, 50 mg

Once daily 12-16 h75

- Maximum dose for pediatric patients (13-17 years): 25 mg/day

- Maximum dose for adults (18-55 years of age): 50 mg/day (“Doses above 50 mg daily have shown no additional clinically meaningful benefit”)

Information matches prescribing information (Maximum dose for adults 18-55 years of age: 50 mg/day)

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

- Maximum dosage for adults and pediatric patients ≥6 years of age with ADHD: 70 mg/day

- Maximum dosage for adults with moderate to severe BED: 70 mg/day

Information matches prescribing information (Maximum dose for adults: 70 mg/day)

Methylphenidate-Containing Products: Short Acting Formulations

Dexmethylphenidate (Focalin)

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

20 mg/day

Dosing recommendations in adults for ADHD (maximum dose: 20 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 old: 60 mg/day


Methylphenidate (Ritalin)

Tablet: 5 mg, 10 mg, 20 mg

2 or 3 times daily

3-5 h Maximum dosage for adults and pediatric patients ≥6 years old: 60 mg/day


Methylphenidate-Containing Products: Long-Acting Formulations

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 dosages for adults: 40 mg/day


15




Administration


32,38,75,80


Focus in Adults)


Methylphenidate (Adhansia XR)


Once daily NR Maximum dosage for adults: 100 mg/day


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. No clinical trials in adults. PK studies in adults

Dosing recommendations for adults with ADHD (maximum dose: 60 mg/day)

Methylphenidate (Concerta)

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

Maximum dosage for adolescents and adults: 72 mg/day


Methylphenidate (Cotempla XR-ODT)

ER ODT: 8.6 mg, 17.3 mg, 25.9 mg Once daily 10-12 h75 Only approved in children 6-17 years of

age. Maximum dose: 51.8 mg/day


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 Only approved in children 6-17 years of age. Maximum dose unspecified. Clinical trials included 400 adults

Lexicomp: Dosing recommendations for adults with ADHD (maximum dose: 60 mg/day, based on an SR and MA) Micromedex: Dosing recommendations for children 6-17 years of age

Methylphenidate (Jornay PM)

ER capsule: 20 mg, 40 mg, 60 mg, 80 mg, 100 mg

Once daily NR Maximum dose for patients ≥ 6 years: 100 mg/day. Clinical trials in patients 6 to 17 years of age. PK studies in adults

Dosing recommendations for adults with ADHD (maximum dose: 100 mg/day)

Methylphenidate (Metadate CD)


Once daily 6-8 h38 Maximum dosage for patients 6-15 years of age: 60 mg/day

Dosing recommendations for adults with ADHD (maximum dose: 60 mg/day); some experts considered individualized doses up to 100 mg/day may be appropriate

16




Administration


32,38,75,80


Focus in Adults)


Methylphenidate (Metadate ER - DSC)

ER tablet: 10 mg and 20 mg

2 or 3 times daily

8 h38 Maximum dosage for adults and children ≥6 years of age: 60 mg/day


Methylphenidate (QuilliChew ER)

ER chewable tablet: 20 mg, 30 mg, 40 mg Once daily NR

Maximum dosage for patients ≥ 6 years of age: 60 mg/day. No clinical trials in adults. PK studies in adults

Dosing recommendations for adults with ADHD (maximum dose: 60 mg/day) Methylphenidate

(Quillivant XR) ER suspension 25 mg/5 mL Once daily 10-12 h75

Maximum dosage for patients ≥ 6 years of age: 60 mg/day. No clinical trials in adults. PK studies in adults

Methylphenidate (Relexxii)

ER tablet: 72 mg Once daily 12 h Maximum dosage for adolescents and adults: 72 mg/day Not reported

Methylphenidate (Ritalin LA)

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

Once daily 6-8 h75 Only approved for children 6-12 years of age (maximum dose: 60 mg/day)


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

daily38 8 h Maximum dosage for adults and

children ≥6 years: 60 mg/day

Micromedex: Dosing recommendations for adults with ADHD (maximum dose: 60 mg/day)

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; BED, binge eating disorder; DSC, discontinued; ER, extended release; FDA, United States Food and Drug Administration; MA, meta-analysis; SR, systematic review; PK, pharmacokinetic

17

Abuse, Misuse, and Diversion of CNS Stimulants

A concern related to stimulant therapy is the potential for abuse, misuse, and diversion occurring among people diagnosed with ADHD, the caretakers of children receiving stimulant medication, and youth without a diagnosis of ADHD.

The FDA prescribing information for stimulants contains a black box warning regarding the high potential for abuse and dependence. Clinicians should assess the risk for abuse prior to initiating therapy and evaluate any sign of abuse, misuse, dependence, and overdose during treatment. In addition, clinicians should regularly assess the need for stimulant medication, keep careful prescription records, and educate patients concerning stimulant medication abuse.6,15,31

There are no standard definitions for abuse, misuse, diversion, and nonmedical use; but all these terms are related to inappropriate use of medications.1 According to the FDA, the term “abuse” of prescription drugs is defined as “…the intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desirable psychological or physiological effect.”51,81,82 Psychological effects include euphoria, hallucinations, cognitive impairment, and mood changes.82 The term “misuse” is defined by the FDA as “…the intentional therapeutic use of a drug product in an inappropriate way and specifically excludes the definition of abuse.”51,81 For example, an individual can misuse or abuse stimulants by taking them in greater amounts or more often than directed by the clinician, or using someone else’s prescription stimulant to improve performance.1 Diversion is the act of transferring (eg, trading, giving, or selling) a prescription drug to other individuals for whom the drug is not prescribed.1,51,52 Nonmedical use is classified by some authors as both abuse and misuse.51 Addiction is defined as “loss of control or compulsive use of a substance.“1 Malingering is a term utilized to refer to individuals faking or exaggerating symptoms to receive a prescription.51

Epidemiology of Stimulant Misuse and Overdose Death in the United States Population

According to the Centers for Disease Control and Prevention (CDC), stimulant medications (or psychostimulants) with potential for abuse or misuse include illicit stimulants (eg, methamphetamine and 3,4-methylenedioxy-methamphetamine [MDMA]) and prescription stimulants (eg, dextroamphetamine and methylphenidate). Data from 2016 showed that approximately 6 million Americans aged 12 years and older (2% of the US population) misused prescription stimulants in the previous year. Around 1.4 million Americans aged 12 years and older (0.5% of the US population) used methamphetamine in the past year. Males reported higher rates of prescription stimulant misuse compared to females (2.3% vs. 1.9%). People between 18-25 years of age reported the highest rate of misuse of prescription stimulants (7.5%), followed by people between 26-34 years of age (3.9%). By race or ethnicity, misuse of prescription stimulants ranged from 2.5% for whites to 0.8% for both blacks and American Indians/Alaska Natives (AI/AN). Reported misuse of prescription stimulants was higher in large metropolitan counties compared to non-metropolitan counties. By US census region of residence, the rate of prescription stimulant misuse was highest in the Northeast or Midwest (2.4%) and lowest in the West (1.8%, including Utah).53,83

Deaths related to psychostimulant overdose have been rising since 2010, with more than 10,000 overdose deaths involving psychostimulants with abuse potential (illicit drugs or prescription stimulants) in 2017. This represents a 37% increase from 2016 (7542 deaths). From 2016 to 2017, females aged 25–

18

44 years and non-Hispanic whites experienced the greatest relative increase in mortality rate due to psychostimulant overdose. AI/AN experienced the greatest absolute increase in overdose death rates involving psychostimulants from 2016 to 2017 and the highest rate of overdose deaths involving psychostimulants in 2017. By US census region of residence, the age-adjusted rate of overdose deaths per 100,000 population involving psychostimulants in 2017 was 5.3 in the West (including Utah), 3.1 in the Midwest, 3.0 in the South, and 1.2 in the Northeast. In Utah, the age-adjusted rate of overdose deaths per 100,000 population involving psychostimulants was 5.1 in 2016 (143 deaths) and 6.8 in 2017 (198 deaths), with a relative increase in death rate of 33.3% from 2016 to 2017.53,84

Source of Prescription Stimulants

A 2019 systematic review stated that 50% to 90% of individuals reporting nonmedical use (NMU) of stimulants obtained the agent from family or friends. College peers that may or may not be a friend were an additional source of prescription stimulants. Around 4% to 35% of individuals reported misuse or abuse of their own prescription stimulant. Some individuals reported malingering to gain a prescription. Another source of stimulants was from fraudulent prescriptions, which was reported by 20% of American adults misusing or abusing stimulants.51

According to reports from college students, it is generally easy to acquire stimulants. Individuals do not usually pay for stimulants but if they purchase them, the price is usually low. Stimulants are sometimes obtained through theft and rarely through a dealer or via the Internet.51

Route of Administration for Nonmedical Use of Prescription Stimulants

Oral administration was the most commonly reported route of administration by individuals non-medically using stimulants (52% to 95%). According to 2012-2016 data from the American Association of Poison Control Centers (AAPCC), 75% of adults and adolescents exposed to amphetamines who contacted AAPCC for consultation abused these drugs. Among those, 94% reported oral administration, 5% reported nasal administration, and 1.3% administered stimulants intravenously. Among individual reporting stimulant NMU in several studies, snorting was reported by 7% to 48% of US college students, smoking was reported by 1% to 6%, and injecting stimulants was reported by 1% to 11%.51

Risk Factors for Nonmedical Use of Stimulants

The systematic review from Faraone et al (2019) described statistically significant predictors of non-medical prescription stimulant use during the past year or lifetime.51 NMU was most commonly reported among adults 18 to 25 years compared to those individuals aged 26 to 49 years. Similarly, greater odds of NMU were reported among middle/high school students in higher grades compared to those in lower grades. NMU of methylphenidate was more frequently reported by 10th and 12th grade students compared to 8th grade students. Most studies showed males are at higher risk for NMU compared to female students. Among all races, whites were more likely to report NMU of stimulants. For instance, a survey in US high-school seniors indicated that lifetime NMU was higher among whites (11.2%), followed by Hispanic students (5.6%) and African American students (2.9%). Another survey of 8th, 10th, and 12th grade students showed that whites were 6 times as likely as African American students to communicate NMU. A study showed that college students with lower grade point average (GPA) were more likely to misuse stimulants compared to those with higher GPA. Observational data indicated that students with academic difficulties abused or misused stimulants to improve school performance.

19

Students affiliated with a fraternity or sorority were more likely to abuse or misuse stimulants compared to non-affiliated students. Individuals with higher levels of ADHD symptoms reported NMU more frequently than individuals with less ADHD symptoms; however, malingering cannot be ruled out.51

Polysubstance Use and Risk of Substance Use Disorders

The DSM-5 handbook defines a substance use disorder (SUD) as a “cluster of cognitive, behavioral, and physiological symptoms indicating that the individual continues using the substance despite significant substance-related problems.”85 SUDs include different drug classes such as alcohol, cannabis, hallucinogens, inhalants, opioids, sedatives, hypnotics, anxiolytics, stimulants, and tobacco.85 All these drugs taken in excess directly activate the brain reward system producing an intense feeling of pleasure or euphoria (also known as “high”).85 In addition, individuals with less ability to self-control are more likely to develop SUDs.85

A study showed that children with a diagnosis of ADHD had a higher risk for developing comorbid mental health or behavioral disorders such as SUDs compared to non-ADHD children.1 Although the relationship between ADHD and SUDs is not clearly understood, it is thought that some ADHD symptoms (eg, impulsivity, problems with executive functioning, and poor judgement), low levels of synaptic dopamine in individuals with ADHD, genetic factors, and academic failures may increase the probability of substance use (eg, alcohol and marijuana) and development of SUDs.1

Generally, the medical use of stimulants for the treatment of ADHD may decrease the risk for SUDs.1 Earlier initiation of treatment for ADHD reduces the risk for SUDs later in life.1 Nonetheless, stimulant nonmedical use is usually accompanied by use of other substances and SUDs. Studies in adults, adolescents, and college students found that the most commonly utilized substances in combination with stimulants were alcohol and marijuana, followed by cocaine, tranquilizers/sedatives, hallucinogens, heroin, inhalants, and pain relievers. An observational study followed US high school seniors from adolescence (age 18) to adulthood (age 35). Adolescents reporting NMU of prescription stimulants at age 18 were at higher risk of experiencing more substance use disorder symptoms in adulthood (age 35) compared to others (eg, adolescents who medically used prescription stimulants or did not use stimulants for ADHD).51,86 On the other hand, the appropriate use of prescription stimulants during adolescence was not related to an increased risk of substance use disorder symptoms in adulthood.51,86 NMU is also associated with other disorders. For example, college students using stimulants for weight loss reported symptoms of eating disorders.51

Motivations for Nonmedical Use

Among college students reporting NMU, 50% to 89% reported improving academic achievement as the most frequent reason for NMU of stimulants. Particularly, higher productivity, academic enhancement, and work performance were the main motivations reported by 38% to 57% of US adults. The second most frequently reported reason for NMU was recreation. “Getting high” as a recreational motivation for NMU was reported by 2% to 31% of college students. Curiosity and seeking new experiences were additional reasons for NMU and reported by 17% to 31% of college students. Other motivations for NMU included to enhance the effects of alcohol, improve social situations, help the student socialize, and stay awake while partying. Some US college students without an ADHD diagnosis (4% to 12%) reported stimulant NMU to self-treat undiagnosed ADHD. Another motivation for NMU is weight loss,

20

which was reported by 3.5% to 11.7% of US college students. Parents with suspected or diagnosed ADHD were more likely to use their children´s stimulants.51

Clinical Practice Guideline Recommendations Related to Abuse, Misuse, and Diversion of CNS Stimulants

In October 2019, the American Academy of Pediatrics (AAP) published an updated guideline for the treatment of ADHD in children and adolescents (4 to 18 years).43 Although recommendations for adults with ADHD are not included in the AAP guideline, relevant information related to abuse, misuse, and diversion in adolescents that may be extrapolated to adults is included in this report.

The AAP guideline states that adolescents 12 through 17 years of age 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 or misuse of ADHD medications should be assessed by monitoring symptoms and new prescription requests. Note that stimulants may be misused or diverted by parents or classmates. Most states require the participation of prescribers in prescription drug monitoring programs that may help identify and prevent diversion activities. In the State of Utah, the Utah´s Controlled Substance Database Program (CSD) 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 help identify potential drug overutilization, misuse, and overprescribing of controlled substances in Utah.87 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.42

The 2019 Updated European Consensus Statement and the 2018 Canadian ADHD practice guideline recommend long-acting stimulant formulations as first-line treatments for adults with ADHD because of several reasons including their lower abuse potential.41,46 Table 3 describes key recommendations from clinical practice guidelines with regards to stimulant abuse, misuse, and diversion in children, adolescents, and adults.

Table 3. Clinical Practice Guideline Recommendations on Abuse, Misuse, and Diversion of Stimulants Organization/Guideline Recommendations to Minimize Abuse, Misuse, and Diversion American Academy of Pediatrics Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents; October 201943 Supplemental information from the AAP (Algorithm)42 (This guideline is specific for children and adolescents)

Adolescents (12-17 years of age): - Evaluate patients for symptoms of substance use and referred to a

subspecialist - Monitor symptoms and prescription refill requests - Use a drug monitoring program (eg, Utah´s Controlled Substance

Database Program) - Use non-stimulants or stimulants formulations with less abuse or

diversion potential (ie, OROS methylphenidate, methylphenidate transdermal patch, or lisdexamfetamine)

21

Table 3. Clinical Practice Guideline Recommendations on Abuse, Misuse, and Diversion of Stimulants Organization/Guideline Recommendations to Minimize Abuse, Misuse, and Diversion European Network Adult ADHD (ENAA) Updated European Consensus Statement on diagnosis and treatment of adult ADHD; 201946 (This guideline is specific for adults)

- Stimulants are first-line medication for adults with ADHD. Long-acting, extended release formulations are preferred for several reasons including the less risk of abuse

- OROS methylphenidate and lisdexamfetamine have lower abuse potential than SA formulations. SA formulations should be avoided in patients with ADHD and SUD

- “The use of atomoxetine as first line in drug abusers continues to be debated with other experts preferring stimulants due to rapid onset and potentially greater effects”

International Collaboration on ADHD and Substance Abuse (ICASA) consensus group International Consensus Statement on diagnosis and treatment of substance use disorders with comorbid ADHD; 201888 (This consensus is specific for adults)

- Treatment should be considered for both ADHD and SUD - Combination of psychotherapy and pharmacotherapy is

recommended - LA methylphenidate, ER amphetamines, and atomoxetine are

effective in the treatment of comorbid ADHD and SUD. For some patients, up-titration to higher dosages may be considered

- LA formulations, particularly OROS methylphenidate and lisdexamfetamine, have lower rates of misuse and diversion in comparison to SA formulations

Canadian ADHD Resource Alliance (CADDRA) Canadian ADHD Practice Guidelines, Fourth Edition; 201841 (This guideline is specific for patients ≥ 6 years of age)

- Screen for concurrent psychiatric and medical issues such as SUD - LA psychostimulants are recommended first-line in all age groups

(patients ≥ 6 years of age). Reasons include SA stimulant formulations have a much greater risk of misuse or diversion than LA stimulant formulations due to their PK profile and easy crushability

- The abuse potential of “pro-drug, osmotic pump and beads delivery systems” is significantly decreased compared to SA formulations due to their specific delivery systems

National Institute for Health and Care Excellence (NICE)

Attention deficit hyperactivity disorder: diagnosis and management (NG87; March 2018)44 (This guideline is specific for children, adolescents, and adults)

- Baseline risk evaluation for substance misuse and drug diversion - Monitor changes in stimulant abuse, misuse, and diversion - Avoid SA stimulant formulations and LA stimulant formulations that

“can be easily injected or insufflated if there is a risk of stimulant misuse or diversion”

- “Be cautious about prescribing stimulants for ADHD if there is a risk of diversion for cognitive enhancement or appetite suppression”

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; 201436 (This guideline is specific for children, adolescents, and adults)

- Baseline risk evaluation for potential substance misuse and drug diversion

- LA formulations have reduced risk for recreational abuse - Atomoxetine is considered first-line treatment in patients with SUDs.

ER methylphenidate or lisdexamfetamine are second-line. Bupropion is considered third-line

22

Table 3. Clinical Practice Guideline Recommendations on Abuse, Misuse, and Diversion of Stimulants Organization/Guideline Recommendations to Minimize Abuse, Misuse, and Diversion Institute for Clinical Systems Improvement (ICSI)

Diagnosis and Management of Attention Deficit Hyperactivity Disorder in Primary Care for School-Age Children and Adolescents; 201269 (This guideline is specific for school-age children and adolescents)

- Atomoxetine is recommended in patients with comorbid anxiety, sleep initiation disorder, substance abuse, or tics

American Academy of Child and Adolescent Psychiatry (AACAP)

Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder; 200740 (This guideline is specific for children and adolescents)

- Consider atomoxetine in patients with active substance abuse

Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ER, extended release; LA, long-acting; OROS; osmotic-release oral system; PK, pharmacokinetic; SA, short-acting; SUD, substance use disorder

Stimulant Formulations Most Commonly Abused, Misused, or Diverted

According to the 2015 Oregon Drug Effectiveness Review Project (DERP) report, comparative evidence in terms of abuse, misuse, and diversion is limited and mainly based on survey data.89 Two studies using 2002 and 2009 data from the National Survey on Drug Use and Health indicated that “lifetime nonmedical use” was more common with IR methylphenidate or dextroamphetamine compared with mixed amphetamine salts.89 Another survey suggested amphetamine/dextroamphetamine is the most frequently diverted ADHD prescribed medication among college students. The rate of diversion was similar between methylphenidate and ER methylphenidate.89 Table 4 includes the suspected relative abuse potential of each stimulant formulation as summarized by the review article of Harstad et al.1 Duration of action and formulation of medication were considered by Harstad et al to determine the susceptive relative abuse potential.1

Table 4. Stimulant Medications and Suspected Relative Abuse Potential1

Generic Brand Name Duration of

Action3-32,38,75,80 Suspected Relative

Abuse Potential1 Amphetamine-Based Products

Short Acting Stimulants Amphetamine tablet Evekeo 4-6 h

NRb Amphetamine tablet ODT Evekeo ODT 4-6 h Dextroamphetamine tablet and oral solution Dexedrine (DSC)

4-6 h Higha Dextroamphetamine oral solution ProCentra Dextroamphetamine tablet Zenzedi Dextroamphetamine/amphetamine tablet Adderall (DSC) 4-6 h Higha Methamphetamine tablet Desoxyn NR NRb

23

Table 4. Stimulant Medications and Suspected Relative Abuse Potential1

Generic Brand Name Duration of

Action3-32,38,75,80 Suspected Relative

Abuse Potential1 Long-Acting Formulations Amphetamine ER oral suspension Adzenys ER 10-12 h Lowa Amphetamine ER ODT Adzenys XR-ODT 10-12 h NRb Amphetamine ER oral suspension Dyanavel XR 10-12 h75 NRb Dextroamphetamine SR oral capsule Dexedrine Spansule 8 h Mediuma Dextroamphetamine/amphetamine ER capsule Adderall XR 8-12 h38 Mediuma Dextroamphetamine/amphetamine ER capsule Mydayis 12-16 h75 NRb Lisdexamfetamine capsule and chewable tablet Vyvanse 8-13 h Low a

Methylphenidate-Based Products Short Acting Formulations Dexmethylphenidate tablet Focalin 3-5 h Higha Methylphenidate oral solution and chewable tablet Methylin 3-5 h Higha

Methylphenidate tablet Ritalin 3-5 h Higha Long-Acting Formulations Dexmethylphenidate ER capsule Focalin XR 9-12 h Low a Methylphenidate ER capsule Adhansia XR NR NRb Methylphenidate ER capsule Aptensio XR ≤16 h NRb Methylphenidate ER tablet Concerta 8-12 h Low a Methylphenidate ER ODT Cotempla XR-ODT 10-12 h75 NRb Methylphenidate ER transdermal patch Daytrana 11-12 h Low a Methylphenidate ER capsule Jornay PM NR NRb Methylphenidate ER capsule Metadate CD 6-8 h38 Mediuma Methylphenidate ER tablet Metadate ER (DSC) 8 h38 Mediuma Methylphenidate ER chewable tablet QuilliChew ER NR NRb Methylphenidate ER suspension Quillivant XR 10-12 h75 Low a Methylphenidate ER tablet Relexxii 12 h NRb Methylphenidate ER capsule Ritalin LA 6-8 h75 Medium a Methylphenidate ER tablet Ritalin-SR (DSC) 8 h Mediuma Abbreviations: DSC, brand discontinued; ER, extended release; FDA, United States Food and Drug Administration; NR, not reported a Information extracted from Table 1 of the article by Harstad et al (2014): Attention-Deficit/Hyperactivity Disorder and Substance Abuse. b Information not reported in the review article of Harstad et al (2014)

Stimulant Effects

Safety outcomes associated with NMU: Self-reported safety data collected by surveys and questionnaires showed that prescription stimulant NMU can cause headache, stomach ache, irritability, feeling sad, reduced appetite, sleep difficulties, and dizziness among university students.51 These effects were similar to those reported in clinical trials. The incidence of adverse events was slightly greater among individuals holding their own prescription compared to those using stimulants without prescription.51

24

The National Institute on Drug Abuse states that repetitive misuse of prescription stimulants, even for short periods of time, may lead to psychosis, anger, or paranoia. The most common prescription stimulant overdose reactions include “restlessness, tremors, overactive reflexes, rapid breathing, confusion, aggression, hallucinations, panic states, abnormally increased fever, muscle pains and weakness.”90 Other symptoms include irregular heartbeat and blood pressure, and neurological impairment. An overdose may lead to a heart attack, seizures, coma, and fatal poisoning.90

Medical outcomes of NMU of prescription stimulants: Data derived from the Drug Abuse Warning Network (DAWN) showed that the number of emergency room (ER) visits by adults associated with NMU increased from 5,212 to 15,585 from 2005 to 2010 while visits by children remain unchanged. National Survey on Drug Use and Health (NSDUH) and DAWN data from 2006 to 2011 indicated an increase in amphetamine-related ER visits by 67% and 156%, respectively. Regarding ER visits involving methylphenidate, a decrease or no changes were observed among adolescents. A study concerning amphetamine abuse among adults and adolescents whom called poison control centers reported higher rates of admission to health care centers in the group of amphetamine abusers compared to amphetamine non-abusers. Among amphetamine abusers, 50% were admitted to a critical care unit.51

Analyses from regional and national databases reported that approximately 35% of amphetamine and methylphenidate NMU exposures in adolescents were related to clinically significant effects. The frequency of these effects increased from 30% in 1998 to 43% in 2005, as per poison control center calls by adolescents. There is a higher risk of adverse medical outcomes in amphetamine abusers compared to non-abusers, according to poison control center data for adults and adolescents. Risk increases dependent on the route of administration. The probability of dying was higher for people abusing the stimulant intravenously (1.2%), followed by those administering the stimulant nasally (0.2%), compared to non-abusers. In addition, mean numbers of adverse medical outcomes were higher for intravenous administration, followed by nasal administration, oral administration, and lastly non-abuser administration.51

Academic outcomes: Improving academic achievement is a frequently reported reason for stimulant NMU; however, evidence does not suggest that stimulant NMU improves academic performance among individuals without a diagnosis of ADHD.51 An observational study using self-administered surveys followed US high school seniors from adolescence (age 18) to adulthood (age 35). Results indicated that adolescents reporting NMU of prescription stimulants at age 18 were at higher risk of lower educational achievement (eg, a college degree) in adulthood (age 35), compared to others (eg, adolescents who medically used prescription stimulants or did not use stimulants for ADHD).51,86 On the other hand, an appropriate use of prescription stimulants for ADHD during adolescence was not related to lower educational achievement in adulthood.51,86 A 2-year study including undergraduate students without ADHD showed that GPAs were significantly higher for students who did not report NMU but not for students reporting NMU.51

Measures to Minimize Nonmedical Use and Diversion of Prescription Stimulants

Faraone et al describes evidence regarding potential methods to decrease NMU of stimulants:51

Educational interventions regarding stimulant NMU and diversion by adolescents: Colaneri et al (2016) developed and sent a survey to US pediatricians (child and adolescent psychiatrists, child neurologists, and developmental-behavioral pediatricians) regarding education strategies on misuse and diversion of

25

stimulants by high-school students with ADHD.52,91 Survey results showed that less than 50% of pediatricians educated adolescents with ADHD “often” or “very often” on health and legal concerns related to stimulant misuse and diversion.51,91 Around 40% of pediatricians did not provide counselling concerning stimulant misuse and diversion and diversion to pre-college students with ADHD.51,52 Although most pediatricians did not often report implementation of educational strategies when NMU or diversion was suspected, 79% and 72% of physicians reported prescribing “often or very often” long-acting stimulants instead of immediate-release formulations and non-stimulants, respectively, to reduce the risk of stimulant misuse or diversion in individuals with suspected misuse or diversion.52 More than 70% of physicians considered prescription of non-stimulants as a “very effective” strategy for preventing misuse and diversion. Prescribing long-acting stimulants were regarded as a “very effective” prevention practice by 35% of physicians. Other less frequently employed prevention strategies were perceived as less effective by physicians. These include medication contracts (“…written agreements between a physician and patient that commit the patient to adhering to a specified treatment plan and medication regimen”), printed educational materials to highlight legal and health risks associated with misuse and diversion, restricting the number of pills per prescription to a one month supply, pill count to control treatment adherence, and referral to drug counselling or substance abuse treatment. Particularly, medication contract and printed materials were reported as rarely utilized by physicians. Evidence regarding the effectiveness of these prevention measures is very limited and the majority of physicians believe that most prevention measures are not very effective.52 Nevertheless, Colaneri et al encouraged physicians to incorporate prevention measures in their clinical practice that may prevent adolescents from misusing or diverting stimulants. In addition, authors encouraged physicians to keep abreast with research on stimulant NMU and check educational resources at the National Institute on Drug Abuse (NIDA) and the Substance Abuse and Mental Health Services Administration (SAMHSA) websites.52

Challenging expectancies for school performance improvement: Students believe that stimulants are effective to increase concentration and alertness. A randomized controlled trial in college students at risk for NMU showed that students who received an educational intervention experienced a change in their perspective on prescription stimulant effects and ultimately this group of students reduced their use of stimulants temporarily. However, NMU was similar among intervention group and control group after 6 months.51,92 Another short-term study reported that students reading evidence regarding the negative effects of stimulants on health and academic performance were less willing to use stimulants.51

Asking college students about diversion activities: A study showed that college students were less eager to use stimulants if the health provider posed questions about their diversion activities.51

Other potential prevention measures include institutional policies addressing stimulant NMU and performance or symptom validity tests to differentiate between false and real ADHD. Evidence on these issues is very limited. Faraone et al suggested that stimulant NMU for cognitive improvement as a form of “academic dishonesty” may prevent its NMU among academic institutions; however, this issue has not been appropriately investigated to date.51 In addition, authors mentioned that modifying the culture of high academic expectations may reduce the NMU of stimulants for cognitive enhancement.51

The Canadian document “Abuse and Diversion of Controlled Substances: A Guide for Health Professionals” describes some strategies to minimize drug diversion and abuse. Strategies for the practitioner include (a) identify the patient, if unknown to the practitioner, (b) “verify the presenting complaint and observe for drug abuse behavior, (c) ask the patient if they have received any controlled

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substance in the last 30 days from another prescriber, (d) talk to the patient’s regular practitioner or family practitioner, (e) use safe prescribing strategies, (f) implement a treatment contract with the patient” that includes information about the rules for prescriptions, amount prescribed, no early refills, and penalties for breaking the contract, (g) “reassess the patient at appropriate intervals, (h) prevent prescription forgery, (i) prevent telephone methods, (j) keep drugs and prescription pad out of sight, and (k) use caution when distributing professional samples.”93 Strategies for the pharmacist include (a) “examine the prescription to ensure its authenticity, (b) identify the patient, (c) talk to the patient, (d) contact the practitioner directly to verify the prescription, (e) install a private telephone line for telephone prescriptions, (f) Provide adequate security for the storage of controlled substances, and (g) keep records of all receipts and disbursements and check inventory regularly.”93

Concomitant Use of Two or More 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.”41

The 2019 American Academy of Pediatrics guideline, the 2018 Canadian guideline, the 2018 NICE guideline, published articles, and information from ADHD organizations mention possible scenarios where concomitant use of 2 stimulant products (eg, LA plus SA products) may be suitable for patients with ADHD41-44:

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 a shorter duration of action than the mean, dosing should be tailored to the individual’s response/experience.41

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 ADHD treatment and constitutes acceptable use.36,41,43,44,80 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)36,41,44 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.41,44

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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.77

C) Two stimulants from different classes

The Children and Adults with Attention-Deficit/Hyperactivity Disorder (CHADD) organization states that “…if one family of stimulants does not improve ADHD symptoms, the practitioner can try a different type. Because MPH and AMP have different mechanisms of action, combining MPH and AMP may be useful in a person who does not respond to either type alone.”95

Currently, no guideline, consensus, or expert panel offers recommendations concerning concurrent use of 2 or more long-acting stimulant formulations or 2 or more short-acting stimulant formulations in adults.

Concomitant Use of Stimulants With Benzodiazepine/Non-benzodiazepine Hypnotics Faraone et al (2019) reported that adults, adolescents, and college students commonly utilize stimulants with alcohol (64% of people), tranquilizers/sedatives (9%), and pain relievers (2%).51 This section focuses on the use of stimulants with agents FDA-approved for insomnia (ie, benzodiazepine and non-benzodiazepine hypnotics) in patients with ADHD and sleep disturbances.

Insomnia and Clinical Practice Guideline Recommendations

Insomnia is defined by the 3rd edition of the International Classification of Sleep Disorders (ICSD-3) as “…a complaint of trouble initiating or maintaining sleep which is associated with daytime consequences and is not attributable to environmental circumstances or inadequate opportunity to sleep.”96 Insomnia is categorized as affecting the onset of sleep, maintenance of sleep, or involve early awakening. Insomnia is considered to be chronic when symptoms are noted for at least 3 times a week during at least 3 months. Symptoms not meeting this threshold constitute short-term insomnia.96 Chronic insomnia is associated with reduced functional status, productivity, and quality of life.96 In older adults, complaints of sleep maintenance disturbances are more common than sleep onset problems.97

The prevalence of occasional, short-term insomnia in the general population is approximately 30% to 50%. Around 5% and 10% of the population suffers from chronic insomnia.96 Insomnia may be precipitated by, or comorbid with, other psychiatric disorders (eg, anxiety, depression, and bipolar disorder).56 It is important to adequately assess patients for these underlying disorders and treat them, which may help improve the insomnia complaint. Nonetheless, treatment of an underlying disorder may not fully attenuate the patient’s insomnia.56 In the presence of comorbidities, clinicians should evaluate which condition to manage first (insomnia, comorbid condition, or both at the same time). Several over-the-counter (OTC) and prescription medications (eg, stimulants such as amphetamine and methylphenidate; antidepressants such as fluoxetine; and decongestants such as pseudoephedrine) can additionally contribute to sleep problems.56,98 The use, dosage, and timing of these medications should be assessed.56

Pharmacotherapy is used alone or in combination with cognitive behavioral therapy for treatment of insomnia (CBT-I).96 The decision to initiate of pharmacotherapy depends on many factors including a

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thorough evaluation of the patient’s sleep history, bed-time routine/environment, symptoms, medical and psychiatric history, and potential sleep-interfering medications, diet, substance-use disorders, or exposure to blue-light from technology devices.96 The 2017 American Academy of Sleep Medicine (AASM) guideline recommends the following agents for the treatment of chronic insomnia in adults: benzodiazepines (temazepam and triazolam), benzodiazepine receptor agonists (eszopiclone, zolpidem, zaleplon), melatonin agonists (ramelteon), the tricyclic antidepressant doxepin (low-dose form), and the orexin receptor antagonist suvorexant.96 Each of these treatment options received a weak strength of recommendations with choice of therapy dependent on the prescriber’s clinical judgment.96 Other OTC and prescription medicines used for treatment of insomnia include diphenhydramine, melatonin, tiagabine, trazodone, l-tryptophan, and valerian. These agents are recommended against for treating insomnia in adults, received a weak strength of recommendation against use from AASM who recommends clinical judgement to determine appropriate use considering patient-specific factors.96 No recommendations regarding efficacy were made for other benzodiazepines with FDA approval for the treatment of insomnia (estazolam, flurazepam, and quazepam) due to methodological limitations of efficacy studies.

The 2016 American College of Physicians guideline for the management of chronic insomnia strongly recommends CBT-I as first-line therapy for all adults with chronic insomnia.97 Low- to moderate-evidence suggested that eszopiclone, zolpidem, and suvorexant improved global and sleep outcomes in the general adult population. Evidence was insufficient to determine the benefits of therapy with benzodiazepines (temazepam, triazolam, flurazepam, or quazepam) in the general population or in older adults with chronic insomnia.99

The FDA recommends use of benzodiazepine and nonbenzodiazepine hypnotics at the lowest effective dosage on a short-term basis for the treatment of insomnia.97,100,101

Benzodiazepines

Benzodiazepines are used as anxiolytics, sedatives, hypnotics, anticonvulsants, and skeletal muscle relaxants for multiple conditions including management of anxiety disorders (eg, preoperative anxiety, generalized anxiety, and panic disorder), procedural sedation, induction and maintenance of anesthesia, treatment insomnia, management of epilepsy (eg, status epilepticus, acute repetitive seizures, seizure clusters, and prophylaxis of epilepsy as adjunct therapy), agitation associated with acute alcohol withdrawal, skeletal muscle spasticity, schizophrenia (as monotherapy or adjunct therapy), cancer chemotherapy-induced nausea and vomiting (as monotherapy or adjunct therapy), and delirium (as monotherapy or adjunct therapy).38 Five benzodiazepines are FDA approved for treatment of short-term insomnia (triazolam, estazolam, temazepam, flurazepam, and quazepam); these 5 agents do not have any additional FDA-approved indications aside from insomnia. Table 5 lists the various benzodiazepines by duration of action. Table 1 of Appendix E includes a table comparing benzodiazepine characteristics.

All benzodiazepine agents enhance the binding of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter, to the GABA-A subtype of GABA receptors, resulting in GABAergic neurotransmission.102,103 All benzodiazepine agents exert similar clinical effects. Differences in their pharmacokinetic profiles, such as rate of absorption, elimination half-life and lipid solubility, contribute to varying patterns of therapeutic application by influencing onset and duration of action.102,103

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Table 5. Duration of Action of Benzodiazepines104,105 Short-acting Intermediate- acting Long-acting Midazolam Alprazolam Clorazepate Triazolam Estazolam Clonazepam Lorazepam Diazepam Oxazepam Flurazepam Temazepam Quazepam Chlordiazepoxide (alone or in combination

with amitriptyline or clidinium) Benzodiazepines highlighted in bold are FDA approved for insomnia

The most common adverse reactions associated with benzodiazepine use include blurred vision, confusion, drowsiness, dizziness, decreased alertness or concentration, euphoria, lack of coordination, nausea, nightmares and sexual effects (decreased libido). Hypotension and suppressed breathing have been reported with intravenous use.106,107 Long-acting benzodiazepines can accumulate increasing the risk of dizziness, confusion, hypotension, and cognitive impairment. Populations at higher risk include the elderly, children, patients with a history of substance abuse, patients on high doses or on long-term use, patients with concurrent opioid and benzodiazepine use or polydrug use, patients with kidney or liver failure, and patients with bipolar disorder.

Benzodiazepines are Schedule IV controlled substances with high potential for abuse. Misuse and abuse is a problem with both benzodiazepines and stimulants, and may result from prescription sharing (using it for a non-prescribed purpose) or other intentional abuse through doctor shopping, fraudulent prescriptions, or obtainment through drug dealers (street drugs or prescription drugs).108-111 When abused, patients become dependent on the misused drug which may result in adverse sequela including overdose. Nonetheless, benzodiazepines may also be prescribed intentionally to treat a possible comorbid condition as mentioned above; thus, not all co-prescribing of stimulants and benzodiazepines can be automatically assumed as inappropriate.

Non-benzodiazepine, Non-barbiturate Hypnotics

Non-benzodiazepine hypnotics are FDA approved for insomnia (eg, sleep onset insomnia and sleep maintenance insomnia). The Z-drugs eszopiclone, zolpidem, and zaleplon are benzodiazepine receptor agonists that interact with GABA-A receptors causing sedation effects.112 Zolpidem and zaleplon bind more selectively to alpha-1 subunit than benzodiazepines. Eszopiclone non-specifically binds to GABA-A subtypes, but is thought to have higher affinity for alpha 1 and 2 subunits than benzodiazepines.112 Compared to benzodiazepines, non-benzodiazepine hypnotics are thought to produce less residual effects, tolerance, and dependence.112 Doxepin is a tricyclic antidepressant. Its sedating effect is thought to be mediated through its antagonist action of histamine-1 receptors.113 Ramelteon has high affinity for melatonin receptors MT1 and MT2, activating a pathway involved in maintenance of circadian rhythm.114 Suvorexant is an orexin receptor antagonist that inhibits the binding of wake-promoting neuropeptides (orexin A and B) to orexin receptors OX1R and OX2R, suppressing wakefulness.115 Table 6 lists the non-benzodiazepine, non-barbiturate hypnotics by mechanism of action. Table 2 of Appendix E compares the recommended non-benzodiazepine hypnotics for chronic insomnia according the 2017 AASM guideline with the FDA-approved indication for these agents.

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Table 6. Non-benzodiazepine, Non-barbiturate Hypnotics Benzodiazepine receptor agonists Tricyclic antidepressant Melatonin receptor

agonist Orexin receptor antagonist

Eszopiclone Low-dose form of doxepin Ramelteon Suvorexant Zaleplon Zolpidem

Label precautions for the non-benzodizepine hypnotics include warnings for (a) potential risk of abnormal thinking (eg, hallucinations), behavioral changes, decreased inhibition, complex sleep behaviors (eg, sleep-driving and sleep-walking), or worsening of depression; (b) CNS-depressant effects and/or day-time somnolence; and (c) additive effects with other CNS depressants. While labeling warns of dependence and possible withdrawal upon abrupt discontinuation with eszopiclone and zolpidem some studies have suggested that use of eszopiclone up to six months was not associated with increased tolerance or withdrawal.112,116,117 Withdrawal is not known to be a problem with zaleplon.118,119 Doxepin, ramelteon, and suvorexant are also not known to induce physical dependence or withdrawal symptoms.113-115

Managing Sleep Problems in Patients With ADHD

Sleepiness alters one’s capability to pay attention and may result in caffeine consumption to stay awake.42 Additionally, sleep problems can cause symptoms and impairment that simulate or aggravate ADHD symptoms.42 The timing of the adverse effect is important to determine whether the effect is caused by the stimulant medication (eg, overstimulation), rebound of ADHD symptoms (eg, racing thoughts) because the stimulant effect wore off, environment in which the patient sleeps, or a coexisting condition (comorbid sleep disorder or comorbid psychiatric disorders such as anxiety).42,120

Overall, it is suggested that clinicians cautiously monitor sleep problems and titrate ADHD treatment (medication type and dosage) to promote optimal sleep and reduce medication-induced sleep problems.

Specific treatment strategies in patients with ADHD and sleep problems that can be modified from alteration of the stimulant are the focus of clinical practice guidelines. Nonetheless, guidelines have very limited information addressing ADHD with comorbid insomnia that is non-medication induced.

Table 7 describes guideline recommendations for managing sleep disturbances in patients with ADHD. The 2019 AAP clinical practice guideline for the treatment of ADHD is specific for children and adolescents. This guideline defines comorbid conditions in patients with ADHD that may include learning problems, language disorder, disruptive behavior, anxiety, mood disorders, tic disorders, seizures, autism spectrum disorder, developmental coordination disorder, and sleep disorders.43 Guideline authors recommend a thorough assessment to identify both ADHD and comorbid conditions.43 Initiation of pharmacotherapy for ADHD in the presence of comorbidities includes concurrent initiation of treatment, or treatment directed first to either address ADHD or the comorbidity.41 Guidelines recommend 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

Stimulant pharmacodynamics (eg, duration of action) are an important consideration for patients that experience problems with sleep initiation. The 2019 AAP supplemental algorithm contains information on the comprehensive diagnostic evaluation for ADHD and comorbid conditions in children and adolescents.42 The evaluation and other considerations suggested by the algorithm would help clinicians determine if sleep difficulties constitute a diagnosis of insomnia (primary sleep disorder such as

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obstructive sleep apnea syndrome and restless legs syndrome), are related to ADHD treatment, or other motives. Children and adolescents with ADHD may experience sleep problems for several reasons:

1) Inadequate sleep hygiene (eg, variable bedtimes and wake time, lack of bedtime routine, use of electronics at bedtime, and use of caffeine)

2) ADHD medication effects including direct effects (extended sleep onset, reduced sleep duration, and increased night awakenings) and indirect effects (eg, rebound symptoms due to inappropriate control of ADHD symptoms in the evening)

3) Comorbid psychiatric conditions (i.e. anxiety, mood disorders, and disruptive behavior disorders)

4) “Circadian-based phase delay in sleep-wake patterns,” which leads to prolonged sleep onset and waking problems in the morning

5) Intrinsic deficit related to ADHD. Studies have shown that untreated children with ADHD and absence of comorbid mood or anxiety have significantly higher bedtime resistance, more sleep onset problems, and more recurring night waking in comparison to “typically developing children in control groups.” Additionally, some ADHD children with or without a primary sleep disorder may experience daytime somnolence.42

Some treatment strategies from the AAP algorithm to improve sleep include adjusting behavior before and at bedtime and changing timing and dosage of stimulant medication.42

The 2018 CADDRA guideline, which includes recommendations for patients 6 years and older, suggests administering ADHD medication as soon as possible in the morning or using a shorter acting agent in patients with stimulant-related insomnia.41

The Institute for Clinical Systems Improvement (ICSI) for the management of ADHD in primary care for school-age children and adolescents recommends to administer the stimulant dose earlier in the day, discontinue afternoon/evening dose, change to short-acting preparation, or consider alternative or adjunctive medications (eg, atomoxetine, clonidine).

In 2011, the European Network for Hyperkinetic Disorders (EUNETHYDIS) guideline for managing adverse effects of medications for ADHD was published. 121 Cortese et al. conducted a review to update these guidelines and provide a summary document for the practical implementation of the guidelines.122 Management of sleep disturbances in patients receiving ADHD treatment is recommended as follows:

1) Review nature and history of sleep disturbance and efficacy of medication. “Sometimes medication can be reduced or stopped; more intensive behavior therapy may achieve good results for ADHD control even without medication.”122

2) If medication is continued, proper sleep hygiene and behavior techniques (eg, adjust bedtime, discourage use of TV or telephone in bed, avoid caffeinated drinks) should be encouraged

3) If behavioral measures do not resolve sleeping problems, clinicians should evaluate the likely cause of insomnia:

a. Restless leg syndrome (monitor ferritin levels in the evening and consider iron supplementation if necessary) and “periodic limb movements of sleep.”122 Up to 44% of patients with ADHD have restless leg syndrome.123

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b. If there is a rebound effect when the ADHD medication effect wears off, the addition of a small dose of short-acting stimulant in the evening should be considered

c. If stimulant action persists:

- Consider decreasing stimulant dose in the evening or switching to a shorter-acting preparation

- If the clinician, family of patient do not support switching to another stimulant class or formulation, melatonin may be added because it reduces the sleep-onset delay linked to methylphenidate

- Consider switching to a non-stimulant medication (atomoxetine given once daily in the evening or guanfacine).122

The aforementioned clinical practice guidelines do not include benzodiazepines or non-benzodiazepine hypnotics as a treatment option in patients with ADHD and sleep disturbances.

The FDA prescribing information for 2 methylphenidate-based products (Methylin and Ritalin) recommends patients with sleep difficulties who take stimulant medication late in the day to administer the last dose before 6 pm.27,31

UpToDate includes recommendations only for children and adolescents. No specific recommendations are available for adults. UpToDate suggests implementing sleep habits as first-step in children and adolescents. Adjusting the dose, time of administration, or formulation of stimulant may be considered as a second step. Switching to a non-stimulant formulation is an option if adjusting stimulant therapy fails. If the aforementioned steps fail, adding a hypnotic (eg, melatonin, clonidine, guanfacine, or non-benzodiazepine receptor agonists) may be considered. Non-benzodiazepine receptor agonists (eg, zolpidem, eszopiclone) are efficacious in adults with insomnia; however, some trials have shown a lack of efficacy and the occurrence of adverse events in children with ADHD-related insomnia.120

Literature Evidence Concerning Management of ADHD and Sleep Problems in Adults

A 2018 systematic review by Instanes et al124 reported evidence regarding adults with ADHD and sleep problems. Authors reported that 80% of adults with ADHD had sleep problems, as stated in a 2014 study. Sleep problems may occur in untreated ADHD adults as well as those receiving stimulants. Approximately 37% of adults with ADHD suffer daytime sleepiness that may predict “academic and overall functional impairment among students with ADHD." Insomnia is a common comorbidity in patients with ADHD, with sleep-onset insomnia the most challenging sleep problem.124 Sleep-onset insomnia is an adverse event that often accompanies initiation of stimulant therapy.124 Authors suggest the following strategies for the management of adults with sleep problems and ADHD:124 (a) screening for sleep disorders and sleep patterns before initiating treatment for ADHD to track any change, (b) administer adequate treatment for the comorbid sleep disorder in addition to ADHD treatment because this may improve ADHD symptoms, (c) if the patient experiences sleep problems while on treatment for ADHD, it is recommended to try sleep hygiene, reduction of stimulant treatment in the late afternoon, addition of a small dose of stimulant earlier in the evening, or switching to a non-stimulant. Sleep disturbance as an adverse event of stimulants decreases after 1 to 2 months of treatment. In adults with ADHD and delayed sleep phase syndrome, stimulants can be combined with melatonin, bright light therapy, and good sleep hygiene. This SR did not mention or evaluate the use of FDA-approved

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treatments for insomnia (eg, benzodiazepine or non-benzodiazepine hypnotics) as a treatment option in patients with ADHD and sleep disturbances.124

Snitselaar et al (2017), was a literature review addressing the effects of stimulants in adults with ADHD and sleep or circadian rhythm problems.125 ADHD in adults is linked to “longer objectively measured sleep onset latency, disrupted sleep maintenance, later wakening up times, and no change in total sleep time.”125 Results from selected studies regarding the effect of stimulants on sleep parameters were inconsistent and no answer as to whether stimulants increase or decrease sleep onset latency or sleep maintenance, or help with waking-up in the morning was found.125

Schneider et al (2014) was a literature review addressing the management of risks related to ADHD treatments.126 Authors reported that it is a challenge to distinguish between insomnia related to prolonged stimulant effects and insomnia related to a rebound effect (ie, emergence of ADHD symptoms when the stimulant effect wears off). Strategies to manage insomnia as a side effect of stimulant medication include education concerning adequate sleep hygiene as the first-line approach. If sleep problems do not improve, switching to another stimulant (eg, a short acting formulation if the long-acting formulation is causing side effects) or to a non-stimulant product may be considered. Adding a dose of a short-acting stimulant later in the day may prevent from a rebound effect. Melatonin, trazodone, clonidine, or antihistamines can additionally help with insomnia;126 however, these agents are recommended against or not included in the 2017 AASM guideline that addresses chronic insomnia treatment in the adult population since other agents have better evidence supporting their use.96

Table 7. Clinical Practice Guideline Recommendations for the Management of Insomnia in Patients with ADHD

Organization/Guideline Recommendations for the Management of Sleep Problems in Patients with ADHD

American Academy of Pediatrics Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents; October 201943 Supplemental information from the AAP (Algorithm)42 (This guideline is specific for children and adolescents)

The AAP guideline does not include recommendations for treatment of ADHD- or stimulant-related insomnia The supplemental information from the AAP (algorithm) states: - If sleep disturbances are caused by stimulant medication

or regular caffeine consumption, “simple modifications of timing and dosage of stimulant consumption can improve sleep onset, duration, and quality.”42

- Sleep disturbances can occur from inappropriate sleep health and/or hygiene or from other disorders (eg, anxiety and mood disorders). Restructuring behavior before and at bedtime can improve sleep

Canadian ADHD Resource Alliance (CADDRA) Canadian ADHD Practice Guidelines, Fourth Edition; 201841 (This guideline is specific for patients ≥ 6 years of age)

Treatment recommendations: - First-line treatment: Behavioral interventions for sleep

problems in patients with ADHD - Melatonin For stimulant-related insomnia, this guideline suggests administering medication as soon as possible in the morning or use of a shorter acting agent

National Institute for Health and Care Excellence (NICE)

Attention deficit hyperactivity disorder: diagnosis and management (NG87; March 2018)44 (This guideline is specific for children, adolescents, and adults)

Patients should be monitored for sleep changes (eg, sleep diary) and medication should be tailored accordingly

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Table 7. Clinical Practice Guideline Recommendations for the Management of Insomnia in Patients with ADHD Institute for Clinical Systems Improvement (ICSI)

Diagnosis and Management of Attention Deficit Hyperactivity Disorder in Primary Care for School-Age Children and Adolescents; 201269 (This guideline is specific for school-age children and adolescents)

Management of insomnia related to stimulant use: - “Low-stress “wind-down time” after school - Administer dose earlier in day - Discontinue afternoon/evening dose - Change to short-acting preparation - Consider alternative or adjunctive medications (eg,

atomoxetine, clonidine, antidepressants)” European Network for Hyperkinetic Disorders: The European ADHD Guidelines Group

The European guidelines on managing adverse effects of medications for ADHD (2011)121

(This guideline is specific for children, adolescents, and adults)

Management of sleep problems: - Due to limited evidence and contradictory findings,

guidelines for the treatment of sleep problems related to ADHD cannot be adequately evidence based

- If severe/significant sleep problems, atomoxetine is suggested as first line

- If medication-related sleep problems, sleep diaries are recommended

- In children with sleep-onset problems and/or possible delayed sleep phase syndrome, sleep hygiene and behavior therapy based on stimulus control, and adequate bedtime scheduling should be encouraged

- If sleep problems persist following careful dose adjustment and dose scheduling of the original medication, switching should be considered (eg, patients may switch from stimulant medication to atomoxetine)

- Clonidine may be effective at improving sleep disturbances associates with ADHD

- Melatonin is effective at improving sleep-onset problems in children with ADHD

American Academy of Child and Adolescent Psychiatry (AACAP)

Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder; 200740 (This guideline is specific for children and adolescents)

The AACAP guideline does not include specific recommendations to treat ADHD- or stimulant-related insomnia. Some related statements include: - Atomoxetine may have less pronounced effects on sleep

compared to stimulants - Alpha-agonists (clonidine and guanfacine) have been

widely prescribed to treat some stimulant adverse effects such as insomnia

- Clonidine, trazodone, or antihistamine at low doses are often helpful for stimulant-induced insomnia

- Melatonin 3 mg has shown to be effective at improving sleep in children with ADHD receiving stimulants

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

Psychopharmacological treatment for very young children: contexts and guidelines; 2007127 (This guideline is specific for preschool-aged children)

PPWG developed a primary sleep disorder algorithm in patients with or without ADHD: - First step: parent education, sleep hygiene, behavioral

intervention for bedtime resistance and night wakings (for at least 2-4 weeks)

- Second step: melatonin for 10 days, if tolerated (treatment should be short-term)

- Third step: clonidine 30 minutes before bedtime (treatment should be short-term)

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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Safety Concerns Related to CNS Stimulant Use in Adults The most common short-term adverse events associated with stimulants are loss of appetite, increased heart rate and blood pressure, and reduced sleep.46 There is a lack of evidence regarding long-term safety with stimulants.46 Table 8 describes CNS stimulant adverse events associated with use of stimulants.

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.3-32 Signs of abuse and dependence should be evaluated before prescribing a stimulant and monitored during treatment.15

Cardiovascular risks

Sudden cardiac death, stroke, and myocardial infarction have occurred in adults with ADHD receiving stimulants at usual doses.15 In 2011, the FDA issued an FDA drug safety communication regarding cardiovascular events with the use of ADHD medications.128 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.128 Before prescribing a stimulant, clinicians should perform a physical exam and evaluate the patient’s cardiac history and family history for sudden death or ventricular arrhythmia.15,43

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 clinically significant increases.8,19,20 Blood pressure and heart rates should be monitored in all patients receiving stimulant therapy.8,19,20,43 Caution should be exercised in patients with underlying cardiovascular conditions such as pre-existing hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia.15

Psychiatric adverse reactions

Stimulant use may aggravate symptoms of behavioral disturbances and thought disorders in patients with a prior psychotic disorder.15

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.23 Treatment of bipolar disorder should be stabilized before the addition of ADHD therapy. In addition, stimulant use at usual doses can cause new psychotic or maniac symptoms (eg, hallucinations, delusional thinking, or mania) in children and adolescents with no prior history of psychotic disease or mania.15 Aggressive behavior may occur with the use of stimulants.15

Long-term suppression of growth

Suppression of growth with the use of stimulants has been reported in several studies including children and adolescents.15,43,129 Children receiving stimulant therapy should have height and weight monitored

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regularly using growth charts. Treatment may be discontinued if children are not growing as expected for their age.15

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.15

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.15

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.130 Signs of loss of skin pigmentation should be monitored.23

Monitoring requirements

Clinicians should regularly monitor blood pressure, pulse, height, weight, and signs of abuse and dependence in patients treated with stimulants.3-32 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.15 Certain patients may require evaluation by a rheumatologist if severe circulation problems in fingers and toes appear.32 Patients applying methylphenidate transdermal patch should be monitored for skin depigmentation.23,130

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Table 8. CNS Stimulant Adverse Events and Recommended Management69,75 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

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Utah Medicaid Utilization Data 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 Medicaid Adult Population Over the Last Year (February 1, 2019 to January 31, 2020)

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 stratified according to their age at the time the prescription claim was filled.

Utilization data for Medicaid FFS and ACO claims show that 6789 unique adult patients (≥ 18 years of age) had a prescription filled for an amphetamine- or methylphenidate-based product over the last year (February 1, 2019 to January 31, 2020).

B) Utilization Data Regarding Potential Stimulant Abuse, Misuse, and Dependence

Table 9 (FFS and ACO adult population) and Table 10 (FFS adult population only) describe the number of adult patients (≥ 18 years of age) who filled at least 1 prescription for a stimulant medication (short-acting or long-acting) over the last year and had an ICD-10 diagnosis code submitted for stimulant abuse, stimulant dependence, or poisoning by amphetamines or methylphenidate (including accidental poisoning) in the last 2 years (between February 2018 and February 2020). ICD-10 codes for stimulant abuse and dependence are not specific to prescription amphetamine and methylphenidate abuse and dependence; they additionally include other stimulants such as caffeine, methamphetamine, and other psychostimulants (excluding cocaine). According to DSM-5 and ICD10Data.com website, ICD-10 codes specific to stimulant dependence include diagnosis of amphetamine-type substance use disorders (moderate or severe), among others.85

Approximately 10% of total ACO and FFS patients and 14% of FFS patients received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse, dependence, or poisoning within the last 2 years. Remember that this percentage may include patients abusing or dependent on stimulants other than prescription amphetamines or methylphenidate products and the sequence of interacting claims is not specified. Most patients received Adderall (IR amphetamine/dextroamphetamine), Adderall XR (ER amphetamine/dextroamphetamine), or Vyvanse (lisdexamfetamine) and had an ICD-10 code for stimulant abuse or stimulant dependence either up to 2 years before the prescription claim or up to 1

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year after the prescription claim. It is unclear whether these patients received an abuse-related ICD-10 code while taking those agents or whether patients had an abuse- or dependence-related ICD-10 code while taking another stimulant and were switched to a stimulant with a lower risk of abuse. Appendix E includes complete tables showing stimulant product claim interactions with ICD-10 codes for stimulant abuse, stimulant dependence, and poisoning by stimulants. The list of ICD-10 codes is described in Appendix F.

Table 9. ACO and FFS Patients Who Received a Stimulant in the Past Year (February 2019 Through January 2020) and Had an ICD-10 Code Submitted Between February 2018 and February 2020 for Stimulant Dependence, Abuse, or Poisoning

Stimulant Dependencea

Stimulant Abuseb

Poisoning by Stimulantsc

Accidental Poisoning by Stimulantsd

Total for Dependence,

Abuse, or Poisoninge

Product Total Unique Pts

Receiving a Stimulant Over the Last Year

Unique pts

% of pts

Unique pts

% of pts

Unique pts

% of pts

Unique pts

% of pts

Unique pts

% of pts

SA or LA Stimulant(Amph or

Mph)

6789 440 6.5% 369 5.4% 18 0.3% 16 0.2% 683 10.1%

Abbreviations: ACO, Accountable Care Organization; Amp, amphetamine; FFS, fee-for-service; LA, long-acting; mph, methylphenidate; pts, patients; pts, patients; SA, short-acting a Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant dependence within the last 2 years. b Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse within the last 2 years. c Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for poisoning by amphetamine or methylphenidate within the last 2 years. d Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for accidental poisoning by amphetamine or methylphenidate within the last 2 years. e Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse, stimulant dependence, or poisoning by amphetamines or methylphenidate within the last 2 years.

Table 10. FFS Patients Who Received a Stimulant in the Past Year (February 2019 Through January 2020) and Had an ICD-10 Code Submitted Between February 2018 and February 2020 for Stimulant Dependence, Abuse, or Poisoning

Stimulant Dependencea

Stimulant Abuseb

Poisoning by Stimulantsc

Accidental Poisoning by Stimulantsd

Total for Dependence,

Abuse, or Poisoninge

Product Total Unique Pts

Receiving a Stimulant Over the Last Year

Unique pts

% of pts

Unique pts

% of pts

Unique pts

% of pts

Unique pts

% of pts

Unique pts

% of pts

SA or LA Stimulant(Amph or

Mph)

3156 287 9.1% 258 8.2% 11 0.3% 10 0.3% 454 14.4%

Abbreviations: Amph, amphetamine; FFS, fee-for-service; LA, long-acting; Mph, methylphenidate; pts, patients; pts, patients; SA, short-acting a Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant dependence within the last 2 years.

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b Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse within the last 2 years. c Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for poisoning by amphetamine or methylphenidate within the last 2 years. d Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for accidental poisoning by amphetamine or methylphenidate within the last 2 years. e Number of patients or percentage of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse, stimulant dependence, or poisoning by amphetamines or methylphenidate within the last 2 years.

C) Data Regarding Concurrent Use of Stimulant and Hypnotics

As stated in the “abuse, misuse, and diversion” section of the report, nonmedical users of stimulants commonly report concurrent use of tranquilizers/sedatives. We explored concurrent use of stimulants and medications FDA approved for insomnia (ie, benzodiazepines and non-benzodiazepine hypnotics). For patients with ADHD and sleep problems related to stimulant therapy, evidence suggests the implementation of different strategies (eg, sleep behavioral interventions, switch to a shorter acting stimulant formulation, change timing of administration, and use of non-stimulants) before taking additional medication for insomnia. These recommendations serve to optimize ADHD therapy and minimize adverse events. However, it is important to remember that patients with ADHD may have insomnia unrelated to stimulant therapy (eg, due to a comorbid psychiatric condition such as anxiety or a comorbid sleep disorder such as restless leg syndrome or periodic limb movements of sleep). The 2017 AASM guideline for insomnia does recommend benzodiazepine and non-benzodiazepine hypnotics for the treatment of adults with chronic insomnia.

Table 11 describes the number of patients with concurrent use of stimulants and hypnotics. Over the last year, data indicate that 704 ACO and FFS adult patients received a stimulant formulation and at least 1 benzodiazepine or non-benzodiazepine hypnotic within 30 days of the stimulant fill. We included only benzodiazepines approved for short-term treatment of insomnia (estazolam, flurazepam, quazepam, temazepam, and triazolam) and the controlled non-benzodiazepine hypnotics (eszopiclone, suvorexant, zaleplon, zolpidem). The most common combination of stimulant and hypnotic was any stimulant in combination with a non-benzodiazepine hypnotic, especially zolpidem. It should be noted that triazolam has some supportive evidence for off-label use prior to outpatient dental procedures.38 It is unclear if all patients are using these agents in Table 11 for insomnia or if some may be using any agent for an off-label condition; however, we think that the majority of use is for insomnia.

Table 11. ACO and FFS Patients with Concurrent Use of Stimulants and Hypnoticsa Benzodiazepine Hypnotics

Estazolam 0 Flurazepam 2 Quazepam 0 Temazepam 87 Triazolam 13

Non-benzodiazepine Hypnotics Eszopiclone 60 Suvorexant 12 Zaleplon 28 Zolpidem 547 Abbreviations: ACO, Accountable Care Organization; FFS, fee-for-service a Concurrent use of stimulants and hypnotics was defined as a patient filling a stimulant within the last year who also had a hypnotic filled within 30 days of the stimulant claim

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Discussion Topics for Developing Prior Authorization Criteria and Safety Edits Point of sale restrictions

• Monthly quantity limits in adults may be determined based on the FDA approved maximum daily doses for adults (as proposed in Table 2).

Points to consider to optimize ADHD care while decreasing abuse, misuse, and diversion of prescription stimulants:

• Clinicians should assess the risk for abuse prior to initiating stimulant therapy and evaluate any sign of abuse, misuse, dependence, and overdose regularly during treatment.

• The potential for abuse, diversion, or misuse of stimulants should be regularly assessed by monitoring symptoms and prescription refill requests. Encourage prescribers to use the Utah controlled substance database (CSD) program to identify and prevent potential drug overutilization, misuse, overprescribing, and diversion activities of stimulants and other controlled substances. Encourage prescribers to educate patients in terms of negative effects and legal penalties associated with stimulant abuse, misuse, and diversion.

• Patients with a history of substance abuse or at risk for stimulant abuse, misuse, or diversion may be treated initially with agents with no abuse potential (ie, non-stimulants) or transitioned to stimulant formulations with less abuse potential compared to other stimulants (eg, LA stimulant formulations, especially lisdexamfetamine and osmotic-release oral system methylphenidate).47

Combination therapy:

A) Concurrent use of 2 or more stimulants:

Consider requiring a PA for the following combination regimens, with the consideration that patients switching to a different agent may be caught as a false positive at the point-of-sale and may be required to submit a PA intended mainly for ongoing combination users:

• Two or more 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).

• Two or more 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).

• Two or more stimulants from different classes (eg, a methylphenidate-based formulation and an amphetamine-based formulation).

B) Concurrent use of a stimulant and a benzodiazepine or a non-benzodiazepine hypnotic:

The following strategies regarding management of ADHD and sleep problems are suggested in clinical practice guidelines and systematic reviews:

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• Ensure proper sleep hygiene, appropriate bed-time scheduling (establish a bedtime routine), and consider cognitive behavioral therapy for treatment of insomnia (CBT-I).

• If there is a rebound of ADHD symptoms, the addition of an SA formulation to an LA formulation when the LA formulation wears off may be considered

• If stimulant effect persists:

o Slowly reduce the dose or change the timing for taking the medication (eg, earlier in the evening). Ensure that the patient does not take a stimulant dose late in the day

o Switch to another methylphenidate or amphetamine formulation (eg, switch to a stimulant with a shorter duration of action [e.g. 12-hour duration to 8-hour duration])

o Switch to a non-stimulant

• If sleep problems persist despite implementing the above strategies, the addition of another medication to treat sleep problems is considered a last line approach. There is a lack of evidence regarding use of benzodiazepine and non-benzodiazepine hypnotics for sleep problems in patients with stimulant-related sleep problems. Guidelines do not promote these agents as alternative therapy.

• If sleep problems are caused by a comorbid sleep disorder (eg, restless leg syndrome, periodic limb movements of sleep, or insomnia), a systematic review in adults does recommend considering administration of adequate treatment for the comorbid sleep disorder. Guidelines do not discuss specifically the treatment of ADHD and comorbid insomnia per ICSD-3 diagnosis in adults. However, few guidelines address ADHD and sleep problems. The 2017 AASM guideline recommends the following agents for the treatment of chronic insomnia in adults: benzodiazepines (temazepam and triazolam), benzodiazepine receptor agonists (eszopiclone, zolpidem, zaleplon), melatonin agonists (ramelteon), the tricyclic antidepressant doxepin (low-dose form), and the orexin receptor antagonist suvorexant.96

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Summary Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder characterized by symptoms of inattention and/or hyperactivity-impulsivity. The average age of first onset of ADHD is 7 years, with more than 50% of children with ADHD continuing to experience symptoms into adulthood. The prevalence of ADHD in US adults is estimated to be 4.4%. This review specifically addresses concerns related to abuse, misuse, and diversion of stimulant medications, dose limits for stimulants, concurrent use of more than 1 stimulant, and concurrent use of stimulants with FDA approved medications for the treatment of insomnia in adults (benzodiazepine or non-benzodiazepine hypnotics).

CNS stimulants approved by the FDA for the treatment of ADHD include amphetamine- and methylphenidate-based products. All stimulants are FDA approved for use in pediatric patients with ADHD. Some of the medications are additionally approved in adults with ADHD. Monthly quantity limits in adults may be based on the FDA approved maximum daily doses for adults (as proposed in Table 2).

In 2016, the Centers for Disease Control and Prevention (CDC) reported that 2.1% of the US population aged 12 years and older misused prescription stimulants in the previous year, with highest rates of misuse reported in adults between 18 and 25 years old (7.5%). Overdose deaths involving psychostimulants with abuse potential (illicit drugs or prescription stimulants) increased by 37% from 2016 to 2017. Abuse and dependence cautions are included in the FDA black box warning in the prescribing information for all stimulants. People with or without a diagnosis of ADHD may abuse stimulants because of their euphoric effects, self-esteem enhancement effects, improvement in mental and physical performance, increase in activity, loss of appetite, wakefulness for longer periods, and recreational effects (ie, to “get high”). Some measures that clinicians may implement or consider to minimize abuse, misuse, or diversion of stimulants may include:

1. Assessment of risk for abuse prior to initiating stimulant therapy and regular monitoring for signs of abuse, misuse, dependence, or overdose during treatment

2. Monitor prescription refill requests using the Utah controlled substance database (CSD) program. This may help identify and prevent potential drug overutilization, misuse, overprescribing, and diversion activities of stimulants and other controlled substances. Educate patients in terms of negative effects and legal penalties associated with stimulant abuse, misuse, and diversion

3. Treat patients with a history of substance abuse or at risk for stimulant abuse, misuse, or diversion with agents of no abuse potential (ie, non-stimulants) or transition to stimulant formulations with less abuse potential (eg, LA stimulant formulations, especially lisdexamfetamine and osmotic-release oral system methylphenidate) compared to other stimulants.

The Utah Medicaid utilization data in adults showed that approximately 10% of total ACO and FFS patients and 14% of FFS patients received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse, stimulant dependence, or poisoning by stimulants within the last 2 years.

Regarding concomitant use of more than 1 stimulant, clinical practice guidelines indicate that some patients may require an LA formulation in the morning followed by an SA formulation later in the day to

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accommodate a recurrence of symptoms as the LA formulation wears off. 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). Considerations regarding concomitant use of 2 LA formulations, 2 SA formulations, or 2 stimulants from different classes are not described in clinical practice guidelines; however, guidelines emphasize the need to tailor therapy according to “when” therapy is needed and the duration of effect required during the day. PA criteria may be required when concomitant use of 2 LA formulations, 2 SA formulations, or 2 stimulants from different classes are prescribed to assure the medications are being used appropriately.

Challenges in ADHD include treatment of coexisting morbidities and use of concurrent adjunctive medication(s). The majority of patients with ADHD present with a diagnosis for another psychiatric disorder. In adults, common comorbid conditions include anxiety, mood disorders, behavioral disorders, and substance use disorders. Patients with ADHD should be carefully screened for comorbid conditions and receive treatment accordingly. Generally, therapy should be initiated for the more severe condition first (ADHD or comorbidity). Psychosis, bipolar disorder, substance abuse, severe depression, and severe anxiety are most commonly treated before ADHD. Comorbid milder mood disorders, anxiety disorders, and emotional instability can be treated concurrent with ADHD therapy. Drug and alcohol abuse problems should be stabilized before the initiation of ADHD therapy.

Sleep problems are very frequently reported in patients with ADHD. Patients with ADHD can experience sleep disturbances because of inadequate sleep hygiene, stimulant treatment, untreated ADHD, comorbid psychiatric condition (eg, anxiety and depression), or comorbid sleep disorder (eg, circadian-based phase delay in sleep-wake patterns, insomnia, restless leg syndrome, or periodic limb movements of sleep). In adults with ADHD and sleep problems related to stimulant therapy, evidence suggests the trials of different strategies (eg, sleep behavioral interventions, switch to another stimulant formulation, change timing of stimulant administration, and use of non-stimulants) before initiating pharmacological treatment for insomnia. These recommendations serve to optimize ADHD therapy and minimize adverse events. Patients with ADHD may have sleep problems unrelated to stimulant therapy (eg, due to a comorbid psychiatric condition or comorbid sleep disorder). In the presence of comorbidities, clinicians should evaluate which condition to manage first. Nonetheless, treatment of an underlying disorder may not fully attenuate the patient’s insomnia, thus pharmacotherapy for insomnia may still be needed. The 2017 AASM guideline for insomnia does recommend benzodiazepine and non-benzodiazepine hypnotics for the treatment of adults with chronic insomnia.

Utah Medicaid utilization data indicated that 704 ACO and FFS adult patients received a stimulant formulation over the last year and had at least 1 claim for a medication approved for insomnia (ie, benzodiazepines or non-benzodiazepine hypnotics) within 30 days of the stimulant fill. The most common combination of stimulant and hypnotic was any stimulant in combination with the non-benzodiazepine hypnotic zolpidem (547 patients).

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References 1. Harstad E, Levy S. Attention-deficit/hyperactivity disorder and substance abuse. Pediatrics.

2014;134(1):e293-301. 2. American Psychiatric Association. Neurodevelopmental Disorders. In: Diagnostic and Statistical

Manual of Mental Disorders, 5th edition. Arlington, VA., American Psychiatric Association, 2013. 3. Adzenys ER (amphetamine) extended-release oral suspension [package insert]. Grand Prairie,

TX: Neos Therapeutics Brands, LLC; revised September 2017. 4. Adzenys XR-ODT (amphetamine) extended-release orally disintegrating tablets [package insert].

Grand Prairie, TX: Neos Therapeutics, LP.; revised January 2017. 5. Dyanavel XR (amphetamine) extended-release oral suspension [package insert]. Monmouth

Junction, NJ: Tris Pharma, Inc.; revised February 2019. 6. Evekeo (amphetamine sulfate) tablets [package insert]. Atlanta, GA: Arbor Pharmaceuticals, LLC;

revised October 2016. 7. Evekeo ODT (amphetamine sulfate) orally disintegrating tablets [package insert]. Atlanta, GA:

Arbor Pharmaceuticals, LLC; revised January 2019. 8. Focalin (dexmethylphenidate hydrochloride) tablets [package insert]. East Hanover, New Jersey:

Novartis Pharmaceuticals Corporation; revised January 2019. 9. Focalin XR (dexmethylphenidate hydrochloride) extended-release capsules [package insert]. East

Hanover, New Jersey: Novartis Pharmaceuticals Corporation; revised January 2019. 10. Dexedrine Spansule (dextroamphetamine sulfate) sustained release capsules [package insert].

Hayward, CA: Impax Specialty Pharma; revised February 2018. 11. Dextroamphetamine sulfate tablets [package insert]. Webster Groves, MO: SpecGx LLC; revised

January 2018. 12. Procentra (dextroamphetamine sulfate) oral solution [package insert]. Newport, KY:

Independence Pharmaceuticals, LLC; revised February 2017. 13. Zenzedi (dextroamphetamine sulfate) tablet [package insert]. Atlanta, GA: Arbor

Pharmaceuticals, LLC; revised December 2018. 14. Adderall (dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate

and amphetamine sulfate) tablets [package insert]. Horsham, PA: Teva Select Brands; revised January 2017.

15. Adderall XR (mixed salts of a single-entity amphetamine product) extended release capsules [package insert]. Lexington, MA: Shire US Inc.; revised June 2018.

16. Mydayis (mixed salts of a single-entity amphetamine product) extended-release capsules [package insert]. Lexington, MA: Shire US Inc.; revised June 2017.

17. Vyvanse (lisdexamfetamine dimesylate) capsules [package insert]. Lexington, MA: Shire US Inc.; revised July 2017.

18. Desoxyn (methamphetamine hydrochloride) tablets [package insert]. Lebanon, NJ: Recordati Rare Diseases Inc.; revised May 2017.

19. Adhansia XR (methylphenidate hydrochloride) extended-release capsules [package insert]. Stamford, CT: Purdue Pharma L.P.; revised February 2019.

20. Aptensio XR (methylphenidate hydrochloride) extended-release capsules [package insert]. Coventry, RI: Rhodes Pharmaceuticals L.P.; revised January 2017.

21. Concerta (methylphenidate HCl) extended-release tablets [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; revised January 2017.

22. Cotempla XR-ODT (methylphenidate extended-release orally disintegrating tablets) [package insert]. Grand Prairie, TX: Neos Therapeutics Brands, LLC.; revised June 2017.

46

23. Daytrana (methylphenidate) transdermal system [package insert]. Miami, FL: Noven Therapeutics, LLC; revised January 2017.

24. Jornay PM (methylphenidate hydrochloride) extended-release capsules [package insert]. Wayne, PA: Ironshore Pharmaceuticals & Development, Inc.; revised August 2018.

25. Metadate CD (methylphenidate HCl) extended-release capsules [package insert]. Smyrna, GA: UCB, Inc.; revised June 2014.

26. Metadate ER (methylphenidate hydrochloride) extended-release tablets [package insert]. Philadelphia, PA: Lannett Company, Inc.; revised April 2018.

27. Methylin (methylphenidate HCl) oral solution [package insert]. Hazelwood, MO: Mallinckrodt Inc.; revised December 2013.

28. Quillichew ER (methylphenidate hydrochloride) extended-release chewable tablets [package insert]. New York, NY: NextWave Pharmaceuticals, Inc. (a subsidiary of Pfizer Inc.); revised March 2017.

29. Quillivant XR (methylphenidate hydrochloride) for extended-release oral suspension [package insert]. New York, NY: NextWave Pharmaceuticals, Inc. (a subsidiary of Pfizer Inc.); revised January 2017.

30. Relexxii (methylphenidate hydrochloride extended-release) tablets [package insert]. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; revised February 2019.

31. Ritalin (methylphenidate hydrochloride) tablets [package insert]. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; revised January 2019.

32. Ritalin LA (methylphenidate hydrochloride) extended-release capsules [package insert]. East Hanover, New Jersey: Novartis Pharmaceuticals Corporation; revised January 2019.

33. Castells X, Blanco-Silvente L, Cunill R. Amphetamines for attention deficit hyperactivity disorder (ADHD) in adults. The Cochrane database of systematic reviews. 2018;8(100909747):CD007813.

34. Finley PR, Perry P, Superman S. Attention Deficit Hyperactivity Disorder in Children, Adolescents, and Adults. In: Tallian KB, ed. Kida-Kimble and Young's Applied Therapeutics. 10th ed. Philidelphia: Wolters Kluwer; 2013.

35. Punja S, Shamseer L, Hartling L, et al. Amphetamines for attention deficit hyperactivity disorder (ADHD) in children and adolescents. Cochrane Database of Systematic Reviews. 2016(2).

36. Bolea-Alamanac B, Nutt DJ, Adamou M, et al. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology. Journal of psychopharmacology (Oxford, England). 2014;28(3):179-203.

37. U.S. Food and Drug Administration. Consumer Updates. Dealing with ADHD: What You Need to Know. https://www.fda.gov/consumers/consumer-updates/dealing-adhd-what-you-need-know. Accessed January 9, 2020.

38. Lexi-Drugs, Drug Monographs. Lexicomp Online. In: Wolters Kluwer. Accessed January 31, 2020. 39. Feldman ME, Charach A, Belanger SA. ADHD in children and youth: Part 2-Treatment. Paediatrics

& child health. 2018;23(7):462-472. 40. Pliszka S, Issues AWGoQ. Practice parameter for the assessment and treatment of children and

adolescents with attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry. 2007;46(7):894-921.

41. ADHD Resource Alliance (CADDRA): Canadian ADHD Practice Guidelines, Fourth Edition, Toronto ON; CADDRA, 2018.

42. American Academy of Pediatrics. Supplemental Information. Algorithm. Implementing the key action statments of the AAP ADHD clinical practice guidelines: an algorithm and explanation for process of care for the evaluation, diagnosis, treatment, and monitoring of ADHD in clidren and adolescents.

https://www.fda.gov/consumers/consumer-updates/dealing-adhd-what-you-need-know

47

https://pediatrics.aappublications.org/content/pediatrics/suppl/2019/09/18/peds.2019-2528.DCSupplemental/PEDS_20192528SupplementaryData1.pdf. Accessed January 14, 2020.

43. Wolraich ML, Hagan JF, Jr., Allan C, et al. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2019;144(4).

44. National Institute for Health and Care Excellence (NICE). Attention deficit hyperactivity disorder: diagnosis and management (NG87; March 2018). https://www.nice.org.uk/guidance/NG87.

45. Centers for Disease Control and Prevention (CDC). Attention-Deficit/Hyperactivity Disorder. Trends in the Parent-Report of Health Care Provider-Diagnosis and Medication Treatment for ADHD: United States, 2003—2011. Page last reviewed: August 29, 2019. http://www.cdc.gov/ncbddd/adhd/features/key-findings-adhd72013.html. Accessed December 10, 2019.

46. Kooij JJS, Bijlenga D, Salerno L, et al. Updated European Consensus Statement on diagnosis and treatment of adult ADHD. Eur Psychiatry. 2019;56:14-34.

47. Kaye S, Darke S. The diversion and misuse of pharmaceutical stimulants: what do we know and why should we care? Addiction (Abingdon, England). 2012;107(3):467-477.

48. Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. The American journal of psychiatry. 2006;163(4):716-723.

49. Kessler RC, Berglund P, Chiu WT, et al. The US National Comorbidity Survey Replication (NCS-R): design and field procedures. International journal of methods in psychiatric research. 2004;13(2):69-92.

50. Biton V, Krauss G, Vasquez-Santana B, et al. A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures. Epilepsia. 2011;52(2):234-242.

51. Faraone SV, Rostain AL, Montano CB, Mason O, Antshel KM, Newcorn JH. Systematic Review: Nonmedical Use of Prescription Stimulants: Risk Factors, Outcomes, and Risk Reduction Strategies. Journal of the American Academy of Child and Adolescent Psychiatry. 2019.

52. Colaneri N, Keim S, Adesman A. Physician practices to prevent ADHD stimulant diversion and misuse. J Subst Abuse Treat. 2017;74:26-34.

53. Centers for Disease Control and Prevention. Opioid Overdose. Data. Other Drugs. Psychostimulants. Page last reviewed: August 12, 2019. https://www.cdc.gov/drugoverdose/data/otherdrugs.html. Accessed December 2, 2019.

54. U.S. Department of Justice - Drug Enforcement Administration. Diversion Control Division. Resources. Title 21 United States Code (USC) Controlled Substances Act. Subchapter I - Control and Enforcement. https://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm. Accessed December 2, 2019.

55. U.S. Department of Justice - Drug Enforcement Administration. Drugs of Abuse. A DEA Resource Guide 2017 Edition.

56. Riemann D, Baglioni C, Bassetti C, et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res. 2017;26(6):675-700.

57. Centers for Disease Control and Prevention (CDC). Attention-Deficit/Hyperactivity Disorder. Data and Statistics About ADHD. Healthcare claims data show treatment gaps. Page last reviewed: October 15, 2019. https://www.cdc.gov/ncbddd/adhd/data.html. Accessed January 13, 2019.

58. Centers for Disease Control and Prevention (CDC). Attention-Deficit/Hyperactivity Disorder (ADHD). National Prevalence of ADHD and Treatment: New statistics for children and adolescents, 2016. Page last reviewed: September 28, 2018.

https://pediatrics.aappublications.org/content/pediatrics/suppl/2019/09/18/peds.2019-2528.DCSupplemental/PEDS_20192528SupplementaryData1.pdf

https://pediatrics.aappublications.org/content/pediatrics/suppl/2019/09/18/peds.2019-2528.DCSupplemental/PEDS_20192528SupplementaryData1.pdf

https://www.nice.org.uk/guidance/NG87

http://www.cdc.gov/ncbddd/adhd/features/key-findings-adhd72013.html

https://www.cdc.gov/drugoverdose/data/otherdrugs.html

https://www.deadiversion.usdoj.gov/21cfr/21usc/812.htm

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

48

https://www.cdc.gov/ncbddd/adhd/features/national-prevalence-adhd-and-treatment.html. Accessed March 26, 2019. .

59. Danielson ML, Bitsko RH, Ghandour RM, Holbrook JR, Kogan MD, Blumberg SJ. Prevalence of Parent-Reported ADHD Diagnosis and Associated Treatment Among U.S. Children and Adolescents, 2016. Journal of clinical child and adolescent psychology : the official journal for the Society of Clinical Child and Adolescent Psychology, American Psychological Association, Division 53. 2018;47(2):199-212.

60. Centers for Disease Control and Prevention (CDC). Attention-Deficit/Hyperactivity Disorder (ADHD). Symptoms and Diagnosis of ADHD. Page last reviewed: November 1, 2019. http://www.cdc.gov/ncbddd/adhd/diagnosis.html. Accessed November 27, 2019.

61. Centers for Disease Control and Prevention (CDC). Attention-Deficit/Hyperactivity Disorder (ADHD). What is ADHD?. Page last reviewed: December 14, 2018. https://www.cdc.gov/ncbddd/adhd/facts.html. Accessed March 26, 2019.

62. Wolraich M, Brown L, Brown RT, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-1022.

63. Centers for Disease Control and Prevention (CDC). Attention-Deficit/Hyperactivity Disorder (ADHD). Treatment of ADHD. Page last reviewed: OCtober 8, 2019. https://www.cdc.gov/ncbddd/adhd/treatment.html. Accessed January 16, 2020.

64. 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.

65. 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.

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

67. 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).

68. 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.

69. Dobie C, Donald WB, Hanson M, Heim C, Huxsahl J, Karasov R, Kippes C, Neumann A, Spinner P, Staples T, Steiner L. Institute for Clinical Systems Improvement. Diagnosis and Management of Attention Deficit Hyperactivity Disorder in Primary Care for School-Age Children and Adolescents. http://bit.ly/ADHD0312. Updated March 2012.

70. 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.

71. Center for Drug Evaluation and Research. Application number: 205831Orig1s000. Clinical Pharmacology and Biopharmaceutics Review. Aptensio XR. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205831Orig1s000ClinPharmR.pdf. Accessed February 24, 2020.

72. Center for Drug Evaluation and Research. Application number: 209311Orig1s000. Clinical Pharmacology and Biopharmaceutics Review. Jornay PM. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209311Orig1s000ClinPharmR.pdf. Accessed February 24, 2020.

https://www.cdc.gov/ncbddd/adhd/features/national-prevalence-adhd-and-treatment.html

http://www.cdc.gov/ncbddd/adhd/diagnosis.html

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

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

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

http://bit.ly/ADHD0312

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/205831Orig1s000ClinPharmR.pdf

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209311Orig1s000ClinPharmR.pdf

49

73. Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database of Systematic Reviews. 2014(2).

74. Najib J, Wimer D, Zeng J, et al. Review of Lisdexamfetamine Dimesylate in Adults With Attention-Deficit/Hyperactivity Disorder. J Cent Nerv Syst Dis. 2017;9:1179573517728090.

75. Dopheide JA, Stutzman DL, Pliszka SR. Attention Deficit/Hyperactivity Disorder. In: DiPiro JT, Yee GC, Posey LM, Haines ST, Nolin TD, Ellingrod V, eds. Pharmacotherapy: A Pathophysiologic Approach, 11e. New York, NY: McGraw-Hill Education; 2020.

76. 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.

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

78. Micromedex (electronic version). Truven Health Analytics; 2020. 79. Adesman, A. Cohen Children's Medical Center of New York, part of Northwell Health.

http://www.adhdmedicationguide.com/. Accessed January 14, 2020. 80. 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). 81. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug

Evaluation and Research (CDER). Abuse-deterrent opioids— evaluation and labeling. Guidance for industry (April 2015). https://www.fda.gov/files/drugs/published/Abuse-Deterrent-Opioids-Evaluation-and-Labeling.pdf. Accessed December 10, 2019.

82. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Assessment of Abuse Potential of Drugs. Guidance for Industry (January 2017). https://www.fda.gov/media/116739/download. Accessed December 16, 2019. .

83. Centers for Disease Control and Prevention. 2018 Annual Surveillance Report of Drug-Related Risks and Outcomes — United States. Surveillance Special Report 2. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Published August 31, 2018. https://www.cdc.gov/drugoverdose/pdf/pubs/2018-cdc-drug-surveillance-report.pdf. Accessed December 2, 2019.

84. Kariisa M, Scholl L, Wilson N, Seth P, Hoots B. Drug Overdose Deaths Involving Cocaine and Psychostimulants with Abuse Potential - United States, 2003-2017. MMWR Morb Mortal Wkly Rep. 2019;68(17):388-395.

85. Substance-Related and Addictive Disorders. In: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. May 2013.

86. McCabe SE, Veliz P, Wilens TE, Schulenberg JE. Adolescents' Prescription Stimulant Use and Adult Functional Outcomes: A National Prospective Study. Journal of the American Academy of Child and Adolescent Psychiatry. 2017;56(3):226-233.e224.

87. Utah Division of Occupational an Professional Licensing. Utah Controlled Substance Database. https://dopl.utah.gov/programs/csdb/. Accessed January 14, 2020.

88. Crunelle CL, van den Brink W, Moggi F, et al. International Consensus Statement on Screening, Diagnosis and Treatment of Substance Use Disorder Patients with Comorbid Attention Deficit/Hyperactivity Disorder. Eur Addict Res. 2018;24(1):43-51.

89. McDonagh M, Peterson K, Holzhammer B. Drug Class Review: Pharmacological Treatments for Attention Deficit Hyperactivity Disorder. Final Update 5 Report. In: Oregon Health and Science University; 2015.

http://www.adhdmedicationguide.com/

https://www.fda.gov/files/drugs/published/Abuse-Deterrent-Opioids-Evaluation-and-Labeling.pdf

https://www.fda.gov/files/drugs/published/Abuse-Deterrent-Opioids-Evaluation-and-Labeling.pdf

https://www.fda.gov/media/116739/download

https://www.cdc.gov/drugoverdose/pdf/pubs/2018-cdc-drug-surveillance-report.pdf

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

50

90. National Institute on Drug Abuse. Drug Facts. Prescription Stimulants. https://www.drugabuse.gov/publications/drugfacts/prescription-stimulants. Last updated June 2018. Accessed December 16, 2019.

91. Colaneri N, Keim S, Adesman A. Adolescent Patient Education Regarding ADHD Stimulant Diversion And Misuse. Patient Educ Couns. 2017;100(2):289-296.

92. Looby A, De Young KP, Earleywine M. Challenging expectancies to prevent nonmedical prescription stimulant use: a randomized, controlled trial. Drug and alcohol dependence. 2013;132(1-2):362-368.

93. Healt Canada. Canada’s Drug Strategy. Working together to reduce the harmful use of substances. Abuse and Diversion of Controlled Substances: A Guide for Health Professionals. https://www.canadianveterinarians.net/documents/abuse-and-diversion-of-controlled-substances. Accesseed February 13, 2020.

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. Children & Adults with ADHD (CHADD). Adults. Treatment. Medication Management. https://chadd.org/for-adults/medication-management/. Accesseed February 18, 2020.

96. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(2):307-349.

97. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians. Ann Intern Med. 2016;165(2):125-133.

98. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4(5):487-504.

99. National Guideline C. Management of chronic insomnia disorder in adults: a clinical practice guideline from the American College of Physicians. Agency for Healthcare Research and Quality (AHRQ). https://guidelines.gov/summaries/summary/50399/management-of-chronic-insomnia-disorder-in-adults-a-clinical-practice-guideline-from-the-american-college-of-physicians?q=benzodiazepine. Published 2016. Accessed.

100. Ambien CR (zolpidem tartrate) [package insert]. Bridgewater, NJ: Sanofi-aventis U.S. LLC; revised August 2019.

101. Halcion (triazolam) [package insert]. NY, NY: Pfizer Inc.; revised October 2019. 102. Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook. 12th ed.

Hudson, OH: Lexi-Comp; 2011. 103. McEvoy GK, Snow EK, Kester L, Litvak K, Miller J, Welsh OH, eds. AHFS 2011 Drug Information.

Bethesda, MD: American Society of Health-System Pharmacists; 2011. 104. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate

Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227-2246. 105. Kaiser Permanente. Benzodiazepine and Z-Drug Safety Guideline. August 2014.

https://www.ghc.org/static/pdf/public/guidelines/benzo-zdrug.pdf. Accessed. 106. Uzun S, Kozumplik O, Jakovljevic M, Sedic B. Side effects of treatment with benzodiazepines.

Psychiatr Danub.22(1):90-93. 107. Lader M, Petursson H. Rational use of anxiolytic/sedative drugs. Drugs. 1983;25(5):514-528. 108. Johnson B, Streltzer J. Risks associated with long-term benzodiazepine use. Am Fam Physician.

2013;88(4):224-226.

https://www.drugabuse.gov/publications/drugfacts/prescription-stimulants

https://www.canadianveterinarians.net/documents/abuse-and-diversion-of-controlled-substances

https://www.canadianveterinarians.net/documents/abuse-and-diversion-of-controlled-substances

https://chadd.org/for-adults/medication-management/

https://guidelines.gov/summaries/summary/50399/management-of-chronic-insomnia-disorder-in-adults-a-clinical-practice-guideline-from-the-american-college-of-physicians?q=benzodiazepine



https://www.ghc.org/static/pdf/public/guidelines/benzo-zdrug.pdf

51

109. Darker Catherine D, Sweeney Brion P, Barry Joe M, Farrell Michael F, Donnelly-Swift E. Psychosocial interventions for benzodiazepine harmful use, abuse or dependence. Cochrane Database of Systematic Reviews. 2015(5). doi:10.1002/14651858.CD009652.pub2.

110. Drug Enforcement Administration. Office of Diversion Control. BENZODIAZEPINES (Street Names: Benzos, Downers, Nerve Pills, Tranks). January 2013. https://www.deadiversion.usdoj.gov/drug_chem_info/benzo.pdf. Accessed.

111. Prescription Drug Misuse and Abuse. https://www.samhsa.gov/prescription-drug-misuse-abuse. Accessed.

112. Rosner S, Englbrecht C, Wehrle R, Hajak G, Soyka M. Eszopiclone for insomnia. The Cochrane database of systematic reviews. 2018;10:Cd010703.

113. Silenor (doxepin hydrochloride) tablet [package insert]. Morristown, NJ: Pernix Therapeutics, LLC; revised March 2010.

114. Rozerem (ramelteon) tablets [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; Revised December 2018.

115. Belsomra (suvorexant) tablet film coated [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; Revised July 2018.

116. Brasure M, MacDonald R, Fuchs E. Comparative Effectiveness Reviews, No. 159: Management of Insomnia Disorder. Vol 2015 Dec. Rockville, MD: Agency for Healthcare Research and Quality US; 2015.

117. Everitt H, Baldwin DS, Stuart B, et al. Antidepressants for insomnia in adults. The Cochrane database of systematic reviews. 2018;5:Cd010753.

118. Zaleplon capsule [package insert]. Princeton, NJ: OrchidPharma Inc; revised February 2016. 119. Israel AG, Kramer JA. Safety of zaleplon in the treatment of insomnia. The Annals of

pharmacotherapy. 2002;36(5):852-859. 120. Ivanenko A. Sleep in children and adolescents with attention deficit hyperactivity disorder.

UpToDate. Last updated: Dec 16, 2019. https://www-uptodate-com.ezproxy.lib.utah.edu/contents/sleep-in-children-and-adolescents-with-attention-deficit-hyperactivity-disorder?sectionName=Subsequent%20management&search=insomnia%20and%20ADHD&topicRef=16642&anchor=H2877487269&source=see_link#H2877487269. Accessed February 18, 2020.

121. Graham J, Banaschewski T, Buitelaar J, et al. European guidelines on managing adverse effects of medication for ADHD. European child & adolescent psychiatry. 2011;20(1):17-37.

122. Cortese S, Holtmann M, Banaschewski T, et al. Practitioner review: current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry. 2013;54(3):227-246.

123. Cortese S, Konofal E, Lecendreux M, et al. Restless legs syndrome and attention-deficit/hyperactivity disorder: a review of the literature. Sleep. 2005;28(8):1007-1013.

124. Instanes JT, Klungsoyr K, Halmoy A, Fasmer OB, Haavik J. Adult ADHD and Comorbid Somatic Disease: A Systematic Literature Review. Journal of attention disorders. 2018;22(3):203-228.

125. Snitselaar MA, Smits MG, van der Heijden KB, Spijker J. Sleep and Circadian Rhythmicity in Adult ADHD and the Effect of Stimulants. Journal of attention disorders. 2017;21(1):14-26.

126. Schneider BN, Enenbach M. Managing the risks of ADHD treatments. Current psychiatry reports. 2014;16(10):479.

127. Gleason MM, Egger HL, Emslie GJ, et al. Psychopharmacological treatment for very young children: contexts and guidelines. Journal of the American Academy of Child and Adolescent Psychiatry. 2007;46(12):1532-1572.

https://www.deadiversion.usdoj.gov/drug_chem_info/benzo.pdf

https://www.samhsa.gov/prescription-drug-misuse-abuse

https://www-uptodate-com.ezproxy.lib.utah.edu/contents/sleep-in-children-and-adolescents-with-attention-deficit-hyperactivity-disorder?sectionName=Subsequent%20management&search=insomnia%20and%20ADHD&topicRef=16642&anchor=H2877487269&source=see_link#H2877487269





52

128. 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.

129. 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.

130. 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.

131. Berman SM, Kuczenski R, McCracken JT, London ED. Potential adverse effects of amphetamine treatment on brain and behavior: a review. Mol Psychiatry. 2009;14(2):123-142.

132. Courtney KE, Ray LA. Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature. Drug and alcohol dependence. 2014;143:11-21.

133. Rusyniak DE. Neurologic manifestations of chronic methamphetamine abuse. Neurologic clinics. 2011;29(3):641-655.

134. Westfall DP. Chapter 12: Adrenergic Agonists and Antagonists. In: Westfall TC, ed. Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011.

135. Stein MA, Waldman I, Newcorn J, Bishop J, Kittles R, Cook EH, Jr. Dopamine transporter genotype and stimulant dose-response in youth with attention-deficit/hyperactivity disorder. Journal of child and adolescent psychopharmacology. 2014;24(5):238-244.

136. Zaleplon capsule , generic [package insert]. Princeton, NJ: OrchidPharma Inc; Revised February 2016

137. Eszopiclone tablet [package insert]. Eatontown, NJ: West-Ward Pharmaceuticals Corp.; Revised November 2018.

138. Ambien (zolpidem tartrate) tablets [package insert]. Bridgewater, NJ: Sanofi-Aventis US LLC.;Revised September 2018.

139. Zolpidem tartrate extended-release, generic [package insert]. Chestnut Ridge, NY: Par Pharmaceutical, Inc.; Revised March 2017.

140. Edluar (zolpidem tartrate) tablet [package insert]. Somerset, NJ: Meda Pharmaceuticals; Revised December 2018.

141. Intermezzo (zolpidem tartrate) tabet [package insert]. Stamford, CT: Purdue Pharma LP; Revised September 2015.

142. Zolpimist (zolpidem tartrate) oral spray [package insert]. Englewood, CO: Aytu BioScience Inc.;Revised February 2016.

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

53

Appendix A - Literature Search Strategies A) Literature Searches for Abuse, Misuse, and Diversion

• Ovid Medline

Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to November 22, 2019 Search Strategy:

# Searches Results

1

Amphetamines/ or (Amphetamin$ or Amfetamin$).ti,ab,kw,kf. or Dexmethylphenidate Hydrochloride/

or Dexmethylphenidat$.ti,ab,kw,kf. or Dextroamphetamine/ or (Dextroamphetamin$ or

Dextroamfetamin$).ti,ab,kw,kf. or Lisdexamfetamine Dimesylate/ or (Lisdexamfetamin$ or

Lisdexamphetamine).ti,ab,kw,kf. or Methamphetamine/ or (Methamphetamin$ or

Methamfetamin$).ti,ab,kw,kf. or Methylphenidate/ or Methylphenidat$.ti,ab,kw,kf.

48270

2 Central Nervous System Stimulants/ or (stimulant$ or psychostimulant$).ti,ab,kw,kf. 43426

3

meta-analysis/ or (metaanaly$ or meta-analy$).ti,ab,kw,kf. or "Systematic Review"/ or ((systematic

adj3 review$) or (systematic adj2 search$) or cochrane$ or (overview adj4 review)).ti,ab,kw,kf. or

(cochrane$ or systematic review?).jw.

313494

4 (MEDLINE or systematic review).tw. or meta analysis.pt. 257985

5

exp Substance-Related Disorders/ or (abuse or misuse or non-medical or nonmedical or illicit or

addict* or diversion or dependenc* or drug-seek* or trafficking or overprescrib* or overtreat* or

overdiagnos* or overdos* or malingering or 'cognitive enhancement' or 'memory enhancement' or

'concentration enhancement' or 'cognitive improvement' or 'memory improvement' or 'concentration

improvement' or 'work performance' or 'doctor shopping' or 'doctor-shopping' or 'weight loss' or

crushing or snorting or insufflation or inhalation or injection).ti,ab,kw,kf.

1316206

6 1 or 2 77397

7 3 or 4 345360

8 5 and 6 and 7 447

• Epistemonikos Search Strategy

Results: 291 systematic reviews, 7 broad synthesis, 4 structured summary

(stimulant* OR psychostimulant* OR amphetamin* OR amfetamin* OR dexmethylphenidat* OR dextroamphetamin* OR dextroamfetamin* OR lisdexamfetamin* OR lisdexamphetamin* OR methamphetamin* OR methamfetamin* OR methylphenidat*) AND (abus* OR misus* OR non-medical OR nonmedical OR illicit OR addict* OR diversion OR depend* OR drug-seek* OR trafficking OR inappropriate OR overprescrib* OR overtreat* OR overdiagnos* OR overdos* OR malingering OR

54

“cognitive enhancement” OR “memory enhancement” OR “concentration enhancement” OR “cognitive improvement” OR “memory improvement” OR “concentration improvement” OR “work performance” OR “doctor shopping” OR “doctor-shopping” OR “weight loss” OR crushing OR snorting OR insufflation OR inhalation OR injection)

B) Literature Searches for Concomitant Use of Stimulants and Hypnotics/Sedatives Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to February 05, 2020 Search Strategy:

# Searches Results

1 (stimulant* or amphetamine* or dextroamphetamine* or lisdexamfet* or

methylphenidate*).ti,ab,kw,kf. 52840

2

Amphetamines/ or central nervous system stimulants/ or amphetamine/ or dexmethylphenidate

hydrochloride/ or dextroamphetamine/ or lisdexamfetamine dimesylate/ or methamphetamine/ or

methylphenidate/

48528

3 (((attenti$ or hyperactiv*) adj3 (defic$ or dysfunc$ or disorder$)) or (ADHD or "AD/HD" or ADDH or

ADD-H or HKD)).ti,ab,kw,kf. 40566

4 "attention deficit and disruptive behavior disorders"/ or attention deficit disorder with hyperactivity/ 29736

5 exp "Hypnotics and Sedatives"/ 122037

6 Orexin Receptor Antagonists/ 305

7

(sedative* or hypnotic* or (orexin adj2 antagonist*) or nonbenzodiazepin* or non-benzodiazepin* or

"Z drug" or Z-drug or eszopiclone or zolpidem or ramelteon or suvorexant or tasimelteon or

zaleplon).ti,kw,kf,ab.

33596

8 (insomni* or sleep*).tw,kw,kf. or exp "Sleep Initiation and Maintenance Disorders"/ or exp Sleep

Wake Disorders/ or exp Sleep Stages/de or exp Sleep Latency/de 201672

9 1 or 2 or 3 or 4 115408

10 5 or 6 or 7 or 8 329821

11 9 and 10 9187

12

meta-analysis/ or (metaanaly$ or meta-analy$).ti,ab,kw,kf. or "Systematic Review"/ or ((systematic

adj3 review$) or (systematic adj2 search$) or cochrane$ or (overview adj4 review)).ti,ab,kw,kf. or

(cochrane$ or systematic review?).jw.

321688

13 (MEDLINE or systematic review).tw. or meta analysis.pt. 264544

14 12 or 13 353848

15 11 and 14 234

55

Appendix B – Diagnosis of ADHD

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)

56

Appendix C – Prescribing Information for CNS Stimulants

Table 1. FDA-Approved CNS Stimulants3-32

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)

57


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

58


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

59


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

60


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

61

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.33-35 Stimulants are used to increase the availability of these catecholamines, which alleviate ADHD symptoms.36 Increased levels of catecholamines result in stimulation of the peripheral and CNS systems and increases in blood pressure and bronchodilation.3,4,10,14,15 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.36,38 They increase the availability of catecholamines such as dopamine or norepinephrine via increased release or reuptake inhibition.3,4,14,15 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.131 Levo-amphetamine acts mainly on norepinephrine at low doses and has slightly more potent cardiovascular and peripheral effects compared to dextro-amphetamine.131 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.38,62,74

Methamphetamine (Desoxyn) or N-methylamphetamine has a chemical structure similar to amphetamine.132 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.132 The central effects of methamphetamine are more prominent than those of amphetamine due its lipophilic nature.133

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.8,9,19-21 Dexmethylphenidate is more potent than l-methylphenidate. Methylphenidate works by decreasing dopamine and norepinephrine reuptake and, overall, exhibits similar pharmacological properties as amphetamines.38,134

Durations of action ranges from 3 to 6 hours with immediate-release (IR) formulations to 6 to 16 hours with extended-release (ER) formulations.39,40 Individual patient genetic variations can result in differences in efficacy and optimal dose between the agents; for example, patients with a 9/9 dopamine

62

transporter gene (SLC6A3/DAT1) genotype may require higher doses of stimulant medications in order to achieve adequate symptom control.135

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 Stimulants3-32,38 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

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

63




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 h38

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

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

64




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)

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)

65




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

66

Table 3. Special Population Considerations for Central Nervous System Stimulant Agents3-32,38 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”6

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

67

Table 4. Warnings and Precautions for CNS Stimulants3-32,38

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)

68

Appendix D: Comparison of Benzodiazepines and Non-Benzodiazepine Hypnotics Table 1. Comparison of Benzodiazepine Agents38,78 Product RoA Available Doses Labeled Uses Unlabeled Uses Adult Oral Dosage Range &

Maximum Oral dose (adults) Alprazolam (Xanax® and Xanax XR®)

Oral Oral tablets: 0.25 mg, 0.5 mg, 1 mg, 2 mg 0.5 mg XR, 1 mg XR, 2 mg XR, 3 mg XR Oral solution: 1mg/mL (30 mL)

Treatment of anxiety disorders and panic disorder

Treatment of depression in adults

0.75 to 6 mg daily Prescribing Limits/Maximum: Anxiety Disorders: 4 mg daily Panic Disorder: 10 mg daily.

Chlordiazepoxide (Librium®, others)

Oral, IM, IV Oral tablets: 5 mg, 10 mg, 25 mg

Treatment of anxiety disorders, withdrawal symptoms of acute alcoholism and preoperative apprehension/anxiety.

N/A 15 to 300 mg daily Mild to moderate anxiety: 5–10 mg 3 or 4 times daily Severe anxiety, 20–25 mg 3 or 4 times daily. Maximum: Acute alcohol withdrawal: 300 mg daily

Chlordiazepoxide/ Amitriptyline (Limbitrol®)

Oral 5/12.5 mg, 10/25 mg Treatment of moderate-to-severe depression associated with moderate to severe anxiety

N/A 2 to 6 tablets daily in one or more divided doses. Maximum daily dose: amitriptyline 150 mg/ chlordiazepoxide 60 mg.

Clidinium/ Chlordiazepoxide (Librax®)

Oral 2.5/5 mg Treatment of irritable bowel syndrome and control emotional and somatic factors in gastrointestinal disorders.

N/A 1 to 2 capsules 3 to 4 times daily

Clobazam (Onfi™) Oral 5 mg, 10 mg, 20 mg Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome.

Alcohol withdrawal syndrome, anxiety, epilepsy, febrile seizure, hyperexplexia, menstrual epilepsy, severe myoclonic epilepsy in infancy

5 to 40 mg daily Maximum: Adjunctive Therapy in Lennox-Gastaut Syndrome: 20 mg daily in those weighing ≤30 kg and 40 mg daily in those weighing >30 kg

Clonazepam (Klonopin®)

Oral 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg

Treatment of Lennox-Gastaut syndrome, akinetic and myoclonic seizures; petit mal (absence) seizures unresponsive to succimides; and panic disorder.

Burning mouth syndrome, sleep walking disorder, and social phobia

1 to 20 mg daily Maximum: Seizure Disorders: 20 mg daily Panic Disorder: 4 mg daily

69

Table 1. Comparison of Benzodiazepine Agents38,78 Product RoA Available Doses Labeled Uses Unlabeled Uses Adult Oral Dosage Range &

Maximum Oral dose (adults) Clorazepate (Traxene®, others)

Oral 3.75 mg, 7.5 mg, 15 mg Treatment of anxiety disorders, alcohol withdrawal syndrome, and adjunct in management of partial seizures.

Epilepsy 15 to 90 mg daily Maximum: Alcohol Withdrawal: 90 mg daily Adjunctive Therapy for Partial Seizures: 90 mg daily

Diazepam (Valium®, others)

Oral, IM, IV, Rectal

Oral tablets: 2 mg, 5 mg, 10 mg Oral solution: 1mg/mL (5 mL, 500 mL), 5mg/mL (30 mL) Injection solution: 5mg/mL (2 mL, 10 mL) Rectal Gel: 5 mg, 10 mg, 20 mg

Oral and injection: Treatment of anxiety disorders, ethanol withdrawal, skeletal muscle relaxant, convulsive disorders Injection: Procedural anxiety, premedication; adjunct in status epilepticus Rectal gel: Treatment of refractory epilepsy patients.

Intoxication (cocaine, methamphetamine, and other sympathomimetics), neuroleptic malignant syndrome, opioid withdrawal, serotonin syndrome, acute episodes of vertigo

4 to 40 mg daily Maximum: Rectal: Maximum recommended frequency for administration by caregivers outside hospital is 1 treatment course every 5 days and 5 treatment courses per month.

Estazolam (Prosom®)

Oral 1 mg, 2 mg Short-term treatment of insomnia.

N/A 1 to 2 mg

Flurazepam (Dalmane®)

Oral 15 mg, 30 mg Short-term treatment of insomnia.

Tinnitus 15 to 30 mg

Lorazepam (Ativan®)

Oral, IM, IV Oral tablets: 0.5 mg, 1 mg, 2 mg Oral solution: 2mg/mL (30 mL) Injection solution: 2mg/mL (1 mL, 10 mL), 4mg/mL (1mL, 10 mL)

Oral: Treatment of anxiety disorders Injection: Status epilepticus, procedural anxiety (premedication).

Treatment of alcohol withdrawal, insomnia, psychogenic catatonia, akathisia, agitation, as antiemetic adjunct, intoxication (eg, cocaine), neuroleptic malignant syndrome, sedation, serotonin syndrome, vertigo

2 to 6 mg daily

Midazolam (Versed®)

Oral, IV, IM Oral solution: 2mg/mL (118 mL) Injection solution: 1mg/mL (2 mL, 5 mL, 10 mL), 5mg/mL (1 mL, 2 mL, 5 mL, 10 mL)

For preoperative, procedural, or sedation, induction/maintenance of general anesthesia, acute treatment of intermittent, stereotypic episodes of frequent seizure activity

Treatment of palliative sedation and status epilepticus.

N/A

Oxazepam (Serax®) Oral 10 mg, 15 mg, 30 mg Treatment of anxiety and alcohol withdrawal syndrome.

Management of simple partial seizures, insomnia

30 to 120 mg daily

Quazepam (Doral®) Oral 15 mg Treatment of insomnia. N/A 7.5 to 15 mg Temazepam (Restoril®)

Oral 7.5 mg, 15 mg, 22.5 mg, 30 mg

Short-term treatment of insomnia.

Treatment of anxiety, panic attacks and as an adjunct in

7.5 to 30 mg

70

Table 1. Comparison of Benzodiazepine Agents38,78 Product RoA Available Doses Labeled Uses Unlabeled Uses Adult Oral Dosage Range &

Maximum Oral dose (adults) the treatment of depression.

Triazolam (Halcion®)

Oral 0.125 mg, 0.25 mg Short-term treatment of insomnia.

Anxiety prior to surgery and behavioral syndrome

0.125 to 0.25 mg Maximum: 0.5 mg daily

Table 2. Medication Benefit According to Insomnia Problem, FDA vs. AASM for Non-Benzodiazepine Hypnotics96,113-115,136-142 Sleep Onset Insomnia Sleep Maintenance Insomnia Midnight awakening with difficulty returning to

sleep

Doxepin rAASM

FDAi

Eszopiclone rAASM

FDAi

Ramelteon rAASM

FDAi

Suvorexant

FDAi

rAASM

FDAi

Zaleplon rAASM

FDAi

Zolpidem

rAASM (based on trials of zolpidem 10 mg and CR 12.5 mg)

FDAi for Intermezzo only

FDAi for Ambien, Ambien CR, Edluar,

Zolpimist

FDAi

for Ambien CR

Abbreviations: FDA, US Food and Drug Administration; FDAi, FDA-approved indication; AASM, American Academy of Sleep Medicine Guideline; rAASM, recommended active ingredient (versus no treatment) by the 2017 American Academy of Sleep Medicine Guideline

71

Appendix E: Utilization Data for Stimulant Abuse, Dependence, and Poisoning

Table 1. ACO and FFS Patients Who Received a Stimulant in the Past Year and Had an ICD-10 Code Submitted Between February 2018 and February 2020 for Stimulant Dependence, Stimulant Abuse, or Poisoning by Stimulants (Data Presented by Agents With the Greatest Identified Risk to Lowest Risk, According to the Column “Total for Stimulant Dependence, Abuse, or Poisoning”)

Total for Stimulant

Dependence, Abuse, or Poisoninga

Diagnosis Code for Stimulant Dependenceb

Diagnosis Code for Stimulant

Abusec

Diagnosis Code for

Poisoning by Stimulantsd

Diagnosis Code for

Accidental Poisoning by Stimulantse

Generic Product Total claims

Total unique pts Pts % of pts Pts % of pts Pts % of pts Pts % of pts Pts % of pts

Amph/Dexamph AMPHET/DEXTR TAB 20MG 9545 2050 240 11.7 154 7.5 134 6.5 5 0.2 4 0.2 Amph/Dexamph AMPHET/DEXTR TAB 30MG 7915 1421 191 13.4 113 8.0 109 7.7 4 0.3 2 0.1 Amph/Dexamph AMPHET/DEXTR TAB 10MG 3362 977 90 09.2 64 6.6 41 4.2 3 0.3 2 0.2 Amph/Dexamph AMPHET/DEXTR CAP 20MG ER 2370 638 72 11.3 49 7.7 36 5.6 1 0.2 3 0.5 Amph/Dexamph AMPHET/DEXTR CAP 30MG ER 2619 555 66 11.9 46 8.3 28 5.0 3 0.5 2 0.4 Amph/Dexamph AMPHET/DEXTR TAB 15MG 1882 503 57 11.3 35 7.0 29 5.8 2 0.4 2 0.4 Lisdex VYVANSE CAP 30MG 849 336 57 17.0 47 14.0 26 7.7 . . . . Lisdex VYVANSE CAP 50MG 1023 311 47 15.1 29 9.3 32 10.3 . . 1 0.3 Lisdex VYVANSE CAP 70MG 1406 256 41 16.0 23 9.0 26 10.2 1 0.4 3 1.2 Lisdex VYVANSE CAP 40MG 1022 306 39 12.7 33 10.8 16 5.3 . . . . Lisdex VYVANSE CAP 60MG 968 209 24 11.5 18 8.6 9 4.3 1 0.5 . . Mph METHYLPHENID TAB 20MG 972 211 21 10.0 15 7.1 10 4.7 3 1.4 . . Amph/Dexamph AMPHET/DEXTR TAB 5MG 399 153 18 11.8 13 8.5 7 4.6 1 0.7 . . Amph/Dexamph AMPHET/DEXTR CAP 10MG ER 449 181 17 9.4 8 4.4 11 6.1 . . . . Amph/Dexamph AMPHET/DEXTR CAP 15MG ER 423 149 17 11.4 9 6.0 10 6.7 . . . . Lisdex VYVANSE CAP 20MG 342 131 17 13.0 10 7.6 11 8.4 . . . . Mph METHYLPHENID TAB 10MG 952 226 17 7.6 5 2.2 14 6.2 1 0.4 . . Mph CONCERTA TAB 27MG 207 87 15 17.2 11 12.6 8 9.2 . . . . Mph CONCERTA TAB 36MG 800 196 13 6.6 11 5.6 7 3.6 . . . . Amph/Dexamph AMPHET/DEXTR CAP 25MG ER 626 156 10 6.4 6 3.8 3 1.9 1 0.6 . . Mph CONCERTA TAB 54MG 650 146 8 5.5 6 4.1 4 2.7 . . . . Lisdex VYVANSE CAP 10MG 86 42 7 16.7 5 11.9 3 7.1 . . . . Mph CONCERTA TAB 18MG 273 81 7 8.6 4 4.9 4 4.9 . . . . Mph METHYLPHENID TAB 5MG 226 77 7 9.1 3 3.9 6 7.8 . . . . Mph METHYLPHENID TAB 20MG ER 142 37 6 16.2 5 13.5 5 13.5 . . . .

72


Total for Stimulant




Abusec

Diagnosis Code for


Diagnosis Code for




Dexamph DEXTROAMPHET TAB 10MG 210 43 5 11.6 3 7.0 2 4.7 . . . . Mph METHYLPHENID TAB 54MG ER 150 45 5 11.1 4 8.9 3 6.7 . . . . Amph/Dexamph MYDAYIS CAP 50MG 79 21 4 19.0 . 0 4 19.0476 1 4.7 . . Mph METHYLPHENID CAP 30MG ER 73 17 4 23.5 2 11.8 2 11.8 . . 1 5.9 Mph METHYLPHENID TAB 36MG ER 161 53 4 7.5 3 5.7 3 5.7 . . . . Dexmph FOCALIN XR CAP 20MG 130 30 3 10 2 6.7 1 3.3 . . . . Mph METHYLPHENID TAB 10MG ER 44 21 3 14.3 3 14.3 2 9.5 . . . . Amph/Dexamph ADDERALL XR CAP 20MG 31 12 2 16.7 1 8.3 1 8.3 . . . . Amph/Dexamph AMPHET/DEXTR TAB 12.5MG 16 9 2 22.2 2 22.2 1 11.1 . . 1 11.1 Amph/Dexamph MYDAYIS CAP 37.5MG 57 18 2 11.1 . 0 2 11.1 1 5.6 . .

Dexamph DEXTROAMPHET CAP 15MG ER 142 26 2 7.7 2 7.7 1 3.8 . . . .

Dexamph DEXTROAMPHET TAB 5MG 46 11 2 18.2 2 18.2 1 9.1 . . . . Mph METHYLPHENID CAP 40MG ER 65 17 2 11.8 1 5.9 1 5.9 . . . . Mph METHYLPHENID TAB 27MG ER 64 23 2 8.7 2 8.7 1 4.3 . . . . Amph/Dexamph AMPHET/DEXTR CAP 5MG ER 30 24 1 4.2 1 4.2 . 0 . . . . Dexmph FOCALIN TAB 5MG 17 8 1 12.5 1 12.5 . 0 . . . . Dexmph FOCALIN XR CAP 25MG 37 9 1 11.1 1 11.1 1 11.1 . . . . Dexmph FOCALIN XR CAP 30MG 46 11 1 9.1 1 9.1 1 9.1 . . . . Dexmph FOCALIN XR CAP 40MG 77 13 1 7.7 1 7.7 . 0 . . . . Lisdex VYVANSE CHW 30MG 7 4 1 25 . 0 1 25 . . . . Mph APTENSIO XR CAP 30MG 2 1 1 100 1 100 . 0 . . . . Mph METHYLPHENID TAB 18MG ER 25 11 1 9.1 1 9.1 . 0 . . . . Total Total 41841 6789 683 10.1 440 6.5 369 5.4 18 0.3 16 0.2 Abbreviations: ACO, accountable care organization; amph/Dexamph, amphetamine/dextroamphetamine; dexamph, dextroamphetamine; dexmph, dexmethylphenidate; FFS, fee-for-service; lisdex, lisdexamfetamine; pts, patients a Number of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse, stimulant dependence, or poisoning by amphetamines or methylphenidate within the last 2 years. b Number of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant dependence within the last 2 years.

73


Total for Stimulant




Abusec

Diagnosis Code for


Diagnosis Code for




c Number of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse within the last 2 years. d Number of patients who received a stimulant over the last year and had a diagnosis code submitted for poisoning by amphetamine or methylphenidate within the last 2 years. e Number of patients who received a stimulant over the last year and had a diagnosis code submitted for accidental poisoning by amphetamine or methylphenidate within the last 2 years.

Table 2. FFS Patients Who Received a Stimulant in the Past Year and Had an ICD-10 Code Submitted Between February 2018 and February 2020 for Stimulant Dependence, Stimulant Abuse, or Poisoning by Stimulants (Data Presented by Agents With the Greatest Identified Risk to Lowest Risk, According to the Column “Total for Stimulant Dependence, Abuse, or Poisoning”)

Total for Stimulant



Dependenceb


Abusec

Diagnosis Code for Poisoning by

Stimulantsd

Diagnosis Code for Accidental Poisoning by Stimulantse


Total unique pts Pts % of

pts Pts % of pts Pts % of


pts Amph/Dexamph AMPHET/DEXTR TAB 20MG 3538 981 161 16,4 97 9,9 98 10,0 4 0,4 4 0,4 Amph/Dexamph AMPHET/DEXTR TAB 30MG 2770 695 123 17,7 73 10,5 74 10,6 3 0,4 2 0,3 Amph/Dexamph AMPHET/DEXTR TAB 10MG 1225 422 49 11,6 35 8,3 22 5,2 2 0,5 2 0,5 Amph/Dexamph AMPHET/DEXTR CAP 20MG ER 722 258 43 16,7 27 10,5 25 9,7 1 0,4 2 0,8 Amph/Dexamph AMPHET/DEXTR CAP 30MG ER 795 226 40 17,7 28 12,4 17 7,5 2 0,9 1 0,4 Lisdex VYVANSE CAP 50MG 362 144 35 24,3 20 13,9 25 17,4 . . Amph/Dexamph AMPHET/DEXTR TAB 15MG 648 223 33 14,8 21 9,4 16 7,2 2 0,9 2 Lisdex VYVANSE CAP 30MG 261 147 31 21,1 26 17,7 16 10,9 . . Lisdex VYVANSE CAP 40MG 282 125 25 20,0 21 16,8 11 8,8 . . Lisdex VYVANSE CAP 70MG 421 107 25 23,4 13 12,1 17 15,9 . .

74


Total for Stimulant



Dependenceb


Abusec


Stimulantsd






pts Lisdex VYVANSE CAP 60MG 308 91 16 17,6 11 12,1 8 8,8 1 1,1 . Mph METHYLPHENID TAB 20MG 316 97 14 14,4 10 10,3 6 6,2 1 1,0 . Lisdex VYVANSE CAP 20MG 130 55 12 21,8 6 10,9 8 14,5 . . Amph/Dexamph AMPHET/DEXTR CAP 10MG ER 158 79 11 13,9 5 6,3 7 8,9 . . Amph/Dexamph AMPHET/DEXTR CAP 15MG ER 161 63 11 17,5 7 11,1 5 7,9 . . Mph CONCERTA TAB 27MG 78 35 11 31,4 9 25,7 4 11,4 . . Amph/Dexamph AMPHET/DEXTR TAB 5MG 110 51 10 19,6 7 13,7 5 9,8 1 2,0 . Mph METHYLPHENID TAB 10MG 340 108 10 9,3 4 3,7 9 8,3 . . Mph CONCERTA TAB 36MG 158 59 7 11,9 6 10,2 3 5,1 . . Amph/Dexamph AMPHET/DEXTR CAP 25MG ER 175 59 6 10,2 4 6,8 2 3,4 . . Mph CONCERTA TAB 18MG 92 30 5 16,7 4 13,3 2 6,7 . . Mph METHYLPHENID TAB 20MG ER 31 15 4 26,7 3 20,0 3 20,0 . . Amph/Dexamph MYDAYIS CAP 50MG 21 9 3 33,3 . 3 33,3 . . Lisdex VYVANSE CAP 10MG 19 12 3 25,0 2 16,7 1 8,3 . . Mph METHYLPHENID CAP 30MG ER 30 9 3 33,3 2 22,2 1 11,1 . 1 11,1 Mph METHYLPHENID TAB 10MG ER 14 8 3 37,5 3 37,5 2 25,0 . . Mph METHYLPHENID TAB 5MG 76 33 3 9,1 2 6,1 3 9,1 . . Dexmph FOCALIN XR CAP 20MG 31 10 2 20,0 1 10,0 1 10,0 . . Dexamph DEXTROAMPHET TAB 10MG 66 18 2 11,1 . 2 11,1 . . Mph CONCERTA TAB 54MG 166 45 2 4,4 1 2,2 1 2,2 . . Mph METHYLPHENID TAB 36MG ER 20 13 2 15,4 1 7,7 1 7,7 . . Amph/Dexamph ADDERALL XR CAP 20MG 12 5 1 20,0 . 1 20,0 . . Amph/Dexamph AMPHET/DEXTR CAP 5MG ER 9 9 1 11,1 1 11,1 . . . Amph/Dexamph MYDAYIS CAP 37.5MG 18 9 1 11,1 . 1 11,1 . . Dexmph FOCALIN XR CAP 25MG 4 3 1 33,3 1 33,3 1 33,3 . . Dexmph FOCALIN XR CAP 30MG 5 3 1 33,3 1 33,3 1 33,3 . . Dexamph DEXTROAMPHET CAP 15MG ER 49 7 1 14,3 1 14,3 . . .

75


Total for Stimulant



Dependenceb


Abusec


Stimulantsd






pts Lisdex VYVANSE CHW 30MG 6 3 1 33,3 . 1 33,3 . . Mph METHYLPHENID CAP 40MG ER 18 8 1 12,5 1 12,5 . . . Mph METHYLPHENID TAB 27MG ER 14 6 1 16,7 1 16,7 1 16,7 . . Mph METHYLPHENID TAB 54MG ER 19 10 1 10,0 . 1 10,0 . . Total Total 13964 3156 454 14,4 287 9,1 258 8,2 11 0,3 10 0,3 Abbreviations: Amph/Dexamph, amphetamine/dextroamphetamine; dexamph, dextroamphetamine; dexmph, dexmethylphenidate; FFS, fee-for-service; lisdex, lisdexamfetamine; pts, patients a Number of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse, stimulant dependence, or poisoning by amphetamine or methylphenidate within the last 2 years. b Number of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant dependence within the last 2 years. c Number of patients who received a stimulant over the last year and had a diagnosis code submitted for stimulant abuse within the last 2 years. d Number of patients who received a stimulant over the last year and had a diagnosis code submitted for poisoning by amphetamine or methylphenidate within the last 2 years. e Number of patients who received a stimulant over the last year and had a diagnosis code submitted for accidental poisoning by amphetamine or methylphenidate within the last 2 years.

76

Appendix F: ICD-10 Diagnosis Codes ICD-10 Codes for Stimulant Abuse, Dependence, or Poisoning

GP Group Description

A Stimulant dependence

B Stimulant abuse

C Poisoning by stimulants

D Accidental poisoning by stimulants

ICD Diagnosis GP

F1520 OTHER STIMULANT DEPENDENCE, UNCOMPLICATED A

F1521 OTHER STIMULANT DEPENDENCE, IN REMISSION A

F15220 OTHER STIMULANT DEPENDENCE WITH INTOXICATION, UNCO A

F15221 OTHER STIMULANT DEPENDENCE WITH INTOXICATION DELIR A

F15222 OTH STIMULANT DEPENDENCE W INTOX W PERCEPTUAL DIST A

F15229 OTHER STIMULANT DEPENDENCE WITH INTOXICATION, UNSP A

F1523 OTHER STIMULANT DEPENDENCE WITH WITHDRAWAL A

F1524 OTH STIMULANT DEPENDENCE W STIMULANT-INDUCED MOOD A

F15250 OTH STIM DEPEND W STIM-INDUCE PSYCH DISORDER W DEL A

F15251 OTH STIMULANT DEPEND W STIM-INDUCE PSYCH DISORDER A

F15259 OTH STIMULANT DEPEND W STIM-INDUCE PSYCHOTIC DISOR A

F15280 OTH STIMULANT DEPENDENCE W STIM-INDUCE ANXIETY DIS A

F15281 OTH STIMULANT DEPENDENCE W STIM-INDUCE SEXUAL DYSF A

F15282 OTH STIMULANT DEPENDENCE W STIMULANT-INDUCED SLEEP A

F15288 OTH STIMULANT DEPENDENCE WITH OTH STIMULANT-INDUCE A

F1529 OTH STIMULANT DEPENDENCE W UNSP STIMULANT-INDUCED A

ICD Diagnosis GP

F1510 OTHER STIMULANT ABUSE, UNCOMPLICATED B

F15120 OTHER STIMULANT ABUSE WITH INTOXICATION, UNCOMPLIC B

F15121 OTHER STIMULANT ABUSE WITH INTOXICATION DELIRIUM B

F15122 OTH STIMULANT ABUSE W INTOXICATION W PERCEPTUAL DI B

F15129 OTHER STIMULANT ABUSE WITH INTOXICATION, UNSPECIFI B

F1514 OTHER STIMULANT ABUSE WITH STIMULANT-INDUCED MOOD B

F15150 OTH STIMULANT ABUSE W STIM-INDUCE PSYCH DISORDER W B

F15151 OTH STIMULANT ABUSE W STIM-INDUCE PSYCH DISORDER W B

F15159 OTH STIMULANT ABUSE W STIM-INDUCE PSYCHOTIC DISORD B

77

F15180 OTH STIMULANT ABUSE WITH STIMULANT-INDUCED ANXIETY B

F15181 OTH STIMULANT ABUSE W STIMULANT-INDUCED SEXUAL DYS B

F15182 OTHER STIMULANT ABUSE WITH STIMULANT-INDUCED SLEEP B

F15188 OTHER STIMULANT ABUSE WITH OTHER STIMULANT-INDUCED B

F1519 OTHER STIMULANT ABUSE WITH UNSP STIMULANT-INDUCED B

ICD Diagnosis GP

T43622A POISONING BY AMPHETAMINES, INTENTIONAL SELF-HARM, C

T43622D POISONING BY AMPHETAMINES, INTENTIONAL SELF-HARM, C

T43622S POISONING BY AMPHETAMINES, INTENTIONAL SELF-HARM, C

T43623A POISONING BY AMPHETAMINES, ASSAULT, INITIAL ENCOUN C

T43623D POISONING BY AMPHETAMINES, ASSAULT, SUBSEQUENT ENC C

T43623S POISONING BY AMPHETAMINES, ASSAULT, SEQUELA C

T43624A POISONING BY AMPHETAMINES, UNDETERMINED, INITIAL E C

T43624D POISONING BY AMPHETAMINES, UNDETERMINED, SUBS ENCN C

T43624S POISONING BY AMPHETAMINES, UNDETERMINED, SEQUELA C

T43632A POISONING BY METHYLPHENIDATE, INTENTIONAL SELF-HAR C

T43632D POISONING BY METHYLPHENIDATE, INTENTIONAL SELF-HAR C

T43632S POISONING BY METHYLPHENIDATE, INTENTIONAL SELF-HAR C

T43633A POISONING BY METHYLPHENIDATE, ASSAULT, INITIAL ENC C

T43633D POISONING BY METHYLPHENIDATE, ASSAULT, SUBSEQUENT C

T43633S POISONING BY METHYLPHENIDATE, ASSAULT, SEQUELA C

T43634A POISONING BY METHYLPHENIDATE, UNDETERMINED, INIT E C

T43634D POISONING BY METHYLPHENIDATE, UNDETERMINED, SUBS E C

T43634S POISONING BY METHYLPHENIDATE, UNDETERMINED, SEQUEL C

ICD Diagnosis GP

T43621A POISONING BY AMPHETAMINES, ACCIDENTAL (UNINTENTION D

T43621D POISONING BY AMPHETAMINES, ACCIDENTAL (UNINTENTION D

T43621S POISONING BY AMPHETAMINES, ACCIDENTAL, SEQUELA D

T43631A POISONING BY METHYLPHENIDATE, ACCIDENTAL, INIT D

T43631D POISONING BY METHYLPHENIDATE, ACCIDENTAL, SUBS D

T43631S POISONING BY METHYLPHENIDATE, ACCIDENTAL, SEQUELA D

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