UTAH MEDICAID DUR REPORT JULY 2017

CONCURRENT USE OF BENZODIAZEPINES AND STIMULANTS

Drug Regimen Review Center Joanita Lake B.Pharm, MSc EBHC (Oxon), Clinical Pharmacist Vicki Frydrich, B.Pharm., Pharm.D., Clinical Pharmacist Valerie Gonzales, Pharm.D., Clinical Pharmacist Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Joanne LaFleur, Pharm.D., MSPH, Associate Professor

Acknowledgement Gary Oderda, PharmD, MPH, Emeritus Professor Melissa Archer, PharmD, Clinical Pharmacist Carin Steinvoort, PharmD, Clinical Pharmacist

University of Utah College of Pharmacy Copyright © 2017 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

Contents

Introduction ...... 3 Disease overview ...... 3 Attention Deficit Disorder ...... 3 Anxiety ...... 4 Insomnia ...... 5 Methodology ...... 6 Drug information ...... 6 Pharmacology ...... 7 Efficacy ...... 8 Safety ...... 9 Distinguishing between ADHD-related and stimulant-related insomnia ...... 10 Clinical Guidelines ...... 11 Systematic reviews & Clinical Trials ...... 17 Summary ...... 19 Patients in whom misuse is a concern or in those with comorbidities ...... 19 Managing sleep problems in patients with ADHD ...... 19 Managing anxiety or mood lability in patients with ADHD ...... 20 Place in therapy and potential criteria to be reviewed ...... 20 Utah Medicaid Utilization Data ...... 24 Conclusions ...... 30 Appendix 1 – Drug information ...... 31 Appendix 2 – Pharmacokinetic properties ...... 39 Appendix 3 – Additional data ...... 44 Appendix 4 ...... 59 Top stimulant prescribers of concurrent stimulant and benzodiazepine treatment ...... 59 Top benzodiazepine prescribers and claims and patients exceeding BZD dose and duration recommendations AND stimulant prescribers involved in concurrent stimulant and BZD treatment .. 61 References ...... 64

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Introduction

The purpose of this review is to review the appropriateness of concurrent use of stimulants and benzodiazepines (colloquially referred to as “uppers” and “downers”, respectively) in patients with attention-deficit/hyperactivity disorder (ADD/ADHD).

Attention-deficit/hyperactivity disorder is a common mental health disorder diagnosed in childhood which may continue into adulthood. ADHD is characterized by symptoms of hyperactivity, impulsivity and/or inattention. Untreated ADHD may lead to delinquent behavior, substance abuse or other comorbidities. The full pathophysiology of ADHD is not well understood but may be tied to inadequate production of norepinephrine and dopamine in the prefrontal cortex. Stimulants medications work by increasing the availability of these catecholamines, resulting in reduced symptoms. Central nervous system (CNS) stimulants used in the treatment of ADHD include amphetamine, dexmethylphenidate, dextroamphetamine, dextroamphetamine/amphetamine, lisdexamfetamine, methamphetamine, and methylphenidate. Stimulants are divided into three categories based on chemical structure: amphetamine (dextro-amphetamine and levo-amphetamine), methamphetamine and methylphenidate (dextro-methylphenidate and levomethylphenidate). The isomers of each of the stimulant moieties are combined in varying ratios to increase desired pharmacologic effects and reduce adverse effects.1,2

Challenges in the treatment of ADHD include coexisting morbidities such as depression, oppositional defiant disorder, substance abuse, cardiovascular disease, anxiety, and sleep disorders. Additionally, patients can experience anxiety or sleep disturbances as a side effect of stimulant treatment. In fact, insomnia is one of the most commonly reported adverse events with the use of stimulants.

Benzodiazepines are used therapeutically for treatment of insomnia, anxiety disorders, seizure disorders, alcohol withdrawal symptoms, conscious sedation and general anesthesia.3-5 Fourteen oral and parenteral benzodiazepine agents are currently available for use in the United States: alprazolam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, midazolam, oxazepam, quazepam, temazepam and triazolam.4 Chlordiazepoxide is also available in two combination products: chlordiazepoxide/amitriptyline and clidinium/chlordiazepoxide.4

Stimulants and benzodiazepines are controlled substances with the potential to be misused/abused. Other treatment options should be considered first in patients with a history of substance abuse or in patients with high risk of misuse.

Disease Overview

Attention Deficit Disorder

ADHD is a neurobehavioral disorder characterized by inattention, hyperactivity and impulsivity. ADHD is most often a disorder of childhood which may continue into adulthood. According to a National Survey of Children’s Health (2010-2012), over 10% (~6.4 million) of US school-aged children have a diagnosis of ADHD. This number continues to rise with an increase of 42% reported between 2003 and 2011. In general, ADHD is diagnosed more frequently in school-aged boys (1 in 5) than in school-aged girls (1 in 11) and the average age of first onset of the disease is 7 years. The prevalence of ADHD in US adults is estimated at 4.1%. ADHD frequently occurs in combination with other mental health disorders (up to ~50%) including aggression-related disorders (Oppositional Defiant Disorder or Conduct Disorder), 3

learning ability disorders, depression and anxiety. Increasing mental health disorder education and screening can help to improve patient outcomes.6

ADHD presents in three different types: predominantly inattentive, predominantly hyperactive- impulsive or as a combined presentation with symptoms of both types equally exhibited.7 There is no single diagnostic test for ADHD. Diagnosis requires six or more symptoms of inattention and/or hyperactivity-impulsivity for children (≤ 16 years old) or five or more symptoms for adolescents (> 17 years old) and adults which have persisted for at least 6 months. Symptoms of inattention may include: failure to pay close attention to details, making careless mistakes, trouble maintaining attention on a single task, inability to listen, failure to finish duties, trouble organizing tasks, avoiding tasks that require mental effort over a long period of time, loses things and is easily distracted or forgetful. Symptoms of hyperactivity-impulsivity may include: fidgeting, trouble remaining seated, feeling restless (may run or climb), trouble participating in quiet activities, always "on the go”, talking excessively, speaking out of turn, trouble waiting their turn and often interrupting or intruding. For diagnosis, symptoms should be present before age 12, present in two or more settings and reduce the quality of school/work and social functioning.8

Recommendations for treatment of ADHD should include a combination of behavioral and medication therapy. For preschool-aged children, behavioral therapy alone is recommended as first line.7 Behavioral therapies include teaching the child new behaviors to replace ones which cause disruptions to activities of daily living in addition to instructing the child’s parents to teach and enforce skills to help the child manage their behavior. Medication therapy may include stimulant and nonstimulant agents. Stimulants, including amphetamine and methylphenidate agents, are the most widely used fast-acting, efficacious agents for reducing ADHD symptoms. Nonstimulant agents, including atomoxetine (Strattera®), guanfacine and clonidine, have a slower onset but are long-acting and may be associated with fewer adverse effects. Often, multiple trials of different medications at various doses are required to determine the optimal drug therapy in children with ADHD.9 Effective treatment plans should include both behavioral and medication therapy, close monitoring and frequent follow-ups.7,10-12

Table 2 contains a summary of clinical guideline recommendations for the treatment of attention- deficit/hyperactivity. In general, the guidelines recommend treatment with medication and behavioral therapy in children and adolescents with ADHD. In preschool-aged children, guidelines recommend behavioral therapy alone as first-line treatment of ADHD. In adults, guidelines recommend medication therapy alone as first-line treatment of ADHD. Recommendations suggest stimulants are more efficacious than non-stimulants in the treatment of ADHD. Medication recommendations include a methylphenidate agent as first-line, with atomoxetine in patients with underlying anxiety disorder or risk for substance abuse, and use of amphetamine agents in patients with methylphenidate-resistant disease. All patients should have a well-thought out treatment plan with close follow-up and appropriate titration of medication therapy.

Anxiety

The DSM (Diagnostic and Statistical Manual of Mental Disorders) classification is the 5-axis diagnostic system developed and published by the American Psychiatric Association (APA). The DSM multi-axial system provides a comprehensive and systematic evaluation of the patient to identify and diagnose mental health disorders.13,14 The axis I DSM psychiatric disorders include the depressive and anxiety disorders including: acute stress disorder, agoraphobia, generalized anxiety disorder (GAD), obsessive- compulsive disorder (OCD), panic disorder and posttraumatic stress disorder (PTSD).13,14 The anxiety

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disorders are the most common outpatient psychiatric illnesses and up to 75% of patients who have experienced a panic attack will meet the diagnosis for a major depressive disorder. Alcohol and/or substance abuse problems may also occur in patients with anxiety disorders, as a form of self- medication.15-20

The medical management of the anxiety disorders includes both pharmacotherapy and psychotherapy. With regard to psychological therapies, cognitive-behavioral therapy (CBT) remains the gold standard.21,22 A number of pharmacotherapy options exist for treatment of the anxiety disorders including: tricyclic antidepressants, monoamine oxidase inhibitors, second-generation antidepressants: selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), anticonvulsants, antipsychotic medications, buspirone and benzodiazepines. Historically, the benzodiazepines were the core of the medical management of anxiety disorders due to their tolerability and rapid onset of action.22 Current guidelines do not recommend benzodiazepines as first-line treatment options. A short course of a benzodiazepine, at the lowest dose and only on an as-needed basis, is recommended for benzodiazepine therapy in the treatment of anxiety disorders. Buspirone, an anxiolytic that may be effective in the treatment of generalized anxiety disorders, is dosed multiple times a day and requires several weeks of therapy before a response is seen.15 The second-generation antidepressants, including the SSRI/SNRI agents escitalopram, paroxetine, venlafaxine and duloxetine, are labeled for use in GAD and may be safer options for the long-term treatment of chronic anxiety (SSRI/SNRI are considered first-line pharmacotherapy). Other agents used in the treatment of anxiety include the GABA-nergic acting anticonvulsants, divalproex, gabapentin, oxcarbazepine, pregabalin and tiagabine.15 Overall, therapy is chosen based on the presenting anxiety disorder and patient history. The combination of both pharmacotherapy and psychotherapy is beneficial in the treatment of all anxiety disorders.21,22

Insomnia

Insomnia is a disorder defined by difficulty with sleep initiation, duration, consolidation, or quality.23,24 Diagnostic criteria for chronic insomnia specify that “symptoms must cause clinically functional distress or impairment; be present for at least 3 nights per week for at least 3 months; and not be linked to other sleep, medical, or mental disorders.”25 General insomnia disorder occurs despite adequate opportunity for sleep, results in daytime impairment, and causes distress.23,24 Insomnia symptoms occur in up to half of the adult population in the United States.24 Risk factors for insomnia include increasing age, female sex, comorbid disorders, and shift work.23,24 There is also a difference reported between the type of insomnia experienced by younger and older people (difficulty falling asleep vs. waking up after sleep onset).26 Older adults are more likely to experience the latter.26

The medical management of insomnia includes both behavioral therapies, pharmacotherapy, or a combination of both.26 Behavioral therapies include: relaxation therapy, stimulus control therapy, and sleep restriction therapy.24 Cognitive Behavioral Therapy (CBT-I) incorporates sleep restriction, stimulus control, sleep hygiene, and cognitive therapy such as relaxation techniques.27 The American College of Physicians (ACP) Guidelines recommend cognitive behavioral therapy for insomnia (CBT-I) as the initial treatment for chronic insomnia disorder and that clinicians use a shared decision-making approach regarding pharmacological therapy (if behavioral therapy fails).26 A number of pharmacotherapy options exist for the treatment of insomnia including: benzodiazepines (triazolam, estazolam, temazepam, flurazepam, and quazepam); benzodiazepine receptor agonists/nonbenzodiazepine hypnotics (zaleplon, zolpidem, and eszopiclone); melatonin receptor agonist (ramelteon); the orexin receptor antagonist (suvorexant); the antidepressant doxepin; and off-label use of other drugs such as other sedating

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antidepressants, anticonvulsants, antipsychotic medications, melatonin, or other over-the-counter antihistamine (e.g. diphenhydramine) and herbal drugs.24,26 According to Lexicomp information, “While experience to date in the management of insomnia principally has been with estazolam, flurazepam, quazepam, temazepam, and triazolam, other benzodiazepines also can be used for insomnia.”28 Before the introduction of the newer benzodiazepine receptor agonist insomnia medications (zolpidem, eszopiclone, zaleplon), drug therapy in the treatment of insomnia was dominated by benzodiazepine agents due to their tolerability and rapid onset of action.24,29 However, the newer agents may now be preferred because of their relatively rapid onset of effect, short duration of action, and lower risk of abuse, tolerance, and dependence than the benzodiazepines.28,29 Pharmacotherapy is second-line and should be used in conjunction with nonpharmacologic therapy. According to the recent ACP guidelines for the management of chronic insomnia, evidence was insufficient to determine the benefits of pharmacologic therapy with benzodiazepines in the general population or in older adults, and only a few trials met the inclusion criteria because many assessed short durations of treatment.26

Methodology

Relevant information from the Benzodiazepine Drug Utilization Review (June 2017) and the P&T Drug Class Review Central Nervous System Stimulants used in the Treatment of Attention Deficit Disorder (May 2016) was incorporated into this report.

Cochrane Library literature searches for systematic reviews were conducted. Medline (PubMed), Up to Date, the Agency for Healthcare Research and Quality (AHRQ), the U.S. Department of Health and Human Services website, the FDA website (including product labeled information), the Substance Abuse and Mental Health Services Administration (SAMHSA) website,30 University of Maryland Center for Substance Abuse Research (CESAR) website,31 Micromedex, Lexicomp, and the Trip database were searched for safety information, systematic reviews, clinical trials, and other guidelines. References of relevant search results were also screened for additional relevant publications. A recent continuing education activity that focused on ADHD medications and the pharmacist’s role in managing side effects was reviewed and relevant information was incorporated into this report and it was used to perform additional searches.32 A focused internet search was also conducted.

Drug Information

Table 3 and 5 (Appendix 1) compares all of the benzodiazepine and stimulant agents.

The CNS stimulant agents are indicated in the treatment of ADHD and in the treatment of exogenous obesity and narcolepsy. This review is limited to the use of CNS stimulants in the treatment of ADHD and not narcolepsy or obesity (anorexiant).28

Non-stimulant medications are alternative options for the treatment of ADHD (e.g., for patients who are not able to achieve their therapeutic goals while on stimulants, or who experience intolerable side effects with stimulants).32,33 These include • Selective noradrenergic reuptake inhibitor: Atomoxetine (Strattera)32,33 32,33 • Specific α2 adrenergic agonist: Guanfacine extended-release (Intuniv) 32,33 • Nonspecific α2 adrenergic agonist: Clonidine extended-release (Kapvay).

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Pharmacology

Appendix 2 provides a summary of the pharmacokinetic properties for each of the benzodiazepine and stimulant agents.

Stimulants

Three types of stimulants—amphetamine (dextro-amphetamine and levo-amphetamine), methamphetamine, and methylphenidate (dextro-methylphenidate and levo-methylphenidate) —are used for treatment of attention deficit/hyperactivity disorder (ADHD), management of narcolepsy or weight reduction.34 Many different formulations exist, ranging from immediate release to extended release formulations.35,36 Amphetamines, methylphenidate and methamphetamine are used to increase the availability of catecholamines and alleviate symptoms. In addition, the various isomers of these agents are commonly combined in differing ratios to exert desired pharmacologic effects and reduce adverse effects. Of note, individual patient genetic variations can result in differences in efficacy between the agents; for example, patients with a 9/9 genotype (SLC6A3/DAT1) may require higher doses of stimulant medications in order to achieve adequate symptom control.37

Amphetamines, which belong to the class of β-phenylethlyamines, are potent noncatecholamine sympathomimetic amines which increase the availability of catecholamines such as dopamine or norepinephrine via increased release or reuptake inhibition.34-36 This results in peripheral as well as central nervous system stimulation and results in increased blood pressure and bronchodilation. The alerting and anorectic effects of amphetamines are thought to originate from norepinephrine release in central noradrenergic neurons. Amphetamine is composed of two active isomers, dextro-amphetamine and levo-amphetamine, with different actions in the body. Dextro-amphetamine is approximately 3-4 times more potent than levo-amphetamine in producing central nervous system (CNS) stimulation. Levo-amphetamine has slightly more potent cardiovascular effects, including increased systolic and diastolic pressure and the production of cardiac arrhythmias at high doses. As a result, amphetamine agents (Adzenys® 3:1, Dyanavel® 3.2:1) and mixed amphetamine salts (Adderall® 3:1) utilize higher ratios of dextro-amphetamine to levo-amphetamine to reduce the risk of unwanted cardiovascular effects. Dextroamphetamine (Dexedrine®) and lisdexamfetamine (an inactive prodrug which is converted to dextro-amphetamine, Vyvanse®) are not mixed-isomer agents and have pharmacological effects solely due to dextro-amphetamine.34-36

Methamphetamine is structurally similar to amphetamine, with the only difference being the addition of a methyl group at the N position. Methamphetamine acts by increasing the availability of catecholamines, enhancing release from storage sites, inhibiting reuptake through monoamine transporters and decreasing metabolism by inhibiting oxidases. The central effects of methamphetamine tend to be more prominent than that of amphetamine.34-36 Desoxyn® is an oral tablet methamphetamine agent indicated in the treatment of ADHD and exogenous obesity. Methylphenidate is also structurally related to amphetamines, with the addition of a piperidine group. Methylphenidate (Concerta®, Ritalin®, others) is composed of two active isomers, the more potent d- methylphenidate and l-methylphenidate. Dexmethylphenidate (Focalin®) constitutes the active d- methylphenidate isomer. Methylphenidate acts by decreasing dopamine and norepinephrine reuptake and, overall, produces similar pharmacological effects as amphetamines.34-36

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Benzodiazepines

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.38,39 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.38,39

Table 1. Duration of action40,41 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)

Efficacy

Stimulants in the treatment of ADHD Sufficient evidence supports the effectiveness of stimulants in the treatment of ADHD. However, limited evidence exist for effectiveness of ADHD treatments in patients with ADHD and comorbid conditions.42

Benzodiazepines in the treatment of anxiety or insomnia Patients with ADHD may experience anxiety or sleep problems due to the condition itself (rebound effect when medication wears off), comorbidities, or as a side effect of stimulants. Appropriate courses of action to manage these problems will be discussed in the rest of the report. This section includes general evidence for the effectiveness of benzodiazepines in the treatment of anxiety or insomnia.

As per the June DUR report on benzodiazepines, clinical guidelines do not recommend benzodiazepines as first line treatment for anxiety or insomnia (reserved for use only after other options have failed). When used to treat anxiety or insomnia, benzodiazepines should be prescribed at the lowest effective dosage on a short-term basis (≤ 4 months) accompanied by a comprehensive treatment plan with careful follow-up. There is insufficient evidence to support long-term use of benzodiazepines and major safety concerns exist.

The American College of Physicians Guideline for the management of chronic insomnia (2016) was based on a systematic review of randomized controlled trials published 2004 through September 2015; a full evidence report,43 and 2 background evidence review papers.44,45 The evidence review was sponsored by the Agency for Healthcare Research and Quality (AHRQ). The full evidence report included “181 unique studies (data from 128 unique RCTs and 3 systematic reviews that synthesize data from 42 unique RCTs) and 12 observational studies,” but most trials were short-term studies.43 Evidence supports cognitive behavioral therapy for insomnia (CBT-I) which “improved global outcomes and nearly all sleep parameters in the general adult population, older adults, and adults with pain”.43 Less evidence exists for other psychological interventions.43 The full publication contains tables that summarize all the available evidence for the general population and for older adults.43

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“Low- to moderate-strength evidence indicated that the nonbenzodiazepine hypnotics eszopiclone and zolpidem, and the orexin receptor antagonist suvorexant, improved short-term global and sleep outcomes in general adult populations. Doxepin improved sleep outcomes. The absolute mean effect was small. Evidence for benzodiazepine hypnotics, melatonin agonists, and antidepressants in general populations and for most pharmacologic interventions in older adults was generally insufficient.”43

Safety

Adverse effects (stimulants) The most common adverse events (based on events occurring in ≥10% of patients) associated with use of the central nervous system (CNS) stimulants, includes headache, insomnia, increased blood pressure, abdominal pain and decreased appetite. Less commonly reported adverse events are restlessness, anxiety, dizziness, weight loss, growth suppression in children and adolescents, changes in libido, dry mouth, nausea, vomiting and diarrhea.35,36 Amphetamines, methylphenidate and methamphetamine also carry black box warnings for high dependence and abuse potential.35,36 Close monitoring and caution should be exercised when prescribed to patients with a known history of drug abuse or dependence. More serious, but rare, adverse effects reported with the CNS stimulant use includes psychosis, sudden death, cardiac arrhythmias, stroke, myocardial infarctions, priapism, anaphylaxis, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Permanent leukoderma has been reported with methylphenidate (Daytrana®) transdermal patches.35,36

Adverse effects (benzodiazepines) The most common adverse reactions associated with benzodiazepine use, includes 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.46,47 Long-acting benzodiazepines can accumulate increasing the risk of dizziness, confusion, hypotension, and cognitive impairment. The risks associated with use of benzodiazepines and risk factors that increase the potential for adverse events are discussed in the June DUR report. Populations at higher risk include the elderly, children, patients with a history of substance abuse, on high doses, on long-term use, with concurrent opioid and benzodiazepine use or polydrug use, patients with kidney or liver failure, and patients with bipolar disorder.

Misuse/abuse/inappropriate use 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).48-51 When abused, patients become dependent on the misused drug and may result in adverse sequela including overdose. “Those with a history of a substance use disorder are at higher risk of misusing substances in their futures.”52 Bihlar Muld et al. report that ADHD is associated with an increased risk of co-existing substance abuse, and they found that patients with both ADHD and substance use disorder (SUD) were “significantly more often in compulsory care during childhood or adolescence, as well as imprisoned more often as adults” compared to patients with SUD without ADHD.53 Patients with untreated ADHD are more likely to develop substance misuse disorder.32 ADHD treatment controls the disorder and reduces their risk for substance use disorder, but use of stimulants as treatment for ADHD is a concern in these patients because of the high abuse potential of stimulants.32 Atomoxetine is an alternative option in patients with a high risk of substance misuse.32

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A growing concern with stimulant therapy is the increasing rate of stimulant abuse occurring among the caretakers of children prescribed the medication and youth without diagnoses of ADHD. In youth without an ADHD diagnosis, the most frequently reported reason for abuse is to improve academic achievement (used as a study aid), with recreational use also reported commonly.54,55 Increased rates of abuse parallel increased rates of overdose. Stimulant medications have a low therapeutic index, with toxicity occurring at levels just above recommended doses. The acute ingestion of more than 1 mg/kg of dextroamphetamine (or equivalent) may be life-threatening; although, the development of tolerance can occur after repeated stimulant use. Acute signs of stimulant overdose include restlessness, agitation, psychosis, seizures, coma and hypertension potentially resulting in myocardial infarction or intracranial hemorrhage. Peripheral signs and symptoms of overdose may include sweating, tremor or rigidity. Death may result from ventricular arrhythmia, status epilepticus or hyperthermia. Effects associated with chronic amphetamine abuse include cardiomyopathy, dental changes, paranoid psychosis, pulmonary hypertension and weight loss.56 The National Poison Data System published a retrospective, observational, case series of non-therapeutic stimulant exposures from 2007 to 2012. According to the report, the majority of patients were referred to health care facilities with most patients reporting no effects or only minor toxicity, while serious adverse effects occurred in approximately 20-25% of reported cases. Toxic effects did not differ across stimulant agents.57 A randomized, controlled trial reported similar outcomes with methamphetamine and dextroamphetamine agents demonstrating equivalence for abuse potential.58

Concurrent use of stimulants and benzodiazepines Using “uppers” (CNS stimulants) and “downers” (benzodiazepines) concurrently cancels the corresponding effect. This may lead to increases in doses to achieve the desired effect and the risk of adverse outcomes including overdose.

Duration of use Inappropriate long-term use of benzodiazepines was presented in the June DUR benzodiazepine report. Long-term concurrent use (stimulant and benzodiazepine) puts the patient at an even higher risk of adverse outcomes.

Specific populations Due to limited evidence and safety concerns, benzodiazepine use in the elderly, children, and in patients with a history of substance abuse should be limited.

Distinguishing between ADHD-related and stimulant-related insomnia

Please refer to the American Academy of Pediatrics (AAP) Algorithm and discussion in the guideline section below. According to UpToDate, the timing of the adverse effect is important to determine whether the effect is caused by the stimulant, an environmental stressor, or a coexisting condition.59

In addition, Adelaide Robb, MD (Associate Professor, Psychiatry and Pediatrics, Children’s National Medical Center, Washington, DC) has responded to a question posed on Medscape in 2006 regarding insomnia in children with ADHD (“How do I differentiate psychostimulant-related insomnia from ADHD- related insomnia? How can I address this issue in my patients?”).60 According to Dr. Robb (and similar to the AAP algorithm), a careful history is the easiest way to answer this question by reviewing bedtime routine, sleep habits, and various bedroom factors that might keep them awake. “For many patients with unmedicated ADHD, sleep issues center around going to bed and bedtime routine” and she

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mentions how these kids would often pop in and out of the bedroom “asking for a snack, drink of water, one more hug, etc.” and this could typically last for 30 to 90 minutes, but they would usually sleep through the night once they had fallen asleep.60

New-onset sleep changes or disruptions can result from stimulant therapy as well as other medications (e.g. steroids, asthma medications, or selective serotonin inhibitors). Stimulants may cause difficulty falling asleep, worsened with higher doses, but once asleep would “experience a good quality of sleep for the rest of the night.” Atomoxetine can cause insomnia or hypersomnia. Dr. Robb states that some patients complain they need to take a nap or sleep longer when switching to atomoxetine. This can be managed by a cross titration from stimulants to atomoxetine (“not just stopping the stimulants and starting atomoxetine”), by titrating the dose more slowly, and by taking the majority of the dose in the evening.60

Approaches to manage insomnia is age dependent, and includes; • All ages: Good sleep hygiene (removing screens: television, computers, games, cell phones), reduce other factors affecting sleep (e.g. caffeine) and review other medications • Young children with little or no homework: Switch to a stimulant with a shorter duration of activity (e.g. 12-hour duration to 8-10 hour duration) • Kindergartners: “Using a short-acting stimulant for the school day may also eliminate insomnia.” • Middle and high school students: Reduce the dose of any short-acting stimulant required in the afternoon.60

UpToDate suggests adjusting the dose, time of administration, or formulation of stimulant if symptoms are mild (caveat: symptoms may resolve over time).59 Dr. Robb mentions other options if the initial changes did not provide sufficient relief of insomnia. These include low dose clonidine or melatonin.60 Only the extended release clonidine (Kapvay) is indicated in the treatment of ADHD as monotherapy or as adjunctive therapy, and it is included in the AAP guidelines as a treatment option for ADHD. Kapvay is not specifically indicated for insomnia. The AAP Algorithm includes factors to consider when selecting an ADHD medication and formulation, and indicated whether the medication alters sleep initiation. 32,61,62 Somnolence is a potential side effect of atomoxetine and clonidine (α2-agonist). In patients with sleep issues, the selection of medications that cause somnolence may be beneficial.

Clinical Guidelines

The 2011 American Academy of Pediatrics Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents includes information about coexisting conditions such as “learning problems, language disorders, disruptive behaviors, anxiety, mood disorders, tic disorders, seizures, developmental coordination disorders, or sleep disorders.”63 In some cases patients do not need additional treatment for the coexisting conditions because treatment of the ADHD somehow resolves the issue. This is particularly true of oppositional defiant disorder or anxiety disorders.63 In some cases additional treatment may be required when conditions are severe and some patients may benefit from additional involvement of specialists i.e. “referral and comanagement with a subspecialist.”63 According to the guidelines, “the subspecialists could include child psychiatrists, developmental behavioral pediatricians, neurodevelopmental disability physicians, child neurologists, or child or school psychologists.”63 An important consideration for adolescents with ADHD is that this population is at greater risk for mood and anxiety disorders, substance abuse, and other risky behaviors.63 No more specific treatment

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recommendations are made within the guideline regarding pharmacological treatment for coexisting conditions, except “Through its Task Force on Mental Health, the AAP has developed algorithms and a toolkit for assessing and treating (or comanaging) the most common developmental disorders and mental health concerns in children.”63 The guideline states that the “accompanying process-of-care algorithm provides a list of the currently available FDA-approved medications for ADHD (Supplemental Table 3). Characteristics of each medication are provided to help guide the clinician’s choice in prescribing medication.”63

Process of Care Supplemental Appendix information33

Non-cost related factors that affect ADHD treatment formulation decisions include33: • Efficacy in a particular patient • Preferred duration/treatment coverage time • Swallowing difficulties (capsules, tablets, immediate-release methylphenidate for example is available in liquid, chewable forms and patches are available that are applied for 9 hours) • Convenience (e.g. fewer administrations and sustained coverage with extended-release formulations; limiting the need for school-based administration) • Better adherence (e.g. with extended-release formulations) • Minimization of adverse effects

Time-related contextual issues affecting treatment decisions (to ensure medications are active during these times) include33: • Time of day when targeted symptoms occur • Time when homework is usually done • Time when teenagers are driving

The time when the stimulant is active is an important consideration for patients that experience problems with sleep initiation.33 The AAP supplemental algorithm contains information on the comprehensive diagnostic evaluation and that it should include a comprehensive history i.e. obtaining information on “the onset, frequency, and duration of behaviors, situations in which they increase or decrease, previous treatments and their results”, family history of mental illness such as ADHD, mood, anxiety, and bipolar disorders, substance disorders, etc. The comprehensive evaluation and other considerations suggested by the algorithm would help clinicians to treat and manage patients with ADHD e.g. to distinguish between primary sleep disorders (which are often associated with ADHD), or sleep problems in ADHD in the absence of primary sleep disorders. Patients could experience sleep problems due to adverse effects of ADHD medication, coexisting psychiatric conditions (i.e. anxiety and mood disorders), altered circadian-based sleep-wake patterns, or inadequate sleep hygiene. The algorithm does not include benzodiazepines as a treatment option.33

The most common adverse effects of ADHD medications mentioned in the AAP guideline: • Stimulants: appetite loss, abdominal pain, headaches, and sleep disturbance. • Atomoxetine (nonstimulant): initial somnolence and gastrointestinal tract symptoms, particularly if the dosage is increased too rapidly; decrease in appetite; increase in suicidal thoughts (less common); and hepatitis (rare). • Extended-release guanfacine and extended-release clonidine (nonstimulants): somnolence and dry mouth.64

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NICE guidance recommends simple drug regimens (i.e. once-daily modified-release doses taken in the morning) for people with ADHD. Modified-release preparations are also recommended for patients in whom misuse or diversion is a concerns. NICE guidance does not directly address insomnia, but states that an individual treatment approach is important and that treatment should be reviewed regularly to determine the effect on coexisting conditions and mood changes and to assess whether changes are needed. With regards to anxiety: “Anxiety symptoms, including panic, may be precipitated by stimulants, particularly in adults with a history of coexisting anxiety. Where this is an issue, lower doses of the stimulant and/or combined treatment with an antidepressant used to treat anxiety can be used; switching to atomoxetine may be effective.”65

In 2011, the European guidelines for managing adverse effects of medications for ADHD66 was published. Thereafter, Cortese et al. conducted a review to update the European guidelines on managing the adverse effects of medications for ADHD (Graham et al., 201166), and provide a summary document for the practical implementation of the guidelines in a question and answer format.62 The European guideline was based on evidence published until October 2010 and the updated review search was done until June, 30th 2012.62 There were three questions included regarding sleep disturbance:

“What is the evidence for an association between drugs used to treat ADHD and sleep disturbance.”62 Inconsistent evidence was found. “[t]he effects of psychostimulants on sleep vary considerably from patient to patient.”62 The authors state that the heterogeneity in the findings can be “explained by several factors, including variations in the length of trials, administration times, the stimulant dosage, and whether the child has just started medication, or whether they have been on medication for an extended period of time.”62,67

“How should I monitor sleep disturbances during treatment with ADHD drugs?”62 Sleep should be carefully assessed (at baseline before initiation of medication, and at follow-up) and should include “bedtime resistance, sleep-onset difficulty, night awakenings, difficulty with morning awakenings, sleep-breathing disorder and daytime sleepiness.” Sleep questionnaires and diaries are suggested. Screening for RLS is recommended and further investigation “if there is a suspicion of sleep- breathing disorder, episodic nocturnal phenomena, limb movements, and unexplained excessive daytime sleepiness.”62

“How should I manage sleep disturbances during treatment with ADHD drugs?”62 (considerations for the clinician) 1) Review nature and history of sleep disturbance and efficacy of medication. “Sometimes medication can be reduced or stopped; more intensive behaviour therapy may achieve good results for ADHD control even without medication.”62 2) If medication is continued, ensure proper sleep hygiene and behavior techniques 3) If behavioral measures do not resolve sleeping problems, consider/determine likely cause: a. “RLS [restless leg syndrome] (monitoring ferritin levels in the evening and considering iron supplementation if needed) and periodic limb movements of sleep”62 b. Rebound effect (“return of restlessness once medication effects worn off”): “consider adding a small dose of short-acting psychostimulant in the evening.” c. Persisting stimulant action: i. “consider reducing psychostimulant levels in the evening or switch to a shorter- acting preparation.”

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ii. Melatonin may “reduce sleep-onset delay associated with MPH when the clinician, the family and the patient do not wish to switch to another class or agent.”68 iii. Consider switching to a nonpsychostimulant (atomoxetine given once daily in the evening or guanfacine). “Given the evidence that atomoxetine may more often lead to somnolence than insomnia, switching to atomoxetine may be warranted in cases of sleep-onset delay.”62

Guanfacine and clonidine were not licensed in the EU for ADHD at the time of this publication, but some information was included in this publication regarding these agents. Clonidine is associated with significantly more somnolence than placebo (Daviss et al. 2008), and “some authors recommend using clonidine for sleep-onset delay associated with psychostimulants, although there are currently no randomized trials supporting this.”62

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Table 2. Current Clinical Treatment Practice Guidelines for Attention Deficit Disorder Guideline Recommendations NICE (NGC: 011017) • No specific information regarding insomnia Feb 2016. Attention • Some information regarding anxiety in the “Monitoring Side Effects and the Potential for Misuse in deficit hyperactivity Children, Young People and Adults” section (discussed above) disorder: diagnosis Treatment for children and young people and management. • Parent-training/education programs are first-line for pre-school children; drug treatment is not recommended for pre-school children • Group-based parent-training/education programs are first-line for school-age children and young people with moderate impairment • Medication therapy is usually first-line for school-age children and young people with severe symptoms and impairment or for those with moderate impairment who have not responded to parent-training/education programs or group psychological treatment o Drug treatment should only be initiated by an ADHD specialist o Drug therapy includes: methylphenidate, atomoxetine and dexamphetamine . “Methylphenidate for ADHD without significant comorbidity . Methylphenidate for ADHD with comorbid conduct disorder . Methylphenidate or atomoxetine when tics, Tourette's syndrome, anxiety disorder, stimulant misuse or risk of stimulant diversion are present . Atomoxetine if methylphenidate has been tried and has been ineffective at the maximum tolerated dose, or the child or young person is intolerant to low or moderate doses” . “Dexamphetamine in children and young people unresponsive to a maximum tolerated dose of methylphenidate or atomoxetine” o Extended-release preparations should be considered: for convenience, improving adherence, reducing stigma, in schools with rules against storing and administering controlled drugs. Modified-release methylphenidate and dexamfetamine may be preferred if the potential for drug misuse or diversion is a concern. o Immediate-release preparations should be considered: for more flexible dosing regimens, during initial titration o Methylphenidate modified-release preparations should be given as a single dose in the morning and immediate-release preparations in two or three divided doses o Atomoxetine can be given as a single dose or divided doses to minimize side effects o Dexamphetamine should be given in divided doses Treatment for adults • Medication therapy is the first-line treatment for adults with moderate or severe levels of impairment o Methylphenidate is the first-line drug . Modified-release should be given once daily (or no more than twice daily) and immediate-release should be given up to four times daily o Psychological interventions without medication may be effective for some adults with moderate impairment o Atomoxetine (may be divided doses) or dexamphetamine (divided doses; usually 2-4 times daily) are recommended in patients who did not respond to methylphenidate treatment There is potential for drug misuse and diversion in adults with ADHD receiving stimulants. If methylphenidate is used, the modified-release preparations may be preferred in cases where substance misuse or abuse is a concern. Modified-release may also be preferred if adherence is a concern American Academy of Recommendations vary depending on the patient’s age: Pediatrics guidelines Preschool-aged children (4–5 years of age) on Attention- • Evidence-based parent- and/or teacher-administered behavior therapy as the first line of treatment Deficit/Hyperactivity • Methylphenidate if the behavior interventions do not provide significant improvement and there is Disorder (2011)64 moderate-to-severe continuing disturbance in functioning Elementary school–aged children (6–11 years of age) • FDA–approved medications for ADHD and/or evidence-based parent and/or teacher-administered behavior therapy as, preferably both o Evidence is strong for stimulant medications and sufficient but less strong for atomoxetine, extended-release guanfacine and extended-release clonidine (in that order)

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Table 2. Current Clinical Treatment Practice Guidelines for Attention Deficit Disorder Guideline Recommendations Adolescents (12–18 years of age) • FDA–approved medications for ADHD and/or evidence-based parent and/or teacher-administered behavior therapy as, preferably both Medication therapy in all patient age groups should titrated to achieve maximum benefit with minimum adverse effects The European Evidence and advice is presented in the guideline publication in terms of areas of concern: guidelines on - Cardiac adverse events managing adverse - Suicide-related events effects of medications - Growth in childhood for ADHD (2011)66 - Sleep disturbance (A workgroup of the - Tics and Tourette’s syndrome European Network - Substance abuse, misuse, and diversion for Hyperkinetic - Epilepsy and seizures Disorders: The - Psychotic symptoms European ADHD - Drug holidays: a way of controlling adverse effects of ADHD drugs? Guidelines Group) - Issues lacking evidence and future evidence sources

Only summaries relevant to this review are included. Please refer to the full publication for additional information.

Sleep Disturbance May be due to condition (ADHD), ADHD medication, or conditions associated with ADHD (e.g. anxiety). Effects of stimulants on sleep vary considerably from one patient to another. Limited number of studies and contradicting findings => “guidelines for the management of sleep disturbances associated with ADHD cannot be properly evidence based”. • Before starting medication: History of sleep problems should be assessed => if a severe/significant issue, consider atomoxetine as first line choice • Problems that arise during treatment: Sleep diaries are recommended. “Sleep hygiene and behaviour therapy techniques based on stimulus control, and appropriate bedtime scheduling, should be encouraged for children with sleep-onset problems and/or possible delayed sleep phase syndrome.” • If sleep problems continue after dose adjustment and dose-scheduling of the original medication: switch to alternative (e.g. stimulant => atomoxetine)

Drugs not licensed in Europe for ADHD were outside the scope of the guidance (including guanfacine, modafinil, clonidine, and tricyclic antidepressants). However, some evidence is mentioned: • Some evidence exist that clonidine may be effective in ADHD with sleep problems (Wilens et al. 199469) • Melatonin is also mentioned as a reasonable option based on recent evidence of effectiveness in “reducing sleep-onset problems in ADHD children.” (Bendz et al. 201070

 Benzodiazepines are not included or mentioned as treatment options for the management of sleep disturbances in patients with ADHD.

American Academy of Initial medication therapy should be with a trial of an agent with a labeled indication for the treatment of Child and Adolescent ADHD by the FDA: dextroamphetamine, methylphenidate, mixed salts amphetamine or atomoxetine: Psychiatry guidelines • Stimulants are highly efficacious on Attention- • Methylphenidate and amphetamine agents are equally efficacious in the treatment of ADHD Deficit/Hyperactivity • Long-acting formulations are equally efficacious as immediate-release agents but may be more Disorder (2007)71 convenient In patients with treatment-refractory disease, Behavior Therapy and/or the use of medications not approved by the FDA for the treatment of ADHD (bupropion or tricyclic antidepressants) should be considered

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Table 2. Current Clinical Treatment Practice Guidelines for Attention Deficit Disorder Guideline Recommendations All patient should be monitored for treatment-emergent side effects and assessed periodically for treatment efficacy • Patients treated with medication for ADHD should have height and weight monitored throughout treatment • Treatment of ADHD should continue as long as symptoms remain present and cause impairment Institute for Clinical Medication therapy Systems • Use FDA-approved treatments for ADHD in children, including psychostimulants and/or non- Improvement: stimulants Diagnosis and • Decision to initiate medication therapy should be made in conjunction with parents and discussion Management of of expected benefits and potential risks Attention Deficit • Age, disease severity and presence of comorbidities should be considered Hyperactivity • Optimal medication management alone is superior to other modalities for the core symptoms of Disorder in Primary ADHD Care for School-Age • If patient does not respond to initial medication choice, a second or third trial with other stimulants Children and is recommended 72 Adolescents (2012) • Atomoxetine is recommended in patients with comorbid anxiety, sleep initiation disorder, substance abuse or tics • Extended-release guanfacine and extended-release clonidine have a labeled indication as adjunctive therapy with stimulant medications • Second-line medications for ADHD therapy include tricyclic antidepressants (imipramine, desipramine), alpha adrenergic agonist (clonidine) a nontricyclic antidepressant (bupropion) or immediate-release guanfacine

Systematic reviews & Clinical Trials

No evidence was identified that supports the use of benzodiazepines for the treatment of insomnia or anxiety in patients with ADHD. The references identified address complexities in associations between ADHD, ADHD medications, comorbidities such as anxiety, and sleep problems; melatonin; and the effectiveness of stimulants in the treatment of patients with ADHD and anxiety.

Insomnia Guidelines do not recommend pharmacological treatment as first line therapy for sleep disturbances in patients with ADHD. Cortese et al. included searches up to June 30th 2012 so relevant publications after this date were included below (only regarding pharmacologic treatment).

Efron et al. (2014) reported that sleep problems are common in children with attention- deficit/hyperactivity disorder (ADHD), and they therefore reviewed sleep medication use in these children to get a better understanding this scenario.73 The authors found that 57/257 (22%) children with ADHD in Australia were taking sleep medication (melatonin 14% and clonidine 9%), and that it was “associated with combined-type ADHD and ADHD medication use.”73 The authors concluded that “Further research is needed on the broad functional benefits and long-term safety of sleep medication in this population.”73

Cortese et al. (2013) reported inconsistent evidence for the association between drugs used to treat ADHD and sleep disturbances and that the effect varied between patients.62 Kidwell et al. (2015) included 9 articles published through March 2015 in their review and meta-analysis and concluded that stimulant medication led to longer sleep latency, worse sleep efficiency, and shorter sleep duration in youth.74 They however also report limitations as “few studies, limited

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methodologic variability, and lack of unpublished study”, but highlight the need for monitoring sleep problems and adjusting treatment to promote optimal sleep based on their results.74

Neto et al. (2016) reviewed the literature (12 articles included) to explore the relationship between epilepsy, sleep disorders, and attention deficit hyperactivity disorder (ADHD). They found that “there were difficulties to start and maintain sleep in patients with epilepsy and ADHD, reduction in sleep efficiency, decreased seizure threshold, as well as behavioral and cognitive deficits in both groups.”75 The authors conclude that “it is important to know which symptom is the predominant one” and to carefully assess patients before starting treatment.75

Holvoet and Gabriëls (2013) reviewed the available evidence published in the last 10 years to evaluate the use, efficacy, and safety of melatonin in the treatment of children with ADHD.76 The authors found that melatonin is effective in the treatment of chronic sleep onset insomnia and is generally well tolerated.76 However, limited evidence is available regarding the possible impact on puberty, the endocrine system and its safety.76 It is therefore best to reserve it for “children with persistent insomnia which is having a severe impact on daily functioning.”76

Anxiety

Cortese et al. mentioned differences in response to stimulants between patients.62 Van Ameringen report that “it has been hypothesized that anxiety may be a feature that is closely tied to the pathogenesis of the ADHD”, but “it has also been proposed that ADHD with comorbid anxiety may represent a subtype of ADHD or that patients with ADHD and comorbid anxiety are phenotypically different from those with the pure disorder.”77 Patients with comorbid anxiety appear to respond differently to methylphenidate with less beneficial effects and a more severe cardiovascular response.78,79

Most studies focus on the treatment of ADHD and only a few on the efficacy of ADHD treatments in patients with ADHD and comorbid conditions such as anxiety.42,80 Atomoxetine appears effective in this population, but evidence is limited, trials were small, and several limitations were noted.

Adler et al. (2009) conducted a randomized, double-blind, placebo-controlled trial (14 week, multisite) assessing the effectiveness of atomoxetine (ATX) in adults with ADHD and social anxiety disorder (171 receiving atomoxetine and 158 placebo), and found that “ATX monotherapy effectively improved symptoms of ADHD and comorbid social anxiety disorder in adults and was well tolerated.”81

Kohn et al. (2015) in a 6 week randomized crossover trial explored how atomoxetine (vs placebo) improves cognition in children and adolescents with cross-disorder symptoms of ADHD and anxiety.82 This trial involved 136 children and adolescents with ADHD (43 with comorbid anxiety disorders).82 The authors found that “the effects of atomoxetine on cognition and anxiety occur independently, suggesting a dual mechanism for the pharmacological mediation of atomoxetine in ADHD.”82

Snircova et al. (2016) compared the effects of atomoxetine and methylphenidate in 69 patients (36 and 33 respectively) and found that both medications reduced the symptoms of ADHD and

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anxiety, but that “atomoxetine was more effective in anxiety symptom reduction from the fourth week of treatment, and lasted through to 8 weeks of medication.”83

An ongoing study regarding lisdexamfetamine dimesylate in the treatment of adult ADHD with anxiety disorder comorbidity exists.84

Summary Patients in whom misuse is a concern or in those with comorbidities

Switching to non-stimulants like atomoxetine or extended-release guanfacine is suggested for patients in whom misuse, abuse or diversion is a concern or in those with comorbidities that may be worsened by stimulants such as anxiety, insomnia, or hypertension.33 An extended-release formulation of methylphenidate (MPH) or lisdexamfetamine (amphetamine prodrug) may be considered if substance abuse is a concern.62 Patients with comorbid conditions such as depression or bipolar disorder may also benefit from alternatives such as bupropion (indicated in the treatment of major depressive disorder; used off-label for the treatment of ADHD)85,86 although the AAP Algorithm (for children and adolescents) does not address bupropion (it includes the FDA-approved non-stimulants; atomoxetine, extended-release guanfacine and extended- release clonidine).33 The 2007 American Academy of Child and Adolescent Psychiatry (AACAP) guidelines recommend bupropion as a second-line option in the management of ADHD in children and adolescents (for treatment-refractory disease).71 Although bupropion causes less CNS stimulation than stimulants, it, too, may cause CNS stimulation (restlessness, anxiety, insomnia).28

“Based on the Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of mood disorders and co-morbid ADHD, bupropion is first- line in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. Additionally, these guidelines recommend bupropion is recommended first-line in patients with ADHD and comorbid major depressive episodes, either as monotherapy or as an adjunct to long-acting stimulant medications.”28

Managing sleep problems in patients with ADHD

1) The European guidelines for the management of adverse effects of medication of ADHD suggest a baseline history of sleep problems prior to starting treatment and “if this is a severe/significant issue, it may suggest atomoxetine as a first line choice.”66

2) Determine cause of sleep problems & consider sleep diaries. Ensure proper sleep hygiene, appropriate bed-time scheduling (establish a bedtime routine), and consider cognitive behavioral therapy (CBT-I).

3) If appropriate, adjust the stimulant dose, formulation and timing of ADHD medications, or switch patients from stimulants to alternatives if dose/formulation adjustments are not effective.32,66,85,86 Timing is important and it is necessary to determine whether sleep problems occur due to too much stimulant activity or a rebound effect.

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• Too much stimulant activity: Reducing/omitting the stimulant dose in the evening, using a shorter-acting medication (if using a long-acting medication), and ensuring that the patient does not take a stimulant dose late in the day.32,59,85,86 • Rebound effect (when energy returns because the stimulant dose is wearing off): Increase the dose of the long-acting agent administered in the morning, or add a short- acting stimulant in the late afternoon, or switch to a longer acting agent if using short- acting medication.32,59,85,86

Some studies indicate potential differences in how different ADHD medications affect sleep. Patients with depression may be more prone to these effects.32,87 Methylphenidate and atomoxetine may increase sleep latency. Methylphenidate use also results in a shorter duration of sleep.32,88,89

When switching medication: - Stimulant to atomoxetine: “stimulant medication should be continued for the first few weeks (unless stimulant treatment was associated with concerning side effects) to allow atomoxetine to reach full effect.”59 - Atomoxetine to stimulants (i.e. lack of response): “atomoxetine can be stopped abruptly.”59

4) The addition of another medication to treat insomnia is considered a last line approach.32 Melatonin or a low dose clonidine could be considered.32,62,66,68

Benzodiazepines should NOT be used to treat adverse effects of stimulants or sleep problems in patients with ADHD (since supporting evidence is lacking).

5) Evaluate for RLS if sleeping problems continue (“estimated to be associated with up to 44% of ADHD patients”).32,62,77

Managing anxiety or mood lability in patients with ADHD

If mood lability occurs • At peak concentration: Consider “reducing the dose or switching to a longer acting preparation;” • Due to wearing off: “irritability, sadness, and increased activity as the medication wears off is particularly common when short-acting medication is used on a morning and noon twice-a-day schedule” Consider “adding an afternoon dose or switching to long-acting form;” • “referral for coexisting mood disorder or anxiety disorder may be warranted.”59

Place in therapy and potential criteria to be reviewed

Factors and limitations to consider:

• Benzodiazepine use in patients with ADHD: No guideline recommends benzodiazepines as a treatment option for insomnia or anxiety. Instead, the various factors to consider specific to each patient when choosing an ADHD treatment formulation is discussed with recommendations for changes to doses, formulations or switching to alternative medications presented (e.g. if patients experience adverse effects).

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• Concurrent use of stimulants and benzodiazepines: Both of these classes are controlled medications with potential for additive inappropriate use/abuse/misuse concerns. These agents have opposing actions on the CNS system which could lead to rebound effects, tolerance leading to use of higher doses putting patients at increased risk of fatal overdoses.

• Exceeding recommended doses: A motion was passed at the June 2017 DUR meeting assigning quantity limitations to benzodiazepines (as per FDA dosage recommendations). Currently diagnosis codes are not a requirement, and limits allow for the maximum dose for any indication for a particular benzodiazepine.

• Practice patterns: McElligot et al. assessed compliance with ADHD guidelines based on a survey that was sent to all physicians within the South Carolina Pediatric Practice Research Network (SCPPRN). A total of 42/76 surveys were returned. They found some differences in practice patterns by practitioner experience, location (urban or rural), and practice type (academic, private, or community health center). Twelve practitioners from the 42 returned surveys (29%) indicated that they were comfortable prescribing a sleep aid, and older graduates were more comfortable using sleep agents (60% vs 15%, p<0.01) although the sleep aids were not defined.90 “Urban practitioners more often preferred long-acting stimulants as first line (urban 91% vs rural 63%, p<0.01).”90 The authors note some of these differences are worth investigating further in the future.90

Fiks et al. evaluated whether there was a change in the diagnosis of ADHD and prescribing of stimulants to children 4 to 5 years old after release of the 2011 American Academy of Pediatrics guideline. Stimulants are not recommended first-line for this age group and the guideline presented a standardized approach to diagnosis. The comparison included 87,067 children with 118,957 visits before the guideline and 56,814 with 92,601 visits after the guideline. “Patterns of change from before to after the guideline varied significantly across practices.” There was a significant increasing trend of ADHD diagnosis before the guideline was released which ended after the guideline was released. However, the rate of prescribing stimulants remained constant.91

The CDC analyzed ADHD patterns in insured children (2- 5 years old) using claims data and found that medication treatment was more common than behavioral/psychological service use and that the 2011 guidelines did not change this pattern. Visser et al. reiterated, “Scaling up evidence-based behavior therapy might lead to increased delivery of effective ADHD management without the side effects of ADHD medications.”92

• Cultural differences in psychotropic use: The UK and US have different approaches when it comes to the use of psychotropics. The UK has a much more conservative approach, as well as much lower rates of psychotropic medication use.93 Murphy et al. described these differences in a recent publication with the UK stepped care approach as “Begin with no, then (only if necessary) start low and go slow” or abbreviated as “no/low/slow” versus what the authors describe as the “go/go/go” US guidelines (which include the 2011 American Academy of Pediatrics guideline).93 The authors acknowledge that patterns of care are the results of more than only guidelines and therefore they also compared prevalence of attention and depression disorders and medication use in the UK and US. Methodological differences in the studies were reported that affect prevalence rate reporting. The authors were unable to 21

determine whether higher (or not) prevalence rates in the US were the reason for the higher prescription rates.93 The authors “conclude by noting that the existence of an alternative standard provides validation for clinicians or families who prefer to take a more conservative approach to medication use. The two different approaches to care also provide a valuable opportunity for research to determine whether the approaches result in different treatment outcomes.”93

• Special Populations: Evidence is limited and inconsistent regarding benzodiazepine use in patients with a history of substance abuse. It is recommended that benzodiazepine use be limited in geriatric patients (refer to BEERS criteria40) and patients with a history of substance abuse. Refer to the June DUR benzodiazepine report for additional information regarding benzodiazepine use in patients with a history of drug or alcohol abuse.

The updated publication for the practical implementation of the European guidelines on the management of adverse events during the treatment of ADHD medications in children and adolescents state: “In case of current or previous substance abuse, an extremely close monitoring of a patient’s psychostimulant use is important.”62 It is recommended to choose atomoxetine or an extended-release formulation of MPH, or lisdexamfetamine (amphetamine prodrug).62

• Monitoring (efficacy and side effects of ADHD medications): General monitoring parameters provided by AAP32,33 Teachers During first Weekly Symptoms: Provide and month of feedback or complete parents initiation or DSM-IV-TR* based ADHD during titration rating scale At end of week: review adverse effects and measure progress towards achieving target goals Second 2-4 ADHD rating scale month/thereafter times/year (monitoring for efficacy)

Clinician Until patient is Monthly Symptoms/Response to consistently medication: Assess levels improving with of core symptoms and note regards to their improvements in target ADHD symptoms goals Monitor for adverse effects and measure pulse, blood pressure, and weight After consistently every 3 improving & months during the first year of treatment After first year twice a (until achieving year clear progress and symptoms are stable) *DSM-IV-TR=Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition

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• Consider consultation with behavioral health service experts/referring patients with complex conditions e.g. current or history of alcohol or drug use disorder, or concurrent severe psychiatric disorder.41

• Other Plans include prior authorization (PA) criteria which states that treatment of hyper- active-impulsive or inattentive symptoms with stimulants are NOT appropriate if caused by other comorbid conditions (e.g. inadequately treated depression or bipolar disorder, thyroid disease, or sleep apnea) or medications (e.g. benzodiazepines). The PA form assesses whether the Prescription Monitoring Program profile for the patient was assessed, time of diagnosis (child or adult), treatments tried (including non-drug), treatment and monitoring plan, implementation of an informed consent contract*, patient history of substance abuse/dependence, seizures, or anorexia/bulimia, or other mental health diagnoses before ADHD diagnosis. Additionally, the, frequency and duration of prescribed stimulants may not exceed FDA limits.94 *Informed consent form for CNS stimulants: Required signage by patient and includes information that these medications can be safe and useful, but have a high potential for misuse; are highly regulated; that it is a felony to acquire these medications inappropriately without a prescription or to give or sell them to anyone; that the patient will not request controlled medication prescriptions from any other prescribers and that controlled prescriptions will be written by only one regular prescriber; information on interactions and to inform prescriber of other medications or OTC products; to not use any illicit substances (may result in change to treatment plan, safe discontinuation of medication or complete termination of doctor/patient relationship); that changes will be made to medication if anxiety or panic attacks occur while on the stimulant (decreased or changed) and that benzodiazepines will not be prescribed to treat a side effects (due to risks of dangerous interactions and overdoses); to take medication as directed (explaining risks of decreasing or stopping medication without physician’s supervision/knowledge as depression or withdrawal, and increasing doses as hypertensive crisis, overdose, death); to inform the prescriber of any medication not needed (explaining on what days medication is not needed); to “take full responsibility to secure both the prescription and the medication safely so that they are not misplaced, lost, or misused by others”; to inform the patient about side-effects of stimulants including risk of addiction if used for other than its prescribed use or in dosages above those prescribed; and an overall statement stating: “By signing this document, I acknowledge I have read the above information, that I will abide by all parts of it and that failure to do so will result in termination of my stimulant medication.”94

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Utah Medicaid Utilization Data

The tables in Appendix 3 contains utilization data from 2014-2017 for all stimulant fills, stimulant fills where a benzodiazepine was filled within 30 days of the stimulant fill (ALL and FFS), and a utilization comparison showing the number of patients that had a concurrent fill at least once and at least twice. The charts and data below represent grand totals from 2014 to 2017.

Age and sex (of ALL patients that received stimulants and benzodiazepines concurrently)

800

600

400 M 200 F 0 <18 18-24 25-34 35-44 45-54 55-64 >64 M 314 133 274 231 134 39 7 F 195 165 752 686 277 124 5

Further breakdown of pediatric patients (ALL patients) AGE* M F Total 0-3 0 0 0 4-5 5 0 5 6-11 126 56 182 12-17 183 139 322 TOTAL 314 195 509

Diagnosis codes submitted for the 509 pediatric patients GP DESCRIPTION Number of patients Percentage A EPILEPSY/SEIZURES 87 17.1% B ALCOHOL MISUSE 16 3.1% C DRUG DEPENDENCE 11 2.2% D DRUG ABUSE 39 7.7% E POISONING 33 6.5% F ACCIDENTAL POISONING 20 4% G RESTLESS LEGS SYNDROME 8 1.6%

The American Academy of Pediatrics guidelines on Attention-Deficit/Hyperactivity Disorder (2011)64 recommend behavior therapy first-line for preschool children (4–5 years of age). Methylphenidate is recommended if the behavior interventions do not provide significant improvement and there is moderate-to-severe continuing disturbance in functioning. • Only one of the 4-5 year old patients received mehylphenidate; the others received amphetamine-dextroamphetamine; lisdexamfetamine dimesylate; and dextroamphetamine sulfate

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• Four prescribers prescribed stimulants to the 5 patients (4-5 years old); Prescriber specialties: 3 psychiatry and 1 pediatric psychiatry • Two of these prescribers were top prescribers for concurrent stimulant and benzodiazepine use as well as benzodiazepine prescriptions alone (June report)

Age and sex (of FFS patients that received stimulants and benzodiazepines concurrently)

300 250 200 150 100 M 50 0 F <18 18-24 25-34 35-44 45-54 55-64 >64 M 58 41 121 111 60 15 3 F 32 38 254 222 113 56 2

Further breakdown of pediatric patients (FFS patients) AGE* M F Total 0-3 0 0 0 4-5 0 0 0 6-11 19 9 28 12-17 39 23 62 TOTAL 58 32

Concurrent stimulant and benzodiazepine use

Table 12 (appendix 4) documents the top stimulant prescribers of concurrent stimulant and benzodiazepine treatment, and whether they were also top benzodiazepine prescribers (top benzodiazepine prescriber information from the June Medicaid DUR report).

• 44 of these concurrent prescribers were top benzodiazepine prescribers with the top 20 concurrent prescribers all being top benzodiazepine prescribers.

Table 13 shows the top benzodiazepine prescribers, claims and patients exceeding BZD dose and duration recommendations AND stimulant prescribers involved in concurrent stimulant and BZD treatment.

Concurrent stimulant and benzodiazepine fills may reflect inappropriate prescribing (e.g. if the same prescriber prescribed both concurrently) or could be related to doctor shopping if multiple prescribers are involved and the prescribers may be unaware of this. In the first instance,

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prescribers may benefit from interventions that would ensure appropriate prescribing. If multiple prescribers (and pharmacies) are involved, informing prescribers of this and encouraging patients to obtain their prescriptions from the same prescriber and pharmacy to reduce potential drug interactions, monitor the patient’s medication profile and address problems at the local pharmacy level. Some patients may benefit from being placed on Restriction to one pharmacy and one provider (or one location).

(1) The types of prescribers that prescribed both the stimulant and benzodiazepine prescriptions (of the concurrent stimulant and BZD use)

Same prescriber (prescribed both stimulant and benzodiazepine)

Physician Nurse Practitioner Osteopath Physician Assistant

0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000

STIMULANTS WITH CONCURRENT BENZODIAZEPINE - Same Prescriber Stimulant Claims/ PRESCRIBER TYPE PRESCRIBERS CLAIMS prescriber Physician Assistant 68 11.11% 1,085 6.77% 16 Osteopath 62 10.13% 1,765 11.01% 28 Nurse Practitioner 90 14.71% 4,281 26.69% 48 Physician 392 64.05% 8,907 55.54% 23 TOTAL 612 16,038

Prescriber specialty (prescribed both stimulant and benzodiazepine) Family Medicine Psychiatry Internal Medicine Pediatrics Physical Medicine & Rehab Neurology Geriatric Medicine Sports Medicine Endocrinology Obstetrics-Gynecology Emergency Medicine Pulmonology Cardiology Pain Management General Surgery Urology 0 2,000 4,000 6,000 8,000 10,000

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STIMULANTS WITH CONCURRENT BENZODIAZEPINE - Same Prescriber Stimulant Claims/ PRESCRIBER SPECIALTY PRESCRIBERS CLAIMS prescriber Urology 1 0.16% 2 0.01% 2 General Surgery 1 0.16% 3 0.02% 3 Pain Management 1 0.16% 3 0.02% 3 Cardiology 1 0.16% 5 0.03% 5 Pulmonology 1 0.16% 8 0.05% 8 Emergency Medicine 3 0.49% 9 0.06% 3 Obstetrics-Gynecology 2 0.33% 16 0.10% 8 Endocrinology 2 0.33% 53 0.33% 27 Sports Medicine 1 0.16% 61 0.38% 61 Geriatric Medicine 3 0.49% 66 0.41% 22 Neurology 8 1.31% 83 0.52% 10 Physical Medicine & Rehab 2 0.33% 84 0.52% 42 Pediatrics 21 3.43% 367 2.29% 17 Internal Medicine 38 6.21% 858 5.35% 23 Psychiatry 70 11.44% 5,220 32.55% 75 Family Medicine 457 74.67% 9,200 57.36% 20 TOTAL CLAIMS 612 16,038

(2) Multiple prescribers

Number of Prescribers Multiple Prescribers of Total Concurrent Therapy* Patients 2 3 4 5 6 7 > 7

2 Prescriptions Concurrently 1,563 473

3 Prescriptions Concurrently 1,358 445 40

4 Prescriptions Concurrently 312 93 16 2

5 Prescriptions Concurrently 70 25 4 0 0

6 Prescriptions Concurrently 26 8 3 0 0 0

7 Prescriptions Concurrently 4 0 0 0 0 0 0

> 7 Prescriptions Concurrently 3 0 0 0 0 0 0 0

3,336 *Any Concurrent stimulant and benzodiazepine filled within 30 days of each other. This included many different combinations (e.g. 2 stimulant prescriptions and 1 benzodiazepine; different products and different strengths).

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Multiple prescribers, multiple pharmacies, and diagnoses

3,336 patients received concurrent stimulant and benzodiazepine therapy from 2014-2017 • 1,109 from >1 prescriber • 838 from >1 pharmacy • 615/3,336 (18.5%) had a diagnosis code submitted for drug abuse • 3% had diagnosis codes for poisoning and 10% for accidental poisoning • 25 patients had diagnosis codes submitted for restless leg syndrome • 33% received >1 stimulant within 30 days  19% had a diagnosis code submitted for drug abuse • 28% received >1 benzodiazepine within 30 days  25.5% had a diagnosis code submitted for drug abuse  These patients had the highest percentages of diagnosis codes submitted for drug abuse and poisoning (including accidental) • For 387 patients, the BZD prescriber(s) were always different from the stimulant prescriber(s) and 106 filled these at >1 pharmacy

28

GP DESCRIPTION A EPILEPSY B ALCOHOL MISUSE C DRUG DEPENDENCE D DRUG ABUSE E POISONING F ACCIDENTAL POISONING G RESTLESS LEGS SYNDROME

DIAGNOSIS ** TOTAL PATIENTS WITH >1: PATIENTS Prescriber Pharmacy GP A GP B GP C GP D GP E GP F GP G

Concurrent Therapy 2014-17: Total Unique Patients 3,336 1,109 838 423 12.68% 355 10.64% 653 19.57% 615 18.44% 107 3.21% 330 9.89% 25 0.75%

>1 Stimulant Claim * 1,096 130 179 159 14.51% 105 9.58% 223 20.35% 210 19.16% 32 2.92% 115 10.49% 6 0.55%

Percent 32.85% 11.72% 21.36%

>1 Benzodiazepine Claim * 941 196 154 128 13.60% 130 13.82% 262 27.84% 239 25.40% 42 4.46% 111 11.80% 9 0.96%

Percent 28.21% 17.67% 18.38%

>1 Prescriber: Stimulant Claim AND Benzodiazepine Claim * AT LEAST ONE benzodiazepine prescriber is different from AT LEAST ONE stimulant prescriber. 1,109 406 171 15.42% 107 9.65% 221 19.93% 202 18.21% 23 2.07% 95 8.57% 4 0.36%

>1 Prescriber: Stimulant Claim VS Benzodiazepine Claim * Benzodiazepine prescriber(s) are ALWAYS different from stimulant prescriber(s). 387 106 45 11.63% 14 3.62% 31 8.01% 35 9.04% 6 1.55% 20 5.17% 0 0.00%

* 2 or more claims within 30 Days of each other at any point during the 2014-17 study period. ** Diagnosis data submitted with any type of claim at any point during the 2014-17 study period.

Conclusions

Concurrent stimulant and benzodiazepines use is not supported by guidelines or currently available evidence. Scenarios where such use may be justifiable are few and far between. Current guidelines do not recommend benzodiazepines as first line treatment for anxiety or insomnia, or for treatment of stimulant adverse effects.

Utah Medicaid utilization data indicate inappropriate concurrent prescribing and potential misuse/abuse of stimulants and benzodiazepines especially with respect to prescribing by multiple prescribers with filling at different pharmacies. Use of benzodiazepines should be limited in the elderly, pediatrics and in patients with a history of substance abuse due to limited evidence and safety concerns. Utah Medicaid utilization data document use of benzodiazepines in these special populations often in combination with stimulant medications.

Concurrent use of stimulants and benzodiazepines put patients at increased risk for adverse outcomes. Strategies to prevent concurrent use while providing coordination of care in patients is important to ensure that patients receive appropriate treatment, whilst monitoring and evaluating patients for potential stimulant and benzodiazepine misuse or abuse. Medication profiles can be monitored and any potential interactions or problems addressed at the local pharmacy level when patients receive their medications from the same prescriber and pharmacy (at least as much as possible). Prior authorization criteria to ensure appropriate use may be one way of dealing with this problem.

Appendix 1 – Drug information

Table 3. Comparison of Benzodiazepine Agents3,4,28,38,39,95 Product Route of Available Doses Labeled Uses Unlabeled Uses Active Adult Oral Dosage Range & Administration Metabolite Maximum Oral dose (adults) Alprazolam Oral Oral tablets: 0.25 mg, Treatment of anxiety Treatment of anxiety in No 0.75 to 6 mg daily (Xanax® and Xanax 0.5 mg, 1 mg, 2 mg disorders, panic disorder children. XR®) 0.5 mg XR, 1 mg XR, and anxiety associated Prescribing Limits/Maximum: 2 mg XR, 3 mg XR with depression. Anxiety Disorders: 4 mg daily Oral solution: 1mg/mL Panic Disorder: 10 mg daily. (30 mL) Chlordiazepoxide Oral, IM, IV Oral tablets: 5 mg, Treatment of anxiety N/A Yes 15 to 300 mg daily (Librium®, others) 10 mg, 25 mg disorders, withdrawal Mild to moderate anxiety: symptoms of acute 5–10 mg 3 or 4 times daily alcoholism and Severe anxiety, 20–25 mg 3 or 4 preoperative times daily. apprehension/anxiety. Maximum: Acute alcohol withdrawal: 300 mg daily Chlordiazepoxide/ Oral 5/12.5 mg, 10/25 mg Treatment of anxiety, N/A Yes 2 to 6 tablets daily in one or more Amitriptyline agitation and depression. divided doses. (Limbitrol®) Maximum daily dose: amitriptyline 150 mg/ chlordiazepoxide 60 mg. Clidinium/ Oral 2.5/5 mg Treatment of irritable N/A Yes 1 to 2 capsules 3 to 4 times daily Chlordiazepoxide bowel syndrome and (Librax®) adjunct treatment of peptic ulcer. Clobazam (Onfi™) Oral 5 mg, 10 mg, 20 mg Adjunctive treatment of Catamenial epilepsy; Yes 5 to 40 mg daily seizures associated with epilepsy (monotherapy) Maximum: Lennox-Gastaut syndrome Adjunctive Therapy in Lennox- Gastaut Syndrome: 20 mg daily in those weighing ≤30 kg and 40 mg daily in those weighing >30 kg Clonazepam Oral 0.125 mg, 0.25 mg, Treatment of petit mal Treatment of RLS, No 1 to 20 mg daily (Klonopin®) 0.5 mg, 1 mg, 2 mg variant (Lennox-Gastaut), neuralgia, multifocal tic akinetic and myoclonic disorder, parkinsonian Maximum: seizures; petit mal dysarthria, bipolar Seizure Disorders: 20 mg daily (absence) seizures disorder, burning mouth Panic Disorder: 4 mg daily unresponsive to syndrome and adjunct succimides; and panic therapy for schizophrenia. disorder.

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Product Route of Available Doses Labeled Uses Unlabeled Uses Active Adult Oral Dosage Range & Administration Metabolite Maximum Oral dose (adults) Clorazepate Oral 3.75 mg, 7.5 mg, 15 mg Treatment of anxiety N/A Yes 15 to 90 mg daily (Traxene®, others) disorders, ethanol Maximum: withdrawal and adjunct in Alcohol Withdrawal: 90 mg daily management of partial Adjunctive Therapy for Partial seizures. Seizures: 90 mg daily Diazepam Oral, IM, IV, Oral tablets: 2 mg, 5 Oral and injection: Treatment of panic Yes 4 to 40 mg daily (Valium®, others) Rectal mg, 10 mg Treatment of anxiety disorders and spasticity in Maximum: Oral solution: 1mg/mL disorders, ethanol children with cerebral Rectal: Maximum recommended (5 mL, 500 mL), withdrawal, skeletal palsy. frequency for administration by 5mg/mL (30 mL) muscle relaxant, caregivers outside hospital is 1 Injection solution: convulsive disorders and treatment course every 5 days and 5 5mg/mL (2 mL, 10 mL) sedation/amnesia. treatment courses per month. Rectal Gel: 5 mg, 10 Rectal gel: Treatment of mg, 20 mg refractory epilepsy patients. Estazolam Oral 1 mg, 2 mg Short-term treatment of N/A No 1 to 2 mg (Prosom®) insomnia. Flurazepam Oral 15 mg, 30 mg Short-term treatment of N/A Yes 15 to 30 mg (Dalmane®) insomnia. Lorazepam Oral, IM, IV Oral tablets: 0.5 mg, Oral: Treatment of anxiety Treatment of ethanol No 2 to 6 mg daily (Ativan®) 1 mg, 2 mg disorders and short-term withdrawal, insomnia, Oral solution: 2mg/mL management of anxiety psychogenic catatonia, (30 mL) associated with partial complex seizures, Injection solution: depressive symptoms. agitation and as 2mg/mL (1 mL, 10 mL), I.V.: Status epilepticus, antiemetic adjunct. 4mg/mL (1mL, 10 mL) amnesia and sedation. Midazolam Oral, IV, IM Oral solution: 2mg/mL For preoperative, Treatment of anxiety and Yes N/A (Versed®) (118 mL) preprocedural, or ICU status epilepticus. Injection solution: sedation and 1mg/mL (2 mL, 5 mL, induction/maintenance of 10 mL), 5mg/mL (1 mL, general anesthesia. 2 mL, 5 mL, 10 mL) Oxazepam (Serax®) Oral 10 mg, 15 mg, 30 mg Treatment of anxiety and Management of simple No 30 to 120 mg daily ethanol withdrawal. partial seizures and as a hypnotic. Quazepam Oral 15 mg Treatment of insomnia. N/A Yes 7.5 to 15 mg (Doral®) Temazepam Oral 7.5 mg, 15 mg, 22.5 mg, Short-term treatment of Treatment of anxiety, No 7.5 to 30 mg (Restoril®) 30 mg insomnia. panic attacks and as an adjunct in the treatment of depression. Triazolam Oral 0.125 mg, 0.25 mg Short-term treatment of N/A No 0.125 to 0.25 mg (Halcion®) insomnia. Maximum: 0.5 mg daily Key: IM = intramuscular, IV = intravenous 32

Table 4. Warnings and Precautions for the Benzodiazepine Agents35,36 Warnings Precautions Other Considerations ALERT: US Boxed Warning Appropriate use: Does not have analgesic, antidepressant, Alprazolam: Contraindicated in acute narrow-angle glaucoma; Risks from concomitant use with opioids: or antipsychotic properties. concurrent use with ketoconazole, itraconazole, or other potent Concomitant use of benzodiazepines and CYP3A4 inhibitors. opioids may result in profound sedation, Breakthrough anxiety: At the end of dosing interval, respiratory depression, coma, and death. breakthrough anxiety may occur. Chlordiazepoxide: Use with caution in patients with an impaired gag Reserve concomitant prescribing of these reflex. drugs for use in patients for whom Tolerance: Alprazolam has a short half-life for a alternative treatment options are benzodiazepine and the duration of action after a single Clonazepam: Contraindicated in significant liver disease and acute inadequate. Limit dosages and durations dose is determined by redistribution rather than narrow-angle glaucoma; Monitor all patients for notable changes in to the minimum required. Follow patients metabolism. Tolerance does not develop to the anxiolytic behavior that might indicate suicidal thoughts or depression; Use for signs and symptoms of respiratory effects. Chronic use of this agent may increase the with caution in patients with porphyria, may have a porphyrogenic depression and sedation. perioperative benzodiazepine dose needed to achieve effect. desired effect. Contraindications: Hypersensitivity to Clorazepate: Contraindicated in acute narrow-angle glaucoma and agent or any component of the Withdrawal: Rebound or withdrawal symptoms, including Myasthenia gravis; Use with caution in the elderly, dosage formulation (cross-sensitivity with other seizures, may occur following abrupt discontinuation or adjustment recommended. benzodiazepines may exist). large decreases in dose (more common in adult patients receiving >4 mg/day or prolonged treatment); the risk of Diazepam: The FDA is alerting health care providers and emergency seizures appears to be greatest 24 to 72 hours following responders that certain lots of CANA (diazepam) autoinjectors discontinuation of therapy. Use caution when reducing dose manufactured by Meridian Medical Technologies can be used or withdrawing therapy; decrease slowly (eg, ≤0.5 mg every beyond the labeled expiration date, which should help mitigate 3 days in adults) and monitor for withdrawal symptoms. potential shortages of these drugs; acute narrow-angle glaucoma; Flumazenil may cause withdrawal in patients receiving long- Contraindicated in untreated open-angle glaucoma, infants <6 term benzodiazepine therapy. months of age (oral), myasthenia gravis, severe respiratory impairment, severe hepatic impairment, sleep apnea syndrome; Use with caution: in patients with depression, particularly if When used as an adjunct in treating convulsive disorders, an suicidal risk may be present; in patients with a history of increase in frequency/severity of tonic-clonic seizures may occur and drug abuse or acute alcoholism; in patients with hepatic require dose adjustment of anticonvulsant, abrupt withdrawal may impairment; in patients with porphyria; in patients with result in a temporary increase in the frequency and/or severity of renal impairment; in patients with respiratory disease; in seizures; Use with caution in patients with an impaired gag reflex debilitated patients; active metabolites with extended half- and in obese patients as diazepam may have prolonged action when lives may lead to delayed accumulation and adverse effects; discontinued in obese patients; Psychotic patients: Use of diazepam in patients who are at risk of falls; in children. is not recommended in place of appropriate therapy.

Drug-drug interactions: Potentially significant interactions Lorazepam: Contraindicated in acute narrow-angle glaucoma, sleep may exist, requiring dose or frequency adjustment, apnea (parenteral), intra-arterial injection of parenteral formulation, additional monitoring, and/or selection of alternative severe respiratory insufficiency (except during mechanical therapy. ventilation); Psychiatric disorders: Preexisting depression may emerge or worsen during therapy, not recommended for use in Benzodiazepines have been associated with anterograde primary depressive or psychotic disorders, should not be used in amnesia. patients at risk for suicide without adequate antidepressant

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Warnings Precautions Other Considerations treatment; Use with caution in patients with an impaired gag reflex; Benzodiazepines may cause CNS depression, which may Appropriate use: as a hypnotic, should be used only after evaluation impair physical or mental abilities; patients must be of potential causes of sleep disturbance, failure of sleep disturbance cautioned about performing tasks which require mental to resolve after 7 to 10 days may indicate psychiatric or medical alertness (eg, operating machinery or driving); Use with illness, a worsening of insomnia or the emergence of new caution in patients receiving other CNS depressants or abnormalities of thought or behavior may represent unrecognized psychoactive medication; effects with other sedative drugs psychiatric or medical illness and requires immediate and careful or ethanol may be potentiated. evaluation.

Paradoxical reactions, including hyperactive or aggressive Oxazepam: May cause hypotension (rare), use with caution in behavior, have been reported with benzodiazepines, patients with cardiovascular or cerebrovascular disease, or in particularly in adolescent/pediatric or psychiatric patients patients who would not tolerate transient decreases in blood pressure; Use with caution in patients with an impaired gag reflex; Relative to other benzodiazepines, oxazepam possesses a short half- life and lacks an active metabolite which may be preferable in the elderly if benzodiazepine use is required for anxiety.

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Table 5. Comparison of the Central Nervous System Stimulant Agents35,36 Agent Preparations Labeled Indications Dosing, Adult Dosing, pediatric Amphetamine (Adzenys® Oral suspension, Treatment of ADHD ADHD: ADHD: XR-ODT; Dyanavel® XR; extended release Adzenys XR-ODT: 12.5 mg once daily. Adzenys XR-ODT: Evekeo®) (Dyanavel XR): Exogenous obesity (IR tablet Dyanavel XR: 2.5-5 mg once daily; may Children ≥6 years: 6.3 mg once daily; 2.5 mg/mL (464 mL) only): Short-term treatment increase 2.5-10 mg/day every 4-7 days may increase 3.1-6.3 mg/day every of exogenous obesity as an until optimal response is obtained; week until optimal response (max: 6-12 Oral tablet (Evekeo): adjunct to caloric restriction max: 20 mg/day years 18.8 mg/day) 5 mg, 10 mg for patients refractory to **Do not substitute extended-release Adolescents: 6.3 mg once daily; may alternative therapy formulation for other amphetamine increase 3.1-6.3 mg/day every week Oral tablet, extended products on a mg-per-mg basis since until optimal response (max: 12.5 release, dispersible Narcolepsy (IR tablet only): base composition & pharmacokinetic mg/day) (Adzenys XR-ODT): Treatment of narcolepsy profiles are not similar Dyanavel XR: 3.1 mg, 6.3 mg, 9.4 mg, Children ≥6 years & Adolescents: Refer 12.5 mg, 15.7 mg, 18.8 Exogenous obesity: to adult dosing mg Evekeo: Up to 30 mg daily in divided Evekeo: doses (5-10 mg per dose) Children 3-5 years: 2.5 mg once daily; may increase 2.5 mg/day every week Narcolepsy: until optimal response Evekeo: 5-60 mg daily in divided doses; Children ≥6 years & Adolescents: 5 mg titrate in 10 mg increments at weekly once or twice daily; may increase 5 intervals until optimal response mg/day every week until optimal response

Exogenous obesity: Evekeo: Children ≥12 years & Adolescents: Up to 30 mg daily in divided doses

Narcolepsy: Evekeo: Children 6-12 years: 5-60 mg daily in divided doses; may increase 5 mg/day every week until optimal response Children ≥12 years & Adolescents: 5-60 mg daily in divided doses; may increase 10 mg/day every week until optimal response Dexmethylphenidate Oral capsule, extended Treatment of ADHD in IR: 2.5 mg twice daily; may increase Children ≥6 years & Adolescents: (Focalin®, Focalin® XR) release: 5 mg, 10 mg, patients ≥6 years 2.5-5 mg/day each week; IR: 2.5 mg twice daily; may increase 15 mg, 20 mg, 30 mg, max: 20 mg/day 2.5-5 mg/day each week; 40 mg max: 20 mg/day ER: 10 mg once daily; may increase Oral tablet: 2.5 mg, 10 mg/day each week; max: 40 mg/day ER: 5 mg once daily; may increase 5 mg, 10 mg 5 mg/day each week; max: 30 mg/day

Agent Preparations Labeled Indications Dosing, Adult Dosing, pediatric **Dose reductions and discontinuation: Reduce dose or discontinue in patients with paradoxical aggravation of symptoms; Discontinue if no improvement is seen after one month of treatment Dextroamphetamine Oral capsule, extended Treatment of ADHD as part of Narcolepsy: ADHD: (Dexedrine®, ProCentra®, release: 5 mg, 10 mg, a total treatment program 5-60 mg daily in divided doses; may Children 3-5 years: IR tablets and oral Zenzedi®) 15 mg that typically includes other increase 10 mg/day each week until solution: 2.5 once daily; may increase remedial measures optimal response 2.5 mg/day each week until optimal Oral solution: (psychological, educational, response; max: 40 mg daily 5 mg/5 mL (473 mL) social) for a stabilizing effect Children ≥6 years and Adolescents: in children 3 to 16 years of IR tablets and oral solution: 5 mg once Oral tablet: 5 mg, age or twice daily; may increase 5 mg/day 10 mg each week until optimal response; max: Narcolepsy: Treatment of 40 mg daily Oral tablet (Zenzedi): narcolepsy ER capsules: 5 mg once or twice daily; 5 mg, 7.5 mg, 10 mg, may increase 5 mg/day each week until 15 mg, 20 mg, 30 mg optimal response; max: 40 mg daily

Narcolepsy: Children 6-12 years: 5-60 mg daily in divided doses; may increase 5 mg/day each week until optimal response Children >12 years & Adolescents: Refer to adult dosing Dextroamphetamine- Oral capsule, extended Treatment of ADHD ADHD: ADHD: Amphetamine Mixed Salts release: 5 mg IR: 5 mg once or twice daily; may Children <3 years: Not recommended (Adderall®, Adderall® XR) [dextroamphetamine Narcolepsy: Treatment of increase 5 mg/day each week until Children 3-5 years: IR: 2.5 mg once sulfate 1.25 mg, narcolepsy optimal response; max: 40 mg daily in daily; may increase 2.5 mg/day each dextroamphetamine divided doses week until optimal response; saccharate 1.25 mg, ER: 20 mg once daily in the morning max: 40 mg daily in divided doses amphetamine Children 6-12 years: aspartate Narcolepsy: IR: 5 mg once or twice daily; may monohydrate 1.25 mg, IR: 10 mg daily; may increase increase 5 mg/day each week until amphetamine sulfate 10 mg/day each week until optimal optimal response; max: 40 mg daily in 1.25 mg (equivalent to response; max: 40 mg daily in divided divided doses amphetamine base 3.1 doses ER: 5-10 mg once daily in the morning; mg)]; 10 mg [2.5 mg, may increase 5-10 mg each week; 2.5 mg, 2.5 mg, 2.5 mg max: 30 mg daily (base 6.3 mg)]; 15 mg [3.75 mg, 3.75 mg, 3.75 Narcolepsy: mg, 3.75 mg (base 9.4 Children 6-12 years: mg)]; 20 mg [5 mg, 5 IR: 5 mg once or twice daily; may mg, 5 mg, 5 mg (base increase 5 mg/day each week until

36

Agent Preparations Labeled Indications Dosing, Adult Dosing, pediatric 12.5 mg)]; 25 mg [6.25 optimal response; max: 60 mg daily in mg, 6.25 mg, 6.25 mg, divided doses 6.25 mg (base 15.6 Children >12 years: Refer to adult mg)]; 30 mg [7.5 mg, dosing 7.5 mg, 7.5 mg, 7.5 mg (base 18.8 mg)]

Oral tablet: 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 30 mg Lisdexamfetamine Oral Capsule (Vyvanse): Attention- ADHD: ADHD: (Vyvanse®) 10 mg, 20 mg, 30 mg, deficit/hyperactivity disorder: 30 mg once daily in the morning; may Children ≥6 years & Adolescents: Oral: 40 mg, 50 mg, 60 mg, Treatment of ADHD increase 10-20 mg/day each week until Refer to adult dosing 70 mg optimal response; max: 70 mg/day Binge eating disorder: **Prior to treatment, assess for Treatment of moderate to Binge eating disorder: presence of cardiac disease and assess severe binge eating disorder 50-70 mg once daily in the morning; for risk of abuse may increase 20 mg/day each week until optimal response; max: 70 mg/day Methamphetamine Oral tablet: 5 mg ADHD: For a stabilizing effect Exogenous obesity: 5 mg given 30 ADHD: (Desoxyn®) in children >6 years with minutes before each meal; treatment Children ≥6 years: 20-25 mg daily in 1 or moderate-severe duration should not exceed a few 2 divided doses; may increase 5 mg/day distractibility, short attention weeks each week until optimum response span, hyperactivity, emotional lability & impulsivity Exogenous obesity: Children ≥12 years: Refer to adult Exogenous obesity: Short- dosing term adjunct in a regimen of weight reduction based on caloric restriction in treatment-resistance

Off-Label: Narcolepsy Methylphenidate Oral capsule, extended Treatment of ADHD ADHD: ADHD: (Aptensio® XR, Concerta®, release: IR products (tablets, chewable tablets IR products (tablets, chewable tablets & Daytrana®, Metadate® CD, Metadate (generic): Narcolepsy: Symptomatic & solution): 5 mg twice daily, before solution): Children ≥6 years and Metadate® ER, Methylin®, 10 mg, 20 mg, 30 mg, management of narcolepsy breakfast and lunch; increase 5-10 mg Adolescents: 5 mg twice daily, before QuilliChew® ER, 40 mg, 50 mg, 60 mg (oral solution, oral ER/IR daily at weekly intervals; max: 60 mg breakfast and lunch; increase 5-10 mg Quillivant® XR, Ritalin®, tablet) daily in 2 to 3 divided doses daily at weekly intervals; max: 60 mg Ritalin® LA) Oral capsule, 24-hour ER & SR products (capsules, tablets, daily in 2 to 3 divided doses extended release: Off-Label: Depression, Fatigue chewable tablets and suspension): 10 ER & SR products (capsules, tablets, Aptensio XR: 10 mg, in adult cancer survivors to 36 mg once every morning; max: 60- chewable tablets and suspension): 15 mg, 20 mg, 30 mg, 72 mg/day Children ≥6 years & Adolescents <18 40 mg, 50 mg, 60 mg Aptensio XR: 10 mg once daily;

37

Agent Preparations Labeled Indications Dosing, Adult Dosing, pediatric Ritalin LA (generic): max: 60 mg daily years: 10 mg, 18 mg, 20 mg once every 10 mg, 20 mg, 30, mg, QuilliChew ER: 20 mg once daily in the morning; max: 54-60 mg/day 40 mg, 50 mg, 60 mg morning; increase 10, 15 or 20 mg at Aptensio XR: 10 mg once daily; weekly intervals; max: 60 mg daily max: 60 mg daily Oral solution: QuilliChew ER: 20 mg once daily in the 5 mg/5 mL; Narcolepsy: morning; increase 10, 15 or 20 mg at 10 mg/5 mL IR products (Methylin, Ritalin): 5 mg weekly intervals; max: 60 mg daily twice daily, before breakfast and Transdermal (Daytrana): Oral suspension lunch; increase 5-10 mg daily at weekly Children ≥6 years & Adolescents <18 (Quillivant XR): intervals; max: 60 mg daily in 2 to 3 years: 10 mg patch once daily; remove 25 mg/5 mL divided doses up to 9 hours after application ER & SR products (Metadate ER, Oral tablet: 5 mg, Ritalin-SR): max: 60 mg daily Narcolepsy: 10 mg, 20 mg Children ≥6 years & Adolescents: Refer to adult dosing Oral tablet, chewable: 2.5 mg, 5 mg, 10 mg

Oral tablet, chewable extended release (QuilliChew ER): 20 mg, 30 mg, 40 mg

Oral tablet, extended release: 10 mg, 18 mg, 20 mg, 27 mg, 36 mg, 54 mg

Transdermal patch (Daytrana): 10 mg, 15 mg, 20 mg, 30 mg Key: DSC = discontinued, IR = immediate release, XR/ER = extended release, ADHD = attention-deficit/hyperactivity disorder, SR = sustained release

38

Appendix 2 – Pharmacokinetic properties

Table 6. Pharmacokinetic Properties of the Central Nervous System Stimulant Agents34-36 Agent Onset/Duration/Tmax Half-life Bioavailability Distribution Metabolism Excretion

Amphetamine Amphetamine Sulfate Amphetamine Sulfate Amphetamine Amphetamine Amphetamine Sulfate Amphetamine (Adzenys® XR-ODT; Onset: 1-3 hours t1/2: 7-34 hours Sulfate Sulfate Hepatic: Linear Sulfate Dyanavel® XR; Evekeo®, Duration (Single Dose): depending on urine Well absorbed, Protein binding: 20% pharmacokinetic one- Renal: 67%-73% Mydayis) up to 10 hours pH Alkaline Vd: 3.5-6.11 L/kg compartment open model excreted Tmax: 4 hours gastrointestinal pH CSF levels: 80% of unchanged with Amphetamine increases plasma levels Amphetamine urine pH <6.6 Amphetamine D-amphetamine t1/2: absorption Hepatic: Extensive, Onset: Not Reported 12.36 hours Amphetamine oxidation, deamination, Amphetamine Duration: 24 hours L-amphetamine T1/2: Amphetamine Protein binding: 16% CYP2D6 Renal: 30%-40% Tmax: 4 hours 15.12 hours D-amphetamine: Vd: 3-4 L/kg excreted 106% compared to unchanged with equal dose IR normal urine pH amphetamine salts L-amphetamine: 111% compared to equal dose IR amphetamine salts Dexmethylphenidate Immediate Release IR/ER t1/2: 2-4.5 hours Mean absolute Protein binding: 12%- Hepatic: Extensive, de- Renal: 90% (Focalin®, Focalin® XR) Onset: 1-2 hours bioavailability: 22- 15% esterification excreted as inactive Duration: 3-5 hours 25% Vd: 2.65 L/kg metabolite, 0.5% Tmax: 1-1.5 hours excreted unchanged (after IV Extended Release dose) Onset: 1-2 hours Duration: 9-12 hours Tmax: First peak-1.5 hours, second peak- 6.5 hours Dextroamphetamine Immediate Release IR/ER t1/2: 10-12 Well-absorbed; Vd: 6.11 L/kg Hepatic: Extensive, CYP Renal: 17%-73% (Dexedrine®, ProCentra®, Onset: 2-3 hours hours The bioavailability CSF levels: 80% of deamination, excreted Zenzedi®) Duration: 4-6 hours of ER capsule is plasma levels hydroxylation unchanged Tmax: 60-180 minutes similar to IR depending on urine capsule pH Extended Release Onset: 2-3 hours Duration: 4-24 hours Tmax: ~8 hours 39

Agent Onset/Duration/Tmax Half-life Bioavailability Distribution Metabolism Excretion

Dextroamphetamine- Immediate Release IR/ER t1/2: 10-13 Well-absorbed Not Reported Hepatic: Variable, depends Renal: 30%-40% Amphetamine Mixed Onset: Not reported hours on renal excretion, excreted Salts (Adderall®, Duration: Not reported oxidation, CYP2D6 unchanged Adderall® XR) Tmax: 3 hours depending on urine pH Extended Release Onset: Not reported Duration: Not reported Tmax: 7 hours Lisdexamfetamine Onset: Not reported t1/2: ~1 hour Rapidly absorbed Dextroamphetamine Lisdexamfetamine Renal: 2% excreted (Vyvanse®) Duration: Not reported lisdexamfetamine, Vd: 3.5-4.6 L/kg hydrolyzed to unchanged as Tmax: 1 hour 10-13 hours dextroamphetamine and L- lisdexamfetamine lisdexamfetamine, 3.5 dextroamphetamine Dextroamphetamine lysine in the blood. Feces: 0.3% hours CSF levels: 80% of Dextroamphetamine excreted dextroamphetamine plasma levels Hepatic: Extensive, CYP deamination, hydroxylation Methamphetamine Onset: Not reported t1/2: 4-5 hours Rapidly absorbed Not reported Hepatic: aromatic Renal: ~33% (Desoxyn®) Duration: Not reported from GI tract hydroxylation, N- excreted Tmax: Not reported dealkylation/deamination unchanged depending on urine pH Methylphenidate Immediate Release IR t1/2: 3 hours Oral: Readily Protein binding: 10%- Hepatic/other tissues: De- Renal: 78%-97% (Aptensio® XR, Onset: 20-60 minutes CR t1/2: 2.1-2.4 hours absorbed 33% esterification via excreted, <1% Concerta®, Daytrana®, Duration: 3-5 hours ER t1/2: 2.45-6.8 carboxylesterase CES1A1 excreted Metadate® CD, Tmax: 1-2 hours hours Transdermal: Less D-methylphenidate unchanged in urine Metadate® ER, SR t1/2: 3.4 hours first-pass effect, Vd: 2.65 L/kg Methylin®, QuilliChew® Extended Release Absorption ER, Quillivant® XR, Onset: 20-60 minutes increased when L-methylphenidate Ritalin®, Ritalin® LA) Duration: 6-12 hours exposed to heat or Vd: 1.8 L/kg Tmax: 1.5-6.6 hours inflamed skin, absorption Sustained Release continues for 9 Onset: 60-180 minutes hours after Duration: 2-6 hours application Tmax: 4.7 hours

Transdermal Onset: 1 hour Duration: 11-12 hours Tmax: 7.5-10 hours Key: Tmax: time to max concentration; t1/2: half-life; BA: bioavailability; Pb: protein binding; Vd: volume of distribution; IM: intramuscular; ER: extended release; IR: immediate release

40

Table 7. Pharmacokinetics Properties of the Benzodiazepine Agents3,4,28,38,39 Product Route of Absorption Distribution t½, hours Metabolism Active Elimination Administration Metabolite ANXIOLYTIC Alprazolam Oral Readily absorbed; Immediate 6.3-26.9 Hepatic via CYP3A4; forms two active No Urine (as Extended release: release: Vd: metabolites (4-hydroxyalprazolam and unchanged drug Slower relative to 0.84 to 1.42 α-hydroxyalprazolam [about half as and metabolites) immediate release L/kg active as alprazolam]) and an inactive formulation resulting metabolite benzophenone metabolite, in a concentration that Protein binding: however, the active metabolites are is maintained 5 to 11 80%; primarily unlikely to contribute to much of the hours after dosing; to albumin pharmacologic effects because of their rate increased low concentrations and lesser following night time potencies. dosing (versus morning dosing)

Bioavailability: Immediate release: 84% to 92%; Extended release: 90% Chlordiazepoxide Oral, IM, IV Well absorbed: peak Vd: 3.3 L/kg 18-96 Extensively hepatic to Yes Urine (minimal as concentrations 1-2 desmethyldiazepam (active and long- unchanged drug) hours after Protein binding: acting), desmethylchlordiazepoxide, administration; rate of 96% and demoxepam absorption is age- related and tends to be delayed in the elderly. Clonazepam Oral Rapidly and Children: Vd: 18-50 Extensively hepatic via glucuronide and No Urine (<2% as completely absorbed 1.5 to 3 L/kg; sulfate conjugation; undergoes unchanged drug); Adults: Vd: 1.5 nitroreduction to 7-aminoclonazepam, metabolites Onset of action: ~20 to to 64.4 L/kg followed by acetylation to 7- excreted as 40 minutes acetamidoclonazepam; nitroreduction glucuronide or Protein binding: and acetylation are via cytochrome sulfate conjugates Bioavailability: ~90% ~85% P450 enzyme system; metabolites undergo glucuronide and sulfate conjugation Clorazepate Oral Rapidly absorbed Nordiazepam: 40-120 Rapidly decarboxylated to Yes Urine (62% to following oral Vd: 0.7 to 2.2 nordiazepam (active) in acidic stomach 67%; primarily administration L/kg prior to absorption; nordiazepam is metabolites of hepatically hydroxylated by CYP 2C19 conjugated Bioavailability: 91% Protein binding: and CYP3A4 to oxazepam (active) and oxazepam); feces Nordiazepam: undergoes glucuronidation to form a (15% to 19%) 97% to 98% glucuronide conjugate

Diazepam Oral, IM, IV, Oral: Well absorbed IV: 1.2 L/kg 40-120a Hepatic; diazepam is N-demethylated Yes Urine Rectal (>90%); delayed and (range: 0.6 to 2 by CYP3A4 and 2C19 to the active (predominantly as decreased when L/kg) metabolite N-desmethyldiazepam, and glucuronide administered with a Oral: 1.1 L/kg is hydroxylated by CYP3A4 to the active conjugates) moderate fat meal (range: 0.6 to metabolite temazepam. N- Rectal: Well absorbed 1.8 L/kg desmethyldiazepam and temazepam Rectal: 1 L/kg are both further metabolized to Bioavailability: oxazepam. Temazepam and oxazepam IM: >90% Protein binding: are largely eliminated by Oral: >90% Oral: Neonates: glucuronidation. Rectal: 90% 84% to 86% Adults: 98% Rectal: 95% to 98% Lorazepam Oral, IM, IV IM: Rapid and IV: Vd: 10-20 Hepatic; rapidly conjugated to No Urine (~88%; complete absorption Neonates: 0.76 lorazepam glucuronide (inactive) predominantly as Oral: Readily absorbed ± 0.37 L/kg inactive (range: 0.14 to metabolites); Onset of action: 1.3 L/kg) feces (~7%) Anticonvulsant: IV: Pediatric Within 10 minutes patients: Hypnosis: IM: 20 to 30 Crosses the minutes blood brain Sedation: IV: Within 2 barrier to 3 minutes 5 months to < 3 years: 1.62 L/kg Bioavailability: Oral: (range: 0.67 to 90% 3.4 L/kg) 3 to <13 years: 1.5 L/kg (range: 0.49 to 3 L/kg) 13 to <18 years: 1.27 L/kg (range: 1 to 1.54 L/kg) Adults: 1.3 L/kg

Protein binding: ~85% to 93%; free fraction may be significantly higher in elderly Oxazepam Oral Slowly absorbed from Vd: 0.6 to 2 L/kg 5-20 Hepatic glucuronide conjugation to No Urine (as inactive the GI tract produce a single, major inactive glucuronide metabolite (benzophenone) conjugate)

42

Protein binding: 96% to 98% SEDATIVE/HYPNOTIC Triazolam Oral Onset (oral): Vd: 0.6 to 1.7 1.5-5.5 Hepatic via CYP3A4 and glucuronide No Urine (as intermediate L/kg (Short) conjugation unchanged drug and metabolites) Protein binding: 89% Temazepam Oral Onset: intermediate Vd: 1.4 L/kg 3.5-18.4 Hepatic No Urine (as inactive to slow (Intermediate) metabolites) Protein binding: 96% Estazolam Oral N/A Vd: N/A 10-24 Hepatic via CYP3A4 No Urine (as (Intermediate) unchanged drug Protein binding: and inactive 93% metabolites) and feces (minimal)

Flurazepam Oral Onset: rapid to Vd: 3.4 L/kg Parent: 2.3 Hepatic Yes Urine (as active intermediate Metabolite: and inactive Protein binding: 74-158 metabolites) 97% (long) Quazepam Oral N/A Vd: 5-8.6 L/kg Parent: 39 Hepatic via CYP3A4, 2C9, 2C19 Yes Urine (primarily Metabolite: metabolites) and Protein binding: 39-73 feces >95% (long) MISCELLANEOUS (used in seizure disorders/Lennox-Gastaut syndrome) Clobazam Oral N/A Vd: 100 L/kg Parent: 36-42 Hepatic via CYP3A4, 2C19, 2B6 Yes Urine (primarily Metabolite: as active and Protein binding: 71-82 inactive 80-90% metabolites)

Clonazepam See under anxiolytics Clorazepate See under anxiolytics aHalf-life of active metabolite, to which effects can be attributed. IM = intramuscular, IV = intravenous

43

Appendix 3 – Additional data

Table 8 STIMULANTS - ALL CLAIMS 2014 2015 2016 2017* ALL AGENT PRODUCT CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS ADZENYS XR TAB Amphetamine 12.5MG 0 0 0 0 1 1 4 3 5 4 ADZENYS XR TAB Amphetamine 18.8MG 0 0 0 0 0 0 5 1 5 1 ADZENYS XR TAB Amphetamine 3.1MG 0 0 0 0 0 0 6 6 6 6 ADZENYS XR TAB Amphetamine 6.3MG 0 0 0 0 1 1 19 8 20 8 ADZENYS XR TAB Amphetamine 9.4MG 0 0 0 0 1 1 13 7 14 8 DYANAVEL XR SUS Amphetamine 2.5MG/ML 0 0 0 0 4 3 47 22 51 23 EVEKEO TAB Amphetamine Sulfate 10MG 0 0 3 2 41 9 20 8 64 15 Amphetamine Sulfate EVEKEO TAB 5MG 0 0 0 0 15 7 5 3 20 10 Amphetamine- ADDERALL TAB Dextroamphetamine 10MG 5 1 11 1 15 3 7 1 38 3 Amphetamine- ADDERALL XR CAP Dextroamphetamine 10MG 10 7 8 5 1082 471 1201 455 2,301 728 Amphetamine- ADDERALL XR CAP Dextroamphetamine 15MG 12 10 6 4 1044 373 1104 373 2,166 554 Amphetamine- ADDERALL XR CAP Dextroamphetamine 20MG 17 7 19 11 1863 637 2275 742 4,174 981 Amphetamine- ADDERALL XR CAP Dextroamphetamine 25MG 14 2 12 2 529 171 703 226 1,258 285 Amphetamine- ADDERALL XR CAP Dextroamphetamine 30MG 65 10 61 9 1135 363 1692 510 2,953 625 Amphetamine- ADDERALL XR CAP Dextroamphetamine 5MG 3 3 0 0 297 151 286 130 586 237 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 10MG ER 2852 924 3027 951 1699 619 158 64 7,736 1,928 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 15MG ER 2741 704 2780 692 1601 504 124 52 7,246 1,375 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 20MG ER 5526 1260 5769 1243 3264 884 258 112 14,817 2,279 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 25MG ER 1725 392 1710 352 1097 280 78 36 4,610 699 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 30MG ER 4053 744 3849 713 2775 586 246 92 10,923 1,267 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 5MG ER 645 267 700 303 420 213 50 21 1,815 666 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 10MG 4078 1038 4041 1043 4571 1236 2552 908 15,242 2,813 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 12.5MG 48 14 32 12 50 14 16 7 146 36 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 15MG 1063 296 1289 314 1647 429 880 299 4,879 911 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 20MG 5386 1115 5641 1096 6940 1474 4172 1217 22,139 2,903 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 30MG 3507 623 3747 640 5384 989 3519 903 16,157 1,710 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 5MG 2205 654 2238 672 2208 643 1075 412 7,726 1,667 44

Table 8 STIMULANTS - ALL CLAIMS 2014 2015 2016 2017* ALL Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 7.5MG 106 35 131 30 161 42 81 22 479 87 DEXMETHYLPH CAP Dexmethylphenidate HCl 15MG ER 83 29 452 132 359 112 26 12 920 213 DEXMETHYLPH CAP Dexmethylphenidate HCl 30MG ER 67 17 405 97 270 90 9 3 751 147 DEXMETHYLPH CAP Dexmethylphenidate HCl 40MG ER 16 6 151 33 137 39 18 5 322 58 DEXMETHYLPH TAB Dexmethylphenidate HCl 10MG 494 126 672 134 381 96 35 13 1,582 220 DEXMETHYLPH TAB Dexmethylphenidate HCl 2.5MG 45 19 38 12 43 12 5 2 131 33 DEXMETHYLPH TAB Dexmethylphenidate HCl 5MG 439 113 408 107 254 91 12 7 1,113 221 DEXMETHYLPHE CAP Dexmethylphenidate HCl 10MG ER 0 0 463 144 354 126 61 24 878 223 DEXMETHYLPHE CAP Dexmethylphenidate HCl 20MG ER 0 0 17 7 75 17 53 20 145 33 DEXMETHYLPHE CAP Dexmethylphenidate HCl 5MG ER 2 2 159 66 169 61 20 9 350 108 DEXMETHYLPHE CAP Dexmethylphenidate HCl ER 25MG 0 0 0 0 0 0 3 2 3 2 DEXMETHYLPHE CAP Dexmethylphenidate HCl ER 35MG 0 0 0 0 0 0 1 1 1 1 Dexmethylphenidate HCl FOCALIN TAB 10MG 17 4 37 7 240 75 221 66 515 98 FOCALIN TAB Dexmethylphenidate HCl 2.5MG 11 5 9 2 30 11 37 11 87 22 Dexmethylphenidate HCl FOCALIN TAB 5MG 13 8 20 4 196 59 184 57 413 92 FOCALIN XR CAP Dexmethylphenidate HCl 10MG 911 228 383 145 471 168 412 153 2,177 489 FOCALIN XR CAP Dexmethylphenidate HCl 15MG 617 153 260 95 397 124 355 105 1,629 327 FOCALIN XR CAP Dexmethylphenidate HCl 20MG 987 222 1026 200 993 203 544 157 3,550 482 FOCALIN XR CAP Dexmethylphenidate HCl 25MG 276 64 280 63 335 65 155 47 1,046 146 FOCALIN XR CAP Dexmethylphenidate HCl 30MG 500 105 276 80 303 77 249 73 1,328 212 FOCALIN XR CAP Dexmethylphenidate HCl 35MG 109 20 93 18 69 16 38 13 309 41 FOCALIN XR CAP Dexmethylphenidate HCl 40MG 228 38 160 36 197 40 164 40 749 88 FOCALIN XR CAP Dexmethylphenidate HCl 5MG 290 112 149 75 199 75 148 59 786 254 DEXTROAMPHET CAP Dextroamphetamine Sulfate 10MG ER 411 91 388 78 288 67 122 39 1,209 174 DEXTROAMPHET CAP Dextroamphetamine Sulfate 15MG ER 483 97 458 79 411 78 167 51 1,519 170 DEXTROAMPHET CAP Dextroamphetamine Sulfate 5MG ER 107 33 103 24 95 19 33 9 338 59 DEXTROAMPHET SOL Dextroamphetamine Sulfate 5MG/5ML 44 12 35 7 27 7 8 2 114 20 DEXTROAMPHET TAB Dextroamphetamine Sulfate 10MG 570 101 678 127 648 132 339 101 2,235 259 DEXTROAMPHET TAB Dextroamphetamine Sulfate 5MG 467 120 441 120 304 89 156 55 1,368 252 Dextroamphetamine Sulfate ZENZEDI TAB 10MG 0 0 0 0 4 1 1 1 5 1

45

Table 8 STIMULANTS - ALL CLAIMS 2014 2015 2016 2017* ALL Dextroamphetamine Sulfate ZENZEDI TAB 15MG 4 1 2 1 0 0 0 0 6 2 ZENZEDI TAB Dextroamphetamine Sulfate 2.5MG 14 9 2 2 6 1 1 1 23 13 Dextroamphetamine Sulfate ZENZEDI TAB 20MG 0 0 6 1 5 1 2 1 13 2 Dextroamphetamine Sulfate ZENZEDI TAB 5MG 9 2 10 2 3 2 0 0 22 4 ZENZEDI TAB Dextroamphetamine Sulfate 7.5MG 16 3 3 1 0 0 1 1 20 4 VYVANSE CAP Lisdexamfetamine Dimesylate 10MG 0 0 223 124 487 229 377 185 1,087 446 VYVANSE CAP Lisdexamfetamine Dimesylate 20MG 1813 630 1915 621 2127 699 1322 535 7,177 1,860 VYVANSE CAP Lisdexamfetamine Dimesylate 30MG 3242 927 3481 925 3493 998 2099 732 12,315 2,488 VYVANSE CAP Lisdexamfetamine Dimesylate 40MG 3084 717 3207 744 3402 810 1881 590 11,574 1,849 VYVANSE CAP Lisdexamfetamine Dimesylate 50MG 2736 604 2804 605 2937 635 1519 463 9,996 1,449 VYVANSE CAP Lisdexamfetamine Dimesylate 60MG 1982 378 2146 410 2224 423 1227 340 7,579 913 VYVANSE CAP Lisdexamfetamine Dimesylate 70MG 1888 309 1924 320 2063 336 976 252 6,851 648 VYVANSE CHW Lisdexamfetamine Dimesylate 10MG 0 0 0 0 0 0 7 5 7 5 VYVANSE CHW Lisdexamfetamine Dimesylate 20MG 0 0 0 0 0 0 5 5 5 5 VYVANSE CHW Lisdexamfetamine Dimesylate 30MG 0 0 0 0 0 0 3 2 3 2 Methamphetamine HCl DESOXYN TAB 5MG 3 1 0 0 0 0 0 0 3 1 METHAMPHETAM TAB Methamphetamine HCl 5MG 23 5 30 4 36 6 10 3 99 9 DAYTRANA DIS Methylphenidate 10MG/9HR 151 46 90 31 63 28 14 9 318 84 DAYTRANA DIS Methylphenidate 15MG/9HR 201 55 192 50 61 29 31 15 485 104 DAYTRANA DIS Methylphenidate 20MG/9HR 143 47 169 42 144 42 51 16 507 101 DAYTRANA DIS Methylphenidate 30MG/9HR 331 55 286 50 168 34 50 15 835 88 APTENSIO XR CAP Methylphenidate HCl 20MG 0 0 0 0 6 1 0 0 6 1 CONCERTA TAB Methylphenidate HCl 18MG 31 18 53 22 40 20 1029 449 1,153 488 CONCERTA TAB Methylphenidate HCl 27MG 35 18 86 47 23 18 1108 439 1,252 499 CONCERTA TAB Methylphenidate HCl 36MG 179 47 238 68 90 33 1956 673 2,463 749 CONCERTA TAB Methylphenidate HCl 54MG 84 31 174 50 70 27 1291 394 1,619 443 METADATE TAB Methylphenidate HCl 20MG ER 43 19 235 75 121 45 55 30 454 124 METADATE CD CAP Methylphenidate HCl 10MG 34 7 16 5 245 106 195 84 490 156 METADATE CD CAP Methylphenidate HCl 20MG 38 20 15 8 350 144 377 134 780 233 METADATE CD CAP Methylphenidate HCl 30MG 66 17 57 10 352 116 299 111 774 180

46

Table 8 STIMULANTS - ALL CLAIMS 2014 2015 2016 2017* ALL METADATE CD CAP Methylphenidate HCl 40MG 14 5 10 7 192 66 235 73 451 112 METADATE CD CAP Methylphenidate HCl 50MG 29 7 21 4 99 32 109 30 258 51 METADATE CD CAP Methylphenidate HCl 60MG 9 6 6 2 103 25 120 27 238 37 METHLPHENIDA CHW Methylphenidate HCl 2.5MG 0 0 8 7 12 9 9 6 29 18 METHYLIN SOL Methylphenidate HCl 5MG/5ML 0 0 0 0 1 1 0 0 1 1 METHYLIN TAB Methylphenidate HCl 10MG ER 1 1 0 0 0 0 0 0 1 1 METHYLPHENID CAP Methylphenidate HCl 10MG 383 139 432 160 263 101 38 21 1,116 328 METHYLPHENID CAP Methylphenidate HCl 20MG 784 235 726 214 467 142 70 36 2,047 454 METHYLPHENID CAP Methylphenidate HCl 20MG ER 367 118 422 144 372 109 204 75 1,365 328 METHYLPHENID CAP Methylphenidate HCl 30MG 668 174 652 159 399 114 72 33 1,791 336 METHYLPHENID CAP Methylphenidate HCl 30MG ER 348 103 382 100 345 94 131 42 1,206 230 METHYLPHENID CAP Methylphenidate HCl 40MG 378 93 368 98 277 65 54 28 1,077 190 METHYLPHENID CAP Methylphenidate HCl 40MG ER 239 47 173 48 164 41 69 24 645 106 METHYLPHENID CAP Methylphenidate HCl 50MG 247 42 242 49 159 40 16 9 664 82 METHYLPHENID CAP 165 Methylphenidate HCl 60MG 23 155 28 148 27 20 12 488 42 METHYLPHENID CAP Methylphenidate HCl 60MG LA 0 0 0 0 0 0 1 1 1 1 METHYLPHENID CHW Methylphenidate HCl 10MG 0 0 1 1 26 12 22 7 49 17 METHYLPHENID CHW Methylphenidate HCl 5MG 0 0 27 13 43 23 48 18 118 39 METHYLPHENID SOL Methylphenidate HCl 10MG/5ML 70 21 89 17 84 16 61 21 304 45 METHYLPHENID SOL Methylphenidate HCl 5MG/5ML 75 18 86 23 79 22 45 21 285 58 METHYLPHENID TAB Methylphenidate HCl 10MG 2932 742 3024 717 3409 832 1678 557 11,043 1,790 METHYLPHENID TAB Methylphenidate HCl 10MG ER 624 224 604 220 612 197 288 125 2,128 579 METHYLPHENID TAB Methylphenidate HCl 18MG ER 2690 985 3059 1081 3025 1058 462 208 9,236 2,602 METHYLPHENID TAB Methylphenidate HCl 20MG 1346 293 1456 314 1661 361 864 264 5,327 772 METHYLPHENID TAB Methylphenidate HCl 20MG ER 1174 323 1161 320 1054 285 407 140 3,796 711 METHYLPHENID TAB Methylphenidate HCl 20MG SR 223 87 24 20 1 1 0 0 248 97 METHYLPHENID TAB Methylphenidate HCl 27MG ER 3545 954 3467 952 3825 955 780 303 11,617 2,235 METHYLPHENID TAB Methylphenidate HCl 36MG ER 6427 1332 6589 1356 6321 1262 1292 469 20,629 2,651 METHYLPHENID TAB Methylphenidate HCl 54MG ER 4753 870 4565 830 4360 797 928 293 14,606 1,606

47

Table 8 STIMULANTS - ALL CLAIMS 2014 2015 2016 2017* ALL METHYLPHENID TAB Methylphenidate HCl 5MG 1860 566 2053 581 2112 631 1099 434 7,124 1,493 QUILLICHEW CHW Methylphenidate HCl 20MG ER 0 0 0 0 17 9 17 7 34 12 QUILLICHEW CHW Methylphenidate HCl 30MG ER 0 0 0 0 6 3 18 6 24 7 QUILLICHEW CHW Methylphenidate HCl 40MG ER 0 0 0 0 6 1 7 2 13 2 QUILLIVANT SUS Methylphenidate HCl 25MG/5ML 1484 374 2117 426 2051 412 1021 298 6,673 894 Methylphenidate HCl RITALIN TAB 10MG 0 0 0 0 2 1 0 0 2 1 Methylphenidate HCl RITALIN TAB 20MG 12 1 12 1 10 1 0 0 34 1 Methylphenidate HCl RITALIN TAB 5MG 1 1 0 0 0 0 0 0 1 1 RITALIN LA CAP Methylphenidate HCl 10MG 126 47 164 60 132 44 38 19 460 131 RITALIN LA CAP Methylphenidate HCl 30MG 19 3 13 2 13 2 5 1 50 5 RITALIN LA CAP Methylphenidate HCl 40MG 5 1 1 1 3 1 1 1 10 3 TOTAL 88,396 12,948 92,108 13,062 95,463 14,042 50,287 11,619 326,254 24,251

Table 9

STIMULANTS WITH CONCURRENT BENZODIAZEPINE - ALL CLAIMS 2014 2015 2016 2017* ALL AGENT PRODUCT CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS EVEKEO TAB Amphetamine Sulfate 10MG 0 0 1 1 4 1 1 1 6 2 Amphetamine Sulfate EVEKEO TAB 5MG 0 0 0 0 1 1 0 0 1 1 Amphetamine- ADDERALL TAB Dextroamphetamine 10MG 0 0 0 0 10 1 0 0 10 1 Amphetamine- ADDERALL XR CAP Dextroamphetamine 10MG 0 0 0 0 27 13 20 10 47 17 Amphetamine- ADDERALL XR CAP Dextroamphetamine 15MG 0 0 0 0 14 7 12 8 26 10 Amphetamine- ADDERALL XR CAP Dextroamphetamine 20MG 0 0 1 1 76 40 92 43 169 70 Amphetamine- ADDERALL XR CAP Dextroamphetamine 25MG 0 0 0 0 21 10 24 13 45 17 Amphetamine- ADDERALL XR CAP Dextroamphetamine 30MG 12 1 12 1 104 50 123 61 251 78 Amphetamine- ADDERALL XR CAP Dextroamphetamine 5MG 0 0 0 0 2 2 3 2 5 4 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 10MG ER 114 39 130 41 61 19 2 1 307 80 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 15MG ER 125 35 134 33 56 19 3 1 318 63 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 20MG ER 549 144 545 130 313 77 14 8 1,421 252 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 25MG ER 91 25 97 25 135 23 11 7 334 51 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 30MG ER 595 120 628 112 432 88 27 11 1,682 211

48

Table 9

STIMULANTS WITH CONCURRENT BENZODIAZEPINE - ALL CLAIMS 2014 2015 2016 2017* ALL Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 5MG ER 2 2 9 5 3 2 1 1 15 10 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 10MG 642 190 561 154 730 212 211 107 2,144 478 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 12.5MG 3 3 1 1 4 3 0 0 8 7 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 15MG 232 59 213 56 384 100 109 48 938 178 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 20MG 1618 352 1756 366 2096 496 754 309 6,224 927 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 30MG 1211 227 1342 264 2014 415 807 310 5,374 665 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 5MG 79 32 50 22 100 39 24 12 253 85 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 7.5MG 6 3 1 1 4 2 3 2 14 6 DEXMETHYLPH CAP Dexmethylphenidate HCl 15MG ER 0 0 9 5 20 7 0 0 29 11 DEXMETHYLPH CAP Dexmethylphenidate HCl 30MG ER 1 1 10 6 11 6 0 0 22 12 DEXMETHYLPH CAP Dexmethylphenidate HCl 40MG ER 0 0 1 1 0 0 0 0 1 1 DEXMETHYLPH TAB Dexmethylphenidate HCl 10MG 22 6 17 7 21 5 1 1 61 13 DEXMETHYLPH TAB Dexmethylphenidate HCl 2.5MG 2 1 0 0 0 0 0 0 2 1 DEXMETHYLPH TAB Dexmethylphenidate HCl 5MG 26 7 7 2 5 3 0 0 38 10 DEXMETHYLPHE CAP Dexmethylphenidate HCl 10MG ER 0 0 11 3 6 3 1 1 18 6 DEXMETHYLPHE CAP Dexmethylphenidate HCl 20MG ER 0 0 2 1 10 2 3 2 15 3 DEXMETHYLPHE CAP Dexmethylphenidate HCl 5MG ER 0 0 2 2 1 1 0 0 3 3 Dexmethylphenidate HCl FOCALIN TAB 10MG 0 0 7 2 13 5 12 5 32 9 FOCALIN TAB Dexmethylphenidate HCl 2.5MG 3 1 0 0 0 0 0 0 3 1 Dexmethylphenidate HCl FOCALIN TAB 5MG 0 0 0 0 2 1 3 2 5 3 FOCALIN XR CAP Dexmethylphenidate HCl 10MG 7 5 2 1 4 1 3 2 16 8 FOCALIN XR CAP Dexmethylphenidate HCl 15MG 13 7 1 1 14 5 8 3 36 13 FOCALIN XR CAP Dexmethylphenidate HCl 20MG 25 12 24 7 22 5 6 4 77 21 FOCALIN XR CAP Dexmethylphenidate HCl 25MG 0 0 3 1 5 2 4 3 12 5 FOCALIN XR CAP Dexmethylphenidate HCl 30MG 29 7 15 3 6 2 2 1 52 9 FOCALIN XR CAP Dexmethylphenidate HCl 35MG 1 1 0 0 0 0 4 2 5 3 FOCALIN XR CAP Dexmethylphenidate HCl 40MG 18 2 13 2 22 3 6 2 59 5 FOCALIN XR CAP Dexmethylphenidate HCl 5MG 3 3 4 1 0 0 3 2 10 5 DEXTROAMPHET CAP Dextroamphetamine Sulfate 10MG ER 40 8 29 7 14 3 8 5 91 18 49

Table 9

STIMULANTS WITH CONCURRENT BENZODIAZEPINE - ALL CLAIMS 2014 2015 2016 2017* ALL DEXTROAMPHET CAP Dextroamphetamine Sulfate 15MG ER 123 21 78 16 96 16 23 10 320 37 DEXTROAMPHET CAP Dextroamphetamine Sulfate 5MG ER 5 2 6 1 6 1 0 0 17 3 DEXTROAMPHET TAB Dextroamphetamine Sulfate 10MG 148 24 144 25 190 36 46 20 528 56 DEXTROAMPHET TAB Dextroamphetamine Sulfate 5MG 40 9 40 12 10 4 3 2 93 17 Dextroamphetamine Sulfate ZENZEDI TAB 20MG 0 0 0 0 0 0 1 1 1 1 ZENZEDI TAB Dextroamphetamine Sulfate 7.5MG 0 0 2 1 0 0 0 0 2 1 VYVANSE CAP Lisdexamfetamine Dimesylate 10MG 0 0 4 2 12 8 3 2 19 10 VYVANSE CAP Lisdexamfetamine Dimesylate 20MG 40 25 69 29 43 25 18 15 170 75 VYVANSE CAP Lisdexamfetamine Dimesylate 30MG 131 50 111 49 162 74 47 27 451 157 VYVANSE CAP Lisdexamfetamine Dimesylate 40MG 168 45 178 52 170 61 78 34 594 141 VYVANSE CAP Lisdexamfetamine Dimesylate 50MG 137 59 140 57 242 78 82 44 601 182 VYVANSE CAP Lisdexamfetamine Dimesylate 60MG 173 41 184 54 221 66 78 32 656 133 VYVANSE CAP Lisdexamfetamine Dimesylate 70MG 249 50 300 58 380 72 121 50 1,050 133 Methamphetamine HCl DESOXYN TAB 5MG 3 1 0 0 0 0 0 0 3 1 METHAMPHETAM TAB Methamphetamine HCl 5MG 10 3 8 1 12 2 0 0 30 4 DAYTRANA DIS Methylphenidate 10MG/9HR 3 1 0 0 1 1 0 0 4 2 DAYTRANA DIS Methylphenidate 15MG/9HR 12 2 2 1 1 1 2 1 17 2 DAYTRANA DIS Methylphenidate 20MG/9HR 0 0 1 1 1 1 0 0 2 2 DAYTRANA DIS Methylphenidate 30MG/9HR 3 2 4 3 0 0 0 0 7 5 APTENSIO XR CAP Methylphenidate HCl 20MG 0 0 0 0 6 1 0 0 6 1 CONCERTA TAB Methylphenidate HCl 18MG 0 0 1 1 0 0 5 3 6 4 CONCERTA TAB Methylphenidate HCl 27MG 0 0 0 0 1 1 5 3 6 4 CONCERTA TAB Methylphenidate HCl 36MG 2 2 4 3 1 1 22 15 29 21 CONCERTA TAB Methylphenidate HCl 54MG 13 2 14 4 2 1 40 19 69 23 METADATE TAB Methylphenidate HCl 20MG ER 1 1 4 2 5 3 1 1 11 5 METADATE CD CAP Methylphenidate HCl 10MG 0 0 0 0 6 4 3 2 9 5 METADATE CD CAP Methylphenidate HCl 20MG 0 0 0 0 7 3 9 4 16 5 METADATE CD CAP Methylphenidate HCl 30MG 0 0 0 0 7 3 7 3 14 5 METADATE CD CAP Methylphenidate HCl 40MG 0 0 0 0 3 2 1 1 4 3 50

Table 9

STIMULANTS WITH CONCURRENT BENZODIAZEPINE - ALL CLAIMS 2014 2015 2016 2017* ALL METADATE CD CAP Methylphenidate HCl 50MG 0 0 0 0 7 2 8 3 15 3 METADATE CD CAP Methylphenidate HCl 60MG 0 0 0 0 1 1 6 2 7 3 METHYLPHENID CAP Methylphenidate HCl 10MG 15 6 9 4 4 2 0 0 28 8 METHYLPHENID CAP Methylphenidate HCl 20MG 7 4 2 2 20 8 0 0 29 13 METHYLPHENID CAP Methylphenidate HCl 20MG ER 10 5 12 5 1 1 3 2 26 12 METHYLPHENID CAP Methylphenidate HCl 30MG 5 4 8 6 6 5 0 0 19 12 METHYLPHENID CAP Methylphenidate HCl 30MG ER 13 3 7 4 11 4 9 3 40 10 METHYLPHENID CAP Methylphenidate HCl 40MG 2 2 4 2 3 2 0 0 9 5 METHYLPHENID CAP Methylphenidate HCl 40MG ER 8 1 4 2 2 1 2 1 16 3 METHYLPHENID CAP Methylphenidate HCl 50MG 26 6 15 3 6 2 0 0 47 7 METHYLPHENID CAP Methylphenidate HCl 60MG 2 1 1 1 0 0 1 1 4 2 METHYLPHENID SOL Methylphenidate HCl 10MG/5ML 2 2 0 0 0 0 0 0 2 2 METHYLPHENID SOL Methylphenidate HCl 5MG/5ML 0 0 7 1 7 1 1 1 15 1 METHYLPHENID TAB Methylphenidate HCl 10MG 277 74 230 65 325 98 110 53 942 202 METHYLPHENID TAB Methylphenidate HCl 10MG ER 6 5 5 1 5 3 2 2 18 9 METHYLPHENID TAB Methylphenidate HCl 18MG ER 51 22 42 22 47 19 7 3 147 59 METHYLPHENID TAB Methylphenidate HCl 20MG 243 56 291 62 354 85 106 44 994 156 METHYLPHENID TAB Methylphenidate HCl 20MG ER 60 20 54 18 30 11 5 2 149 38 METHYLPHENID TAB Methylphenidate HCl 20MG SR 15 6 1 1 0 0 0 0 16 7 METHYLPHENID TAB Methylphenidate HCl 27MG ER 73 30 43 16 39 17 6 4 161 56 METHYLPHENID TAB Methylphenidate HCl 36MG ER 174 55 131 49 148 50 15 10 468 130 METHYLPHENID TAB Methylphenidate HCl 54MG ER 248 58 177 47 134 32 18 11 577 98 METHYLPHENID TAB Methylphenidate HCl 5MG 56 19 66 22 62 25 15 8 199 60 QUILLIVANT SUS Methylphenidate HCl 25MG/5ML 8 5 25 12 30 13 1 1 64 27 Methylphenidate HCl RITALIN TAB 20MG 12 1 11 1 8 1 0 0 31 1 RITALIN LA CAP Methylphenidate HCl 10MG 9 2 10 1 6 1 0 0 25 2 TOTAL 8,052 1,516 8,087 1,473 9,608 1,844 3,215 1,188 28,962 3,336

51

Table 10 STIMULANTS WITH CONCURRENT BENZODIAZEPINE - FFS CLAIMS 2014 2015 2016 2017* ALL AGENT PRODUCT CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS Amphetamine- ADDERALL XR CAP Dextroamphetamine 10MG 0 0 0 0 3 3 4 2 7 3 Amphetamine- ADDERALL XR CAP Dextroamphetamine 20MG 0 0 0 0 3 2 5 2 8 4 Amphetamine- ADDERALL XR CAP Dextroamphetamine 25MG 0 0 0 0 0 0 1 1 1 1 Amphetamine- ADDERALL XR CAP Dextroamphetamine 30MG 0 0 0 0 11 7 17 8 28 12 Amphetamine- ADDERALL XR CAP Dextroamphetamine 5MG 0 0 0 0 0 0 2 1 2 1 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 10MG ER 13 7 9 6 8 3 0 0 30 13 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 15MG ER 5 3 6 2 6 3 0 0 17 7 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 20MG ER 122 38 81 27 38 12 5 2 246 61 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 25MG ER 24 7 20 6 3 3 0 0 47 13 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 30MG ER 122 40 93 26 53 17 5 2 273 65 Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 5MG ER 0 0 0 0 0 0 1 1 1 1 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 10MG 164 56 108 45 107 51 33 17 412 140 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 12.5MG 1 1 0 0 2 1 0 0 3 2 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 15MG 28 10 51 14 61 23 17 9 157 44 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 20MG 550 130 465 126 442 144 144 67 1,601 335 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 30MG 380 85 330 83 557 135 204 92 1,471 257 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 5MG 29 7 18 6 26 13 9 4 82 25 Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 7.5MG 6 3 1 1 1 1 2 1 10 4 DEXMETHYLPH CAP Dexmethylphenidate HCl 15MG ER 0 0 3 1 6 2 0 0 9 2 DEXMETHYLPH CAP Dexmethylphenidate HCl 30MG ER 0 0 1 1 0 0 0 0 1 1 DEXMETHYLPH TAB Dexmethylphenidate HCl 10MG 2 2 3 2 2 1 0 0 7 4 DEXMETHYLPH TAB Dexmethylphenidate HCl 5MG 1 1 0 0 0 0 0 0 1 1 DEXMETHYLPHE CAP Dexmethylphenidate HCl 10MG ER 0 0 0 0 1 1 0 0 1 1 DEXMETHYLPHE CAP Dexmethylphenidate HCl 20MG ER 0 0 0 0 3 2 3 2 6 2 Dexmethylphenidate HCl FOCALIN TAB 10MG 0 0 0 0 1 1 0 0 1 1 FOCALIN XR CAP Dexmethylphenidate HCl 15MG 0 0 0 0 7 2 3 1 10 2 FOCALIN XR CAP Dexmethylphenidate HCl 20MG 3 2 4 2 1 1 2 2 10 5

52

Table 10 STIMULANTS WITH CONCURRENT BENZODIAZEPINE - FFS CLAIMS 2014 2015 2016 2017* ALL FOCALIN XR CAP Dexmethylphenidate HCl 30MG 1 1 0 0 0 0 0 0 1 1 FOCALIN XR CAP Dexmethylphenidate HCl 35MG 1 1 0 0 0 0 0 0 1 1 FOCALIN XR CAP Dexmethylphenidate HCl 40MG 1 1 0 0 0 0 0 0 1 1 DEXTROAMPHET CAP Dextroamphetamine Sulfate 10MG ER 17 3 11 3 2 1 2 1 32 5 DEXTROAMPHET CAP Dextroamphetamine Sulfate 15MG ER 37 7 27 5 45 7 16 5 125 11 DEXTROAMPHET TAB Dextroamphetamine Sulfate 10MG 35 7 27 5 39 9 13 5 114 17 DEXTROAMPHET TAB Dextroamphetamine Sulfate 5MG 1 1 3 2 0 0 0 0 4 3 Dextroamphetamine Sulfate ZENZEDI TAB 20MG 0 0 0 0 0 0 1 1 1 1 ZENZEDI TAB Dextroamphetamine Sulfate 7.5MG 0 0 2 1 0 0 0 0 2 1 VYVANSE CAP Lisdexamfetamine Dimesylate 20MG 14 9 27 8 12 4 4 3 57 18 VYVANSE CAP Lisdexamfetamine Dimesylate 30MG 29 13 37 14 24 12 11 5 101 36 VYVANSE CAP Lisdexamfetamine Dimesylate 40MG 41 10 30 10 11 6 4 4 86 24 VYVANSE CAP Lisdexamfetamine Dimesylate 50MG 35 14 16 8 21 6 7 6 79 30 VYVANSE CAP Lisdexamfetamine Dimesylate 60MG 24 8 18 8 36 16 11 5 89 26 VYVANSE CAP Lisdexamfetamine Dimesylate 70MG 57 17 61 12 67 17 19 8 204 34 Methamphetamine HCl DESOXYN TAB 5MG 3 1 0 0 0 0 0 0 3 1 METHAMPHETAM TAB Methamphetamine HCl 5MG 10 3 6 1 0 0 0 0 16 3 DAYTRANA DIS Methylphenidate 15MG/9HR 0 0 0 0 0 0 1 1 1 1 CONCERTA TAB Methylphenidate HCl 18MG 0 0 0 0 0 0 1 1 1 1 CONCERTA TAB Methylphenidate HCl 27MG 0 0 0 0 0 0 2 1 2 1 CONCERTA TAB Methylphenidate HCl 36MG 1 1 0 0 0 0 2 2 3 3 CONCERTA TAB Methylphenidate HCl 54MG 0 0 0 0 0 0 5 2 5 2 METADATE TAB Methylphenidate HCl 20MG ER 0 0 1 1 2 1 0 0 3 1 METADATE CD CAP Methylphenidate HCl 10MG 0 0 0 0 1 1 3 2 4 2 METADATE CD CAP Methylphenidate HCl 20MG 0 0 0 0 1 1 2 1 3 2 METADATE CD CAP Methylphenidate HCl 30MG 0 0 0 0 0 0 1 1 1 1 METHYLPHENID CAP Methylphenidate HCl 10MG 5 3 3 2 0 0 0 0 8 3 METHYLPHENID CAP Methylphenidate HCl 20MG 1 1 0 0 0 0 0 0 1 1 METHYLPHENID CAP Methylphenidate HCl 20MG ER 1 1 3 2 0 0 0 0 4 3 53

Table 10 STIMULANTS WITH CONCURRENT BENZODIAZEPINE - FFS CLAIMS 2014 2015 2016 2017* ALL METHYLPHENID CAP Methylphenidate HCl 30MG 1 1 1 1 1 1 0 0 3 3 METHYLPHENID CAP Methylphenidate HCl 30MG ER 4 1 0 0 3 1 4 1 11 2 METHYLPHENID CAP Methylphenidate HCl 40MG 1 1 1 1 0 0 0 0 2 2 METHYLPHENID CAP Methylphenidate HCl 40MG ER 0 0 1 1 0 0 0 0 1 1 METHYLPHENID CAP Methylphenidate HCl 50MG 1 1 0 0 0 0 0 0 1 1 METHYLPHENID CAP Methylphenidate HCl 60MG 0 0 0 0 0 0 1 1 1 1 METHYLPHENID SOL Methylphenidate HCl 5MG/5ML 0 0 7 1 7 1 1 1 15 1 METHYLPHENID TAB Methylphenidate HCl 10MG 79 22 65 20 57 20 19 15 220 56 METHYLPHENID TAB Methylphenidate HCl 10MG ER 3 2 0 0 3 2 0 0 6 3 METHYLPHENID TAB Methylphenidate HCl 18MG ER 8 8 8 5 10 6 1 1 27 18 METHYLPHENID TAB Methylphenidate HCl 20MG 78 22 71 18 96 29 26 13 271 62 METHYLPHENID TAB Methylphenidate HCl 20MG ER 8 5 9 6 7 2 0 0 24 10 METHYLPHENID TAB Methylphenidate HCl 27MG ER 24 10 10 6 8 3 0 0 42 16 METHYLPHENID TAB Methylphenidate HCl 36MG ER 37 16 21 9 16 8 3 2 77 31 METHYLPHENID TAB Methylphenidate HCl 54MG ER 44 13 43 10 36 6 6 3 129 22 METHYLPHENID TAB Methylphenidate HCl 5MG 14 4 14 7 5 4 2 2 35 15 QUILLIVANT SUS Methylphenidate HCl 25MG/5ML 0 0 3 1 6 3 0 0 9 3 TOTAL 2,066 489 1,719 441 1,858 493 625 261 6,268 1,126

Table 11 ALL claims STIMULANTS: CONCURRENT PERCENT CONCURRENT PERCENT PERCENT AGENT PRODUCT CLAIMS PATIENTS PATIENTS 1X * OF ALL PATIENTS 2X ** OF 1X OF ALL ADZENYS XR TAB Amphetamine 12.5MG 5 4 0 0.00% 0 NA 0.00% ADZENYS XR TAB Amphetamine 18.8MG 5 1 0 0.00% 0 NA 0.00% Amphetamine ADZENYS XR TAB 3.1MG 6 6 0 0.00% 0 NA 0.00% Amphetamine ADZENYS XR TAB 6.3MG 20 8 0 0.00% 0 NA 0.00% Amphetamine ADZENYS XR TAB 9.4MG 14 8 0 0.00% 0 NA 0.00% DYANAVEL XR SUS Amphetamine 2.5MG/ML 51 23 0 0.00% 0 NA 0.00% Amphetamine Sulfate EVEKEO TAB 10MG 64 15 2 13.33% 1 50.00% 6.67% Amphetamine Sulfate EVEKEO TAB 5MG 20 10 1 10.00% 0 0.00% 0.00%

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Table 11 ALL claims STIMULANTS: CONCURRENT PERCENT CONCURRENT PERCENT PERCENT AGENT PRODUCT CLAIMS PATIENTS PATIENTS 1X * OF ALL PATIENTS 2X ** OF 1X OF ALL Amphetamine- Dextroamphetamine ADDERALL TAB 10MG 38 3 1 33.33% 0 0.00% 0.00% Amphetamine- Dextroamphetamine ADDERALL XR CAP 10MG 2,301 728 17 2.34% 12 70.59% 1.65% Amphetamine- Dextroamphetamine ADDERALL XR CAP 15MG 2,166 554 10 1.81% 8 80.00% 1.44% Amphetamine- Dextroamphetamine ADDERALL XR CAP 20MG 4,174 981 70 7.14% 56 80.00% 5.71% Amphetamine- Dextroamphetamine ADDERALL XR CAP 25MG 1,258 285 17 5.96% 12 70.59% 4.21% Amphetamine- Dextroamphetamine ADDERALL XR CAP 30MG 2,953 625 78 12.48% 65 83.33% 10.40% Amphetamine- Dextroamphetamine ADDERALL XR CAP 5MG 586 237 4 1.69% 1 25.00% 0.42% Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 10MG ER 7,736 1,928 80 4.15% 50 62.50% 2.59% Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 15MG ER 7,246 1,375 63 4.58% 42 66.67% 3.05% Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 20MG ER 14,817 2,279 252 11.06% 180 71.43% 7.90% Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 25MG ER 4,610 699 51 7.30% 38 74.51% 5.44% Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 30MG ER 10,923 1,267 211 16.65% 177 83.89% 13.97% Amphetamine- AMPHET/DEXTR CAP Dextroamphetamine 5MG ER 1,815 666 10 1.50% 4 40.00% 0.60% Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 10MG 15,242 2,813 478 16.99% 312 65.27% 11.09% Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 12.5MG 146 36 7 19.44% 3 42.86% 8.33% Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 15MG 4,879 911 178 19.54% 139 78.09% 15.26% Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 20MG 22,139 2,903 927 31.93% 717 77.35% 24.70% Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 30MG 16,157 1,710 665 38.89% 569 85.56% 33.27% Amphetamine- Dextroamphetamine AMPHET/DEXTR TAB 5MG 7,726 1,667 85 5.10% 48 56.47% 2.88% Amphetamine- AMPHET/DEXTR TAB Dextroamphetamine 7.5MG 479 87 6 6.90% 4 66.67% 4.60% DEXMETHYLPH CAP Dexmethylphenidate HCl 15MG ER 920 213 11 5.16% 7 63.64% 3.29% DEXMETHYLPH CAP Dexmethylphenidate HCl 30MG ER 751 147 12 8.16% 9 75.00% 6.12% DEXMETHYLPH CAP Dexmethylphenidate HCl 40MG ER 322 58 1 1.72% 1 100.00% 1.72% DEXMETHYLPH TAB Dexmethylphenidate HCl 10MG 1,582 220 13 5.91% 11 84.62% 5.00% DEXMETHYLPH TAB Dexmethylphenidate HCl 2.5MG 131 33 1 3.03% 0 0.00% 0.00% Dexmethylphenidate HCl DEXMETHYLPH TAB 5MG 1,113 221 10 4.52% 6 60.00% 2.71% DEXMETHYLPHE CAP Dexmethylphenidate HCl 10MG ER 878 223 6 2.69% 5 83.33% 2.24% DEXMETHYLPHE CAP Dexmethylphenidate HCl 20MG ER 145 33 3 9.09% 3 100.00% 9.09% DEXMETHYLPHE CAP Dexmethylphenidate HCl 5MG ER 350 108 3 2.78% 0 0.00% 0.00%

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Table 11 ALL claims STIMULANTS: CONCURRENT PERCENT CONCURRENT PERCENT PERCENT AGENT PRODUCT CLAIMS PATIENTS PATIENTS 1X * OF ALL PATIENTS 2X ** OF 1X OF ALL DEXMETHYLPHE CAP ER Dexmethylphenidate HCl 25MG 3 2 0 0.00% 0 NA 0.00% DEXMETHYLPHE CAP ER Dexmethylphenidate HCl 35MG 1 1 0 0.00% 0 NA 0.00% Dexmethylphenidate HCl FOCALIN TAB 10MG 515 98 9 9.18% 6 66.67% 6.12% Dexmethylphenidate HCl FOCALIN TAB 2.5MG 87 22 1 4.55% 1 100.00% 4.55% Dexmethylphenidate HCl FOCALIN TAB 5MG 413 92 3 3.26% 2 66.67% 2.17% Dexmethylphenidate HCl FOCALIN XR CAP 10MG 2,177 489 8 1.64% 3 37.50% 0.61% Dexmethylphenidate HCl FOCALIN XR CAP 15MG 1,629 327 13 3.98% 7 53.85% 2.14% Dexmethylphenidate HCl FOCALIN XR CAP 20MG 3,550 482 21 4.36% 9 42.86% 1.87% Dexmethylphenidate HCl FOCALIN XR CAP 25MG 1,046 146 5 3.42% 4 80.00% 2.74% Dexmethylphenidate HCl FOCALIN XR CAP 30MG 1,328 212 9 4.25% 5 55.56% 2.36% Dexmethylphenidate HCl FOCALIN XR CAP 35MG 309 41 3 7.32% 3 100.00% 7.32% Dexmethylphenidate HCl FOCALIN XR CAP 40MG 749 88 5 5.68% 5 100.00% 5.68% Dexmethylphenidate HCl FOCALIN XR CAP 5MG 786 254 5 1.97% 5 100.00% 1.97% DEXTROAMPHET CAP Dextroamphetamine Sulfate 10MG ER 1,209 174 18 10.34% 12 66.67% 6.90% DEXTROAMPHET CAP Dextroamphetamine Sulfate 15MG ER 1,519 170 37 21.76% 35 94.59% 20.59% DEXTROAMPHET CAP Dextroamphetamine Sulfate 5MG ER 338 59 3 5.08% 2 66.67% 3.39% DEXTROAMPHET SOL Dextroamphetamine Sulfate 5MG/5ML 114 20 0 0.00% 0 NA 0.00% DEXTROAMPHET TAB Dextroamphetamine Sulfate 10MG 2,235 259 56 21.62% 46 82.14% 17.76% DEXTROAMPHET TAB Dextroamphetamine Sulfate 5MG 1,368 252 17 6.75% 12 70.59% 4.76% Dextroamphetamine Sulfate ZENZEDI TAB 10MG 5 1 0 0.00% 0 NA 0.00% Dextroamphetamine Sulfate ZENZEDI TAB 15MG 6 2 0 0.00% 0 NA 0.00% Dextroamphetamine Sulfate ZENZEDI TAB 2.5MG 23 13 0 0.00% 0 NA 0.00% Dextroamphetamine Sulfate ZENZEDI TAB 20MG 13 2 1 50.00% 1 100.00% 50.00% Dextroamphetamine Sulfate ZENZEDI TAB 5MG 22 4 0 0.00% 0 NA 0.00% Dextroamphetamine Sulfate ZENZEDI TAB 7.5MG 20 4 1 25.00% 1 100.00% 25.00% Lisdexamfetamine Dimesylate VYVANSE CAP 10MG 1,087 446 10 2.24% 9 90.00% 2.02% Lisdexamfetamine Dimesylate VYVANSE CAP 20MG 7,177 1,860 75 4.03% 45 60.00% 2.42% Lisdexamfetamine Dimesylate VYVANSE CAP 30MG 12,315 2,488 157 6.31% 92 58.60% 3.70% Lisdexamfetamine Dimesylate VYVANSE CAP 40MG 11,574 1,849 141 7.63% 108 76.60% 5.84% Lisdexamfetamine Dimesylate VYVANSE CAP 50MG 9,996 1,449 182 12.56% 131 71.98% 9.04% Lisdexamfetamine Dimesylate VYVANSE CAP 60MG 7,579 913 133 14.57% 98 73.68% 10.73% Lisdexamfetamine Dimesylate VYVANSE CAP 70MG 6,851 648 133 20.52% 117 87.97% 18.06% Lisdexamfetamine Dimesylate VYVANSE CHW 10MG 7 5 0 0.00% 0 NA 0.00% Lisdexamfetamine Dimesylate VYVANSE CHW 20MG 5 5 0 0.00% 0 NA 0.00% Lisdexamfetamine Dimesylate VYVANSE CHW 30MG 3 2 0 0.00% 0 NA 0.00%

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Table 11 ALL claims STIMULANTS: CONCURRENT PERCENT CONCURRENT PERCENT PERCENT AGENT PRODUCT CLAIMS PATIENTS PATIENTS 1X * OF ALL PATIENTS 2X ** OF 1X OF ALL Methamphetamine HCl DESOXYN TAB 5MG 3 1 1 100.00% 1 100.00% 100.00% METHAMPHETAM TAB Methamphetamine HCl 5MG 99 9 4 44.44% 3 75.00% 33.33% DAYTRANA DIS Methylphenidate 10MG/9HR 318 84 2 2.38% 2 100.00% 2.38% DAYTRANA DIS Methylphenidate 15MG/9HR 485 104 2 1.92% 2 100.00% 1.92% DAYTRANA DIS Methylphenidate 20MG/9HR 507 101 2 1.98% 0 0.00% 0.00% DAYTRANA DIS Methylphenidate 30MG/9HR 835 88 5 5.68% 2 40.00% 2.27% Methylphenidate HCl APTENSIO XR CAP 20MG 6 1 1 100.00% 1 100.00% 100.00% Methylphenidate HCl CONCERTA TAB 18MG 1,153 488 4 0.82% 4 100.00% 0.82% Methylphenidate HCl CONCERTA TAB 27MG 1,252 499 4 0.80% 4 100.00% 0.80% Methylphenidate HCl CONCERTA TAB 36MG 2,463 749 21 2.80% 16 76.19% 2.14% Methylphenidate HCl CONCERTA TAB 54MG 1,619 443 23 5.19% 19 82.61% 4.29% METADATE TAB 20MG Methylphenidate HCl ER 454 124 5 4.03% 4 80.00% 3.23% METADATE CD CAP Methylphenidate HCl 10MG 490 156 5 3.21% 4 80.00% 2.56% METADATE CD CAP Methylphenidate HCl 20MG 780 233 5 2.15% 5 100.00% 2.15% METADATE CD CAP Methylphenidate HCl 30MG 774 180 5 2.78% 4 80.00% 2.22% METADATE CD CAP Methylphenidate HCl 40MG 451 112 3 2.68% 3 100.00% 2.68% METADATE CD CAP Methylphenidate HCl 50MG 258 51 3 5.88% 2 66.67% 3.92% METADATE CD CAP Methylphenidate HCl 60MG 238 37 3 8.11% 1 33.33% 2.70% METHLPHENIDA CHW Methylphenidate HCl 2.5MG 29 18 0 0.00% 0 NA 0.00% METHYLIN SOL Methylphenidate HCl 5MG/5ML 1 1 0 0.00% 0 NA 0.00% METHYLIN TAB 10MG Methylphenidate HCl ER 1 1 0 0.00% 0 NA 0.00% METHYLPHENID CAP Methylphenidate HCl 10MG 1,116 328 8 2.44% 6 75.00% 1.83% METHYLPHENID CAP Methylphenidate HCl 20MG 2,047 454 13 2.86% 8 61.54% 1.76% METHYLPHENID CAP Methylphenidate HCl 20MG ER 1,365 328 12 3.66% 9 75.00% 2.74% METHYLPHENID CAP Methylphenidate HCl 30MG 1,791 336 12 3.57% 5 41.67% 1.49% METHYLPHENID CAP Methylphenidate HCl 30MG ER 1,206 230 10 4.35% 10 100.00% 4.35% METHYLPHENID CAP Methylphenidate HCl 40MG 1,077 190 5 2.63% 5 100.00% 2.63% METHYLPHENID CAP Methylphenidate HCl 40MG ER 645 106 3 2.83% 2 66.67% 1.89% METHYLPHENID CAP Methylphenidate HCl 50MG 664 82 7 8.54% 4 57.14% 4.88% METHYLPHENID CAP Methylphenidate HCl 60MG 488 42 2 4.76% 2 100.00% 4.76%

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Table 11 ALL claims STIMULANTS: CONCURRENT PERCENT CONCURRENT PERCENT PERCENT AGENT PRODUCT CLAIMS PATIENTS PATIENTS 1X * OF ALL PATIENTS 2X ** OF 1X OF ALL METHYLPHENID CAP Methylphenidate HCl 60MG LA 1 1 0 0.00% 0 NA 0.00% METHYLPHENID CHW Methylphenidate HCl 10MG 49 17 0 0.00% 0 NA 0.00% METHYLPHENID CHW Methylphenidate HCl 5MG 118 39 0 0.00% 0 NA 0.00% METHYLPHENID SOL Methylphenidate HCl 10MG/5ML 304 45 2 4.44% 1 50.00% 2.22% METHYLPHENID SOL Methylphenidate HCl 5MG/5ML 285 58 1 1.72% 0 0.00% 0.00% METHYLPHENID TAB Methylphenidate HCl 10MG 11,043 1,790 202 11.28% 137 67.82% 7.65% METHYLPHENID TAB Methylphenidate HCl 10MG ER 2,128 579 9 1.55% 4 44.44% 0.69% METHYLPHENID TAB Methylphenidate HCl 18MG ER 9,236 2,602 59 2.27% 23 38.98% 0.88% METHYLPHENID TAB Methylphenidate HCl 20MG 5,327 772 156 20.21% 126 80.77% 16.32% METHYLPHENID TAB Methylphenidate HCl 20MG ER 3,796 711 38 5.34% 24 63.16% 3.38% METHYLPHENID TAB Methylphenidate HCl 20MG SR 248 97 7 7.22% 6 85.71% 6.19% METHYLPHENID TAB Methylphenidate HCl 27MG ER 11,617 2,235 56 2.51% 38 67.86% 1.70% METHYLPHENID TAB Methylphenidate HCl 36MG ER 20,629 2,651 130 4.90% 78 60.00% 2.94% METHYLPHENID TAB Methylphenidate HCl 54MG ER 14,606 1,606 98 6.10% 69 70.41% 4.30% Methylphenidate HCl METHYLPHENID TAB 5MG 7,124 1,493 60 4.02% 26 43.33% 1.74% QUILLICHEW CHW 20MG Methylphenidate HCl ER 34 12 0 0.00% 0 NA 0.00% QUILLICHEW CHW 30MG Methylphenidate HCl ER 24 7 0 0.00% 0 NA 0.00% QUILLICHEW CHW 40MG Methylphenidate HCl ER 13 2 0 0.00% 0 NA 0.00% QUILLIVANT SUS Methylphenidate HCl 25MG/5ML 6,673 894 27 3.02% 11 40.74% 1.23% Methylphenidate HCl RITALIN TAB 10MG 2 1 0 0.00% 0 NA 0.00% Methylphenidate HCl RITALIN TAB 20MG 34 1 1 100.00% 1 100.00% 100.00% Methylphenidate HCl RITALIN TAB 5MG 1 1 0 0.00% 0 NA 0.00% Methylphenidate HCl RITALIN LA CAP 10MG 460 131 2 1.53% 1 50.00% 0.76% Methylphenidate HCl RITALIN LA CAP 30MG 50 5 0 0.00% 0 NA 0.00% Methylphenidate HCl RITALIN LA CAP 40MG 10 3 0 0.00% 0 NA 0.00% TOTAL 326,254 24,251 3,336 13.76% 2,519 75.51% 10.39%

* 1X = At least 1 benzodiazepine claim AND 1 stimulant claim between Patient Index Fill Date and Patient Index Fill Date plus 30 Days. ** 2X = At least 1 benzodiazepine claim AND 1 stimulant claim within 30 Days of each other at any point after Patient Index Fill Date plus 30 Days.

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Appendix 4 Top stimulant prescribers of concurrent stimulant and benzodiazepine treatment Table 12 Stimulant Top BZD Type Specialty Claims Patients prescribera Nurse Practitioner Psychiatry 1,555 148 YES Physician Psychiatry 755 73 YES Nurse Practitioner Psychiatry 536 59 YES Physician Psychiatry 410 33 YES Nurse Practitioner Family Medicine 348 36 YES Physician Psychiatry 345 42 YES Physician Family Medicine 341 37 YES Nurse Practitioner Psychiatry 315 50 YES Nurse Practitioner Psychiatry 313 44 YES Osteopath Psychiatry 306 26 YES Physician Psychiatry 303 35* YES Physician Psychiatry 290 44* YES Registered Nurse Psychiatry 231 28 YES Nurse Practitioner Psychiatry 231 35 YES Nurse Practitioner Psychiatry 230 33 YES Osteopath Family Medicine 228 21 YES Physician Family Medicine 222 26 YES Physician Psychiatry 219 41 YES Physician Psychiatry 214 32 YES Osteopath Family Medicine 207 24 YES Nurse Practitioner Psychiatry 197 23 YES Physician Assistant Family Medicine 194 8 Physician Assistant Family Medicine 161 25 YES Physician Psychiatry 158 39 Physician Internal Medicine 147 12 Nurse Practitioner Family Medicine 147 21 Nurse Practitioner Psychiatry 146 18 Physician Family Medicine 143 26 Physician Psychiatry 140 18 YES Nurse Practitioner Family Medicine 137 15 Physician Family Medicine 135 14 YES Nurse Practitioner Psychiatry 134 36 YES Osteopath Family Medicine 133 26 Physician Family Medicine 133 12 Physician Family Medicine 132 14 Physician Psychiatry 132 14 Osteopath Family Medicine 127 13 YES Physician Family Medicine 120 12 YES Physician Family Medicine 115 8 YES Nurse Practitioner Psychiatry 113 18 Physician Family Medicine 109 11 Physician Family Medicine 108 10 Physician Assistant Family Medicine 102 16 YES Osteopath Family Medicine 100 9 Physician Psychiatry 100 9 Nurse Practitioner Psychiatry 100 14 Osteopath Sports Medicine 99 8 Physician Family Medicine 99 11 YES

Stimulant Top BZD Type Specialty Claims Patients prescribera Nurse Practitioner Psychiatry 99 13 YES Physician Pediatrics 98 10 Nurse Practitioner Psychiatry 97 10 Osteopath Family Medicine 93 8 Nurse Practitioner Family Medicine 93 10 YES Physician Assistant Family Medicine 91 14 Physician Family Medicine 89 9 Physician Assistant Family Medicine 89 20 Osteopath Family Medicine 89 12 Osteopath Family Medicine 87 11 YES Nurse Practitioner Psychiatry 87 17 YES Physician Family Medicine 86 23 Physician Psychiatry 86 10 Physician Family Medicine 85 12 Physician Family Medicine 85 17 Physician Psychiatry 83 7 YES Nurse Practitioner Family Medicine 82 10 Physician Family Medicine 82 6 Nurse Practitioner Family Medicine 80 18 YES Nurse Practitioner Family Medicine 79 22 Physician Family Medicine 79 12 YES Physician Family Medicine 78 12 Physician Family Medicine 77 14 Physician Family Medicine 76 5 Nurse Practitioner Family Medicine 76 14 Osteopath Family Medicine 76 17 YES Physician Assistant Family Medicine 75 18 Physician Family Medicine 73 10 Nurse Practitioner Family Medicine 72 11 Nurse Practitioner Psychiatry 72 9 Physician Family Medicine 71 6 Osteopath Family Medicine 71 5 Nurse Practitioner Psychiatry 70 18 Physician Psychiatry 69 9 YES Physician Psychiatry 69 10 Physician Internal Medicine 69 9 Physician Family Medicine 68 6 Osteopath Family Medicine 67 16 YES Physician Family Medicine 67 12 YES Physician Assistant Family Medicine 67 10 Physician Family Medicine 67 10 Nurse Practitioner Family Medicine 67 10 YES Physician Family Medicine 66 10 Physician Assistant Family Medicine 66 13 Physician Assistant Family Medicine 65 18 YES Physician Family Medicine 63 4 Nurse Practitioner Family Medicine 63 10 Nurse Practitioner Psychiatry 62 5 Osteopath Family Medicine 62 10 YES Physician Family Medicine 62 9 Nurse Practitioner Psychiatry 61 5 Nurse Practitioner Pediatrics 61 13 Nurse Practitioner Family Medicine 61 7 a Top prescriber as shown in table 19 of the June DUR report on benzodiazepines *Includes pediatric patient(s) 4-5 years old

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Top benzodiazepine prescribers and claims and patients exceeding BZD dose and duration recommendations (as per June Medicaid DUR report) AND stimulant prescribers involved in concurrent stimulant and BZD treatment

Table 13 CONCURRENT STIMULANT BENZO: Type Specialty STIMULANT CLAIMS Claims Exceed ADD Percent Patients Exceed ADD Percent Exceed DUR Percent Nurse Practitioner Psychiatry YES 1555 5743 1015 17.67% 465 94 20.22% 360 77.42% Physician Psychiatry YES 755 2431 431 17.73% 221 37 16.74% 170 76.92% Nurse Practitioner Psychiatry YES 56 2392 121 5.06% 224 14 6.25% 156 69.64% Physician Psychiatry YES 345 2333 185 7.93% 211 22 10.43% 157 74.41% Osteopath Family Medicine YES 207 2247 85 3.78% 314 17 5.41% 229 72.93% Nurse Practitioner Psychiatry YES 87 2246 17 0.76% 85 2 2.35% 68 80.00% Physician Family Medicine YES 67 2004 20 1.00% 194 5 2.58% 129 66.49% Physician Family Medicine 1984 2 0.10% 59 2 3.39% 40 67.80% Nurse Practitioner Psychiatry YES 197 1893 11 0.58% 151 2 1.32% 121 80.13% Nurse Practitioner Family Medicine YES 93 1702 10 0.59% 180 4 2.22% 125 69.44% Physician Family Medicine YES 341 1605 142 8.85% 168 21 12.50% 121 72.02% Nurse Practitioner Family Medicine YES 57 1556 0 0.00% 137 0 0.00% 103 75.18% Nurse Practitioner Psychiatry YES 313 1537 4 0.26% 170 1 0.59% 129 75.88% Physician Family Medicine YES 6 1526 16 1.05% 219 5 2.28% 140 63.93% Nurse Practitioner Psychiatry YES 536 1496 10 0.67% 134 2 1.49% 101 75.37% Physician Geriatric Medicine YES 15 1447 43 2.97% 247 13 5.26% 136 55.06% Physician Psychiatry YES 214 1258 67 5.33% 178 8 4.49% 146 82.02% Nurse Practitioner Family Medicine YES 348 1246 218 17.50% 134 22 16.42% 79 58.96% Physician Psychiatry YES 410 1240 81 6.53% 139 14 10.07% 101 72.66% Physician Family Medicine YES 115 1234 14 1.13% 77 4 5.19% 62 80.52% Physician Psychiatry YES 303 1229 52 4.23% 135 6 4.44% 97 71.85% Nurse Practitioner Psychiatry YES 231 1185 29 2.45% 197 8 4.06% 119 60.41% Physician Internal Medicine 1165 97 8.33% 112 4 3.57% 78 69.64% Osteopath Family Medicine YES 228 1104 262 23.73% 101 26 25.74% 65 64.36% Physician Family Medicine YES 222 1096 93 8.49% 117 16 13.68% 96 82.05% Osteopath Psychiatry YES 306 1095 2 0.18% 100 2 2.00% 77 77.00% Nurse Practitioner Family Medicine YES 80 1087 66 6.07% 117 10 8.55% 84 71.79%

CONCURRENT STIMULANT BENZO: Type Specialty STIMULANT CLAIMS Claims Exceed ADD Percent Patients Exceed ADD Percent Exceed DUR Percent Nurse Practitioner Psychiatry YES 315 1073 43 4.01% 156 4 2.56% 130 83.33% Physician Family Medicine YES 23 1056 169 16.00% 94 17 18.09% 63 67.02% Physician Neurology 1044 0 0.00% 15 0 0.00% 13 86.67% Physician Neurology YES 25 1005 0 0.00% 65 0 0.00% 51 78.46% Physician Pediatrics 1003 39 3.89% 97 6 6.19% 33 34.02% Physician Family Medicine YES 9 988 1 0.10% 56 1 1.79% 35 62.50% Nurse Practitioner Family Medicine YES 67 986 81 8.22% 205 25 12.20% 172 83.90% Physician Family Medicine YES 45 971 147 15.14% 190 29 15.26% 145 76.32% Physician Psychiatry YES 37 966 1 0.10% 81 1 1.23% 59 72.84% Osteopath Family Medicine YES 76 927 47 5.07% 143 8 5.59% 89 62.24% Physician Assistant Family Medicine YES 59 920 86 9.35% 172 25 14.53% 115 66.86% Nurse Practitioner Nephrology YES 3 877 107 12.20% 170 17 10.00% 147 86.47% Physician Family Medicine YES 8 877 23 2.62% 184 14 7.61% 118 64.13% Nurse Practitioner Psychiatry YES 134 874 11 1.26% 168 3 1.79% 130 77.38% Physician Family Medicine YES 99 869 0 0.00% 115 0 0.00% 53 46.09% Nurse Practitioner Psychiatry YES 99 865 16 1.85% 150 3 2.00% 129 86.00% Physician Assistant Neurology 856 1 0.12% 66 1 1.52% 19 28.79% Nurse Practitioner Psychiatry YES 230 855 11 1.29% 185 3 1.62% 149 80.54% Physician Assistant Family Medicine YES 65 785 109 13.89% 180 35 19.44% 134 74.44% Osteopath Family Medicine YES 40 778 21 2.70% 85 6 7.06% 52 61.18% Physician Psychiatry YES 18 776 199 25.64% 55 11 20.00% 48 87.27% Physician Pediatrics YES 2 773 2 0.26% 73 2 2.74% 24 32.88% Physician Family Medicine YES 21 770 44 5.71% 96 6 6.25% 62 64.58% Nurse Practitioner Psychiatry YES 231 745 0 0.00% 88 0 0.00% 61 69.32% Osteopath Family Medicine YES 67 737 30 4.07% 99 8 8.08% 54 54.55% Physician Psychiatry YES 37 734 47 6.40% 92 3 3.26% 69 75.00% Physician Assistant Family Medicine 733 39 5.32% 72 3 4.17% 55 76.39% Dentist Family Medicine 716 0 0.00% 570 0 0.00% 0 0.00% Physician Assistant Family Medicine YES 161 714 90 12.61% 74 9 12.16% 49 66.22% Physician Psychiatry YES 219 712 142 19.94% 128 29 22.66% 108 84.38% Nurse Practitioner Family Medicine YES 36 701 12 1.71% 105 5 4.76% 62 59.05% Physician Family Medicine YES 79 697 133 19.08% 140 29 20.71% 97 69.29%

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CONCURRENT STIMULANT BENZO: Type Specialty STIMULANT CLAIMS Claims Exceed ADD Percent Patients Exceed ADD Percent Exceed DUR Percent Physician Psychiatry YES 290 693 20 2.89% 87 6 6.90% 60 68.97% Physician Assistant Family Medicine YES 15 692 4 0.58% 88 1 1.14% 60 68.18% Nurse Practitioner Family Medicine 690 5 0.72% 74 3 4.05% 56 75.68% Osteopath Family Medicine YES 127 690 81 11.74% 67 6 8.96% 47 70.15% Osteopath Family Medicine YES 87 685 55 8.03% 65 4 6.15% 31 47.69% Physician Psychiatry YES 83 671 4 0.60% 52 1 1.92% 35 67.31% Physician Family Medicine YES 135 665 156 23.46% 67 16 23.88% 56 83.58% Physician Family Medicine YES 58 659 20 3.03% 111 8 7.21% 69 62.16% Physician Psychiatry YES 140 658 7 1.06% 84 2 2.38% 68 80.95% Physician Psychiatry YES 69 655 7 1.07% 76 3 3.95% 55 72.37% Nurse Practitioner Family Medicine YES 27 655 5 0.76% 109 1 0.92% 85 77.98% Osteopath Family Medicine YES 62 651 153 23.50% 76 17 22.37% 45 59.21% Physician Family Medicine YES 120 650 329 50.62% 84 34 40.48% 56 66.67% Physician Family Medicine YES 40 648 39 6.02% 64 2 3.13% 31 48.44% Physician Geriatric Medicine YES 54 638 39 6.11% 127 19 14.96% 84 66.14% Physician Internal Medicine 620 84 13.55% 44 6 13.64% 32 72.73% Physician Assistant Family Medicine YES 102 619 33 5.33% 95 5 5.26% 58 61.05% Osteopath Family Medicine YES 9 612 97 15.85% 141 17 12.06% 108 76.60% Physician Family Medicine YES 5 609 2 0.33% 156 2 1.28% 111 71.15%

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