hyperactivity disorder in children and adults

Clinical Therapeutics/Volume 31, Number 1, 2009

New Drug

The Efficacy and Safety Profile of Lisdexamfetamine Dimesylate, a Prodrug of d-Amphetamine, for the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adults Jadwiga Najib, PharmD

Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Division of Pharmacy Practice, Long Island University, Brooklyn, New York, and Departments of Pharmacy and Psychiatry, St. Luke's/Roosevelt Hospital Center, New York, New York ABSTRACT Background: Lisdexamfetamine dimesylate (LDX) is a once-daily medication approved by the US Food and Drug Administration for the management of attention-deficit/hyperactivity disorder (ADHD) in children (aged 6-12 years) and adults. Objective: This article reviews the pharmacologic and pharmacokinetic properties, clinical efficacy, and safety profile of LDX. Methods: Studies, abstracts, reviews, and consensus statements published in English were identified through computerized searches of MEDLINE (1966August 2008) and International Pharmaceutical Abstracts (1977-August 2008) using search headings lisdexamfetamine dimesylate. attention-deficit/hyperactivity disordel:. NRP104. NRP104-201. NRP104-301. NRP 104-302. NRP 104-303. and stimulant. Selected information provided by the manufacturer of LDX was included, as were all pertinent clinical trials. The reference lists of identified articles were also searched for pertinent information. Relevant abstracts presented at annual professional meetings were included as well. Results: Several studies have evaluated the pharmacokinetics of LDX in pediatric patients (6-12 years of age) and healthy adults with ADHD. LDX, a prodrug that is therapeutically inactive until metabolized in the body to dextroamphetamine (d-amphetamine), follows linear pharmacokinetics at therapeutic doses (30-70 mg). The efficacy of LDX in the treatment of ADHD was established on the basis of 1 long-term and 2 short-term controlled clinical trials in children who met Diagnostic and Statistical Manual of Mental 142

Disorders_. Fourth Edition. Text Revision. criteria for ADHD (either the combined or the hyperactiveimpulsive subtype) and in 1 clinical trial with adults with ADHD. The efficacy trials in children found significant improvements in scores on the Swanson, Kotkin, Agler, M-Flynn, and Pelham deportment subscales, the Permanent Product Measure of Performance (Attempted and Correct), and the ADHD Rating Scale Version IV (ADHD-RS-IV) compared with placebo (all, P < 0.001). In the clinical studies designed to measure duration of effect, LDX, compared with placebo, provided efficacy for a full treatment day, up through and including 6 PM, based on parent ratings (Conners' Parent Rating Scale-Revised Short Form) in the morning, afternoon, and early evening (all, P < 0.001). Data from a long-term, open-label extension study that assessed the safety, tolerability, and efficacy of LDX for up to 12 months found LDX treatment resulted in significant improvement (>60%) from baseline in the ADHD-RS-IV at end point (P < 0.001), with good tolerability. The trial in adults found significant improvements in ADHD-RS scores at end point in patients receiving LDX (30, 50, and 70 mg) (P < 0.001 for all active doses); significant improvements in ADHD-RS (using adult prompts) scores were observed at each postbaseline weekly assessment, with improvements noted within the first week in all active treatment arms. Results from human abuse liability Accepted for publicatIOn October 9, 2008 dOl:1 OJ 016!J-cIinthera_2009_01_015 0149-2918/$ - see front matter

© 2009 Excerpta Medica Inc All nghts reserved_

Volume 31 Number 1

J. studies noted that LDX had lower abuse-related drug-liking scores compared with immediate-release d-amphetamine at equivalent doses. The most common adverse events reported with LDX were typical of amphetamine products and included decreased appetite, insomnia, upper abdominal pain, headache, irritability, weight loss, and nausea. Conclusions: Current evidence supports the efficacy and tolerability of LDX as a treatment option for the management of children (aged 6-12 years) and adults with ADHD. As such, LDX may be an integral part of a total treatment program for ADHD that can include other measures such as psychological, educational, and social interventions. (Clin Ther. 2009; 31:142-176) © 2009 Excerpta Medica Inc. Key words: lisdexamfetamine dimesylate, attentiondeficit/hyperactivity disorder, NRP104, NRP104-201, NRP104-301, NRP104-302, NRP104-303, stimulant.

INTRODUCTION According to the American Academy of Pediatrics (AAP), attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in childhood, I estimated to affect 8% to 12% of schoolaged children worldwide. 2 The prevalence of ADHD varies in different studies depending on the method of ascertainment, diagnostic system, setting, gender, population sampled, and assessment measures used. 2- s A systematic review of the literature noted the pooled worldwide prevalence of ADHD to be 5.29% (95% CI, 5.01-5.56), with significant heterogeneity across studies (P < 0.001).5 ADHD is a neurological developmental disorder appearing first in childhood that manifests as a persistent pattern of inattention and/or hyperactivity-impulsivity that is more frequent and severe than is typically observed in individuals at a comparable level of age or development. Due to the greater number of males in clinically referred samples (clinical settings), the sex ratio ranges from 3:1 to 9:1. In nonreferred population samples (community surveys), the sex ratio is closer to 2: 1.6 The male-to-female ratio ranges from 4:1 for the predominantly hyperactive-impulsive subtype to 2: 1 for the predominantly inattentive subtype. 7 ,8 During the school years of higher education, this ratio among older adolescents has been found to be 1:1; on average, symptoms of hyperactivity-impulsivity decrease by 50% every 5 years between ages 10 and 25 years, January 2009

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while problems with attention remain or even worsen. 9 Recent research suggests that ADHD may persist into adulthood in 10% to 60% of childhood-onset cases, becoming a relatively common disorder in adults. 4 A retrospective survey of adults between the ages of 18 and 44 years, projected to the full adult population in the United States, estimates that the disorder affects ~4.4 % or 9.8 million individuals. 10 ADHD is associated with cognitive, social, and academic impairments that if left untreated, can acutely affect an individual's life, leading to low self-esteem; higher injury rates due to accidents; poor performance at school, work, sports, or after-school activities; conflict with family, friends, teachers, classmates, and coworkers; and impaired social and emotional development, as well as impaired success in academic and vocational activities. 11 Additionally, untreated ADHD is associated with increased risk for school failure/ dropout, behavior and discipline problems, alcohol and substance abuse, depression, driving accidents, delinquency, and criminality.12 Children with ADHD who receive stimulant therapy are 3 to 4 times less likely to abuse drugs than those who are untreated. 13 In 2005, a cost-of-illness framework examined the economic impact of ADHD in childhood and adolescence on health care costs, education, parental work loss, and juvenile justice. 14 The estimated annual cost of illness of ADHD in children and adolescents was US $14,576 per individual, with a projected estimate of the annual societal cost of illness of US $42.5 billion (using a 5% prevalence rate). The etiology of ADHD has not been clearly identified, although neurobiologic and genetic abnormalities have been implicated, as have environmental factors. 1S Environmental factors that are associated with a higher risk of ADHD include perinatal stress; complications during pregnancy, at birth, or shortly after birth; and low birth weight. 16 Other factors include traumatic brain inj ury l7 and exposure to environmental toxins such as lead. 18- 20 Additionally, delivery of children by young mothers, delivery of low-birth-weight children, maternal smoking, and maternal alcohol use have also been associated with an increased risk for ADHD.21-23 Because the catecholaminergic neurotransmitter system is associated with executive and cognitive functions, norepinephrine and dopamine are also intimately involved in the pathophysiology of ADHD.24 Research involving family, twin, and adoption studies provides evidence that genes playa role in mediating 143

Clinical Therapeutics

susceptibility to ADHD; although the genetic architecture of ADHD is complex,25-27 heritability is estimated to be 0.76. 25 Guidelines for diagnosing and treating patients with ADHD have been created by the AAP, the American Academy of Child & Adolescent Psychiatry, the European Society for Child and Adolescent Psychiatry, and the Scottish Intercollegiate Guidelines Network. The AAP has addressed the large variations in medical practice regarding the diagnosis and management of ADHD, and recommends using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV- TR)28 criteria to diagnose ADHD, as well as basing the assessment on evidence obtained from patients and teachers. 1,23 ADHD can be classified into 3 subtypes: inattentive, hyperactive-impulsive, and combined. 1,28 Symptomatic behaviors are grouped into 2 categories: inattention and hyperactivity-impulsivity. To be diagnosed with ADHD, a patient must exhibit ::::6 of 9 symptoms of inattention and/or ::::6 of 9 symptoms of hyperactivityimpulsivity that cause some impairment in ::::2 settings (eg, home, school, work) and that appear before 7 years of age (Table 1).28 If a child has primary inattention symptoms, hyperactivity-impulsivity symptoms, or both, the diagnosis is ADHD predominantly inattentive, predominantly hyperactive-impulsive, or predominantly combined, respectively. According to the AAP guideline recommendations, 1 primary care clinicians should initiate an ADHD evaluation for any child aged 6 to 12 years who presents with inattention, hyperactivity, impulsivity, academic underachievement, or behavior problems. Although ADHD is a childhood-onset disorder, the requirement of a precise age-at-onset (particularly for the inattentive subtype) is probably not warranted because many adults with ADHD may not have been diagnosed with ADHD as children. Some experts in the field suggest that late-onset adult ADHD is valid and that the ageat-onset criterion of the DSM-IV-TR is too stringent. 29 ,3o The symptoms must be present for ::::6 months and cause significant impairment in social, academic, or occupational functioning and cannot be better explained by another psychiatric or medical disorder. Impairments in executive functions, impulse control, attention, and activity modulation may lead to secondary impairments in organization tasks, academics, and decision making in social and academic environments. 144

Because no current neuropsychological, laboratory, or radiographic tests can reliably identify ADHD, the approach to diagnosing this disorder includes multiple sources of information, including parents, teachers, other caregivers, and the patient. 23 ,31 Although there is no cure for ADHD, the accepted treatments specifically target its core symptoms, and the primary goal of treatment should be to maximize function. Desired results include improvements in relationships, decreased disruptive behaviors, improved academic performance, increased independence in self-care or assignments, and improved self-esteem. 31 ,32 These standard treatments include educational approaches, psychological or behavioral modifications, medications, or a combination of these factors (multimodal) (Table 11).23,31-34 Regardless of at what point in the patient's life the ADHD is being treated, stimulants remain the first-line agents, unless a patient has a history of substance abuse or bipolar disorder or has an active psychotic disorder. 35 Approximately 70% to 90% of patients with ADHD respond to these medications, and much data are available on stimulants in terms of their efficacy and tolerability, based on hundreds of controlled trials in all age groups with ADHD.36-38 Recently, an algorithm developed by the Texas Consensus Conference Panel on Pharmacotherapy of Childhood Attention Deficit Hyperactivity Disorder confirmed the use of stimulants (methylphenidate and mixed amphetamine salts) as first-line agents based on evidence of their tolerability and efficacy.33 Although there are no substantive differences in response among the various stimulant classes and formulations when dosed equivalently throughout the day,3 9 there are important differences in mode of action that may account for selective individual response. 40 Few studies have directly compared stimulants and nonstimulants, but 1 review of 55 studies suggests that there is a greater benefit associated with stimulant treatment (mean effect size, probability of benefit, odds of benefit, relative percent improvement, and odds ratio for the immediate-release preparations [0.91, 0.74, 2.8, 3.6, and 5.0, respectively] and the long-acting preparations [0.95, 0.75,3.0,3.7, and 5.3, respectively] compared with nonstimulant treatment [0.62,0.67,2.0,2.5, and 3.1, respectively]); however, the benefit is dependent on the amount of stimulant administered. 41 Stimulants used in the treatment of ADHD include nonamphetamines (methylphenidate hydrochloride and dexmethylphenidate hydrochloride), and amVolume 31 Number 1

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Table I. Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for attention-deficit/hyperactivity disorder (ADH D). Patient exhibits either A or B: A

Symptoms of inattention will be exhibited when a patient often: 1. does not give close attention to details or makes careless mistakes in schoolwork, work, or other activities. 2. has trouble keeping attention on tasks or play activities. 3. does not seem to listen when spoken to directly. 4. does not follow instructions and fails to finish schoolwork, chores, or duties in the workplace (not due to oppositional behavior or failure to understand instructions). 5. has trouble organizing activities. 6. avoids, dislikes, or does not want to do things that take a lot of mental effort for a long period of time (eg, schoolwork, homework). 7. loses things needed for tasks and activities (eg, toys, school assignments, pencils, books, tools). 8. is easily distracted. 9. is forgetful in daily activities. B

Symptoms of hyperactivity will be exhibited when a patient often: 1. fidgets with hands or feet or squirms in seat. 2. gets up from seat when remaining in seat is expected. 3. runs about or climbs when and where it is not appropriate (adolescents or adults may feel very restless). 4. has trouble playing or enjoying leisure activities quietly. 5. is "on the go" or often acts as if "driven by a motor." 6. talks excessively. Symptoms of impulsivity will be exhibited when a patient often: 1. blurts out answers before questions have been finished. 2. has trouble waiting one's turn. 3. interrupts or intrudes on others. Other diagnostic criteria: · For either A or B, :::6 symptoms have persisted for :::6 months to a degree that is maladaptive and inconsistent with developmental level. · Symptoms are present before 7 years of age. · Some impairment from symptoms must be present in :::2 settings (eg, home, school, work). · Symptoms cause significant impairment in social, academic, or occupational functioning. · Cannot be better explained by another psychiatric or medical disorder. Based on these criteria, 3 subtypes of ADHD are identified: 1. ADH D, predominantly inattentive subtype: if:::6 symptoms of inattention are met for the past 6 months. 2. AD H D, predominantly hyperactive-impulsive subtype: if:::6 sym pto ms of hyperactivity-impulsivity are met fo r th e past 6 months. 3. ADH D, combined subtype: if:::6 symptoms of both inattention and hyperactivity-impulsivity are met for the past 6 months. Adapted from DSM-IV-TR.28

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Table II. Multimodal management of attention-deficit/hyperactivity disorder (ADHD).23,31-34 Education about and comprehension of ADHD · Support groups · Parenting skills training Behavior management · Positive reinforcement: providing rewards or privileges contingent on performance · Time out: removing access to positive reinforcement contingent on performance of undesired and/or problematic behavior · Response cost: withdrawing rewards or privileges contingent on performance of unwanted and/or problematic behavior · Token economy: combining positive reinforcement and response cost (subject earns rewards/privileges based on desired performance/behavior and loses rewards/privileges based on undesired performance/ behavior) Educational interventions · Classroom accommodations (eg, resource room) · Coaching · Social skills Pharmacologic treatment · Stimulants . Amphetamine · Dextroamphetamine sulfate · Mixed amphetamine salts (combination of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate) · Lisdexamfetamine dimesylate . Nonamphetamine · Methylphenidate hydrochloride · Dexmethylphenidate hydrochloride · Selective norepinephrine reuptake inhibitor (nonstimulant) · Atomoxetine · Heterocyclic antidepressants · Bupropion · Venlafaxine · Tricyclic antidepressants (eg, imipramine, desipramine, nortriptyline, amitriptyline) · cx[Adrenergic agonists · Clonidine · Guanfacine · Arousal agent/hypothalamic center activator · Modafinil

phetamines (dextroamphetamine [d-amphetamine] sulfate and the mixed amphetamines [combination of d-amphetamine, d-amphetamine saccharate, amphetamine aspartate monohydrate, and amphetamine sulfate]). Pemoline, another nonamphetamine stimulant, was removed from the Canadian and the US markets in 1999 and 2005, respectively, due to risk of liver toxici146

ty.42 In addition to the psychostimulants (nonamphetamines and amphetamines) previously mentioned, various nonstimulants have been used (all off label) in managing the symptoms of ADHD. These pharmacologic classes of agents include heterocyclic antidepressants (eg, bupropion, venlafaxine, tricylic antidepressants), cx 2-adrenergic agonists (eg, clonidine, guanfacine), Volume 31 Number 1

J. and arousal agents/hypothalamic center activators (eg, modafinil). In 2002, the first nonstimulant, atomoxetine (a selective norepinephrine reuptake inhibitor), was approved by the US Food and Drug Administration (FDA) for the treatment of ADHD in children, adolescents, and adults. 34 Clinical trials reporting robust, short-term, stimulantrelated improvements in ADHD symptoms in preschool and school-aged children, adolescents, and adults with ADHD have been published. 43 ,44 These studies found that stimulants increase short-term memory, improve ability to focus, decrease distractions, boost attentiveness and academic performance, improve behavior and impulse control, decrease aggressive behavior, enhance peer relations, and improve fine motor skills. Although stimulants remain the first-line agents for the treatment of ADHD, problematic issues associated with shorter-acting agents are both emotional, for the children, and administrative, for the schools. Similarly, adults, who require multiple daily doses, will experience disruption during the day with the use of these immediaterelease preparations. The need for multiple dosing and concerns about the general risk profile of these stimulants have led to the development of new pharmacologic agents, including long-acting formulations that provide an extended duration of action when administered once daily. Additionally, concerns about the general risk profile of stimulants used in ADHD patients and the association between ADHD and substance use disorder, as well as tampering or mechanical manipulations of some formulations leading to misuse via intended or nonintended routes of administration, have led to the development of new agents-with less abuse potential-as alternatives for management of ADHD. The objective of this article was to review the pharmacologic and pharmacokinetic properties, clinical efficacy, and safety profile of lisdexamfetamine dimesylate (LDX),·- a once-daily medication approved by the FDA for the management of ADHD in children (aged 6-12 years) in February 2007 and for the adult population in April 2008. METHODS Relevant articles were identified through computerized searches of MEDLINE (1966-August 2008) *Trademark: Vyvanse'R' (manufactured for New River Pharmaceuticals Inc., Blacksburg, Virginia; distributed by Shire US Inc., Wayne, Pennsylvania).

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and International Pharmaceutical Abstracts (1977August 2008), using search headings lisdexamfetamine dimesylate, attention-deficit/hyperactivity disordel; NRP104, NRP104-201, NRP104-301, NRP104-302, NRP104-30], and stimulant. Entries were selected if they were in English and relevant to the topic reviewed. Selected information provided by the manufacturer of LDX was included, as were all pertinent clinical trials. The reference lists of identified articles were also searched for pertinent information. Abstracts presented at the annual meetings of the American Psychiatric Association, the US Psychiatric & Mental Health Congress, the Institute on Psychiatric Services, and the New Clinical Drug Evaluation Unit Meeting were reviewed and included if judged to be relevant. PHARMACOLOGY LDX, a prodrug of d-amphetamine, belongs to the amphetamine class of stimulant drugs. It has a chemical designation of (2S)-2,6-diamino-N-[( lS)-l-methyl2-phenylethyl] hexanamide dimethanesulfonate, and the corresponding molecular formula is C 1s H 2S N 30 . (CH 4 0 3S2 ). The chemical structures of LDX and d-amphetamine are shown in the figure. 4s LDX is therapeutically inactive and requires oral ingestion to be converted to the active drug moiety, d-amphetamine. d-Amphetamine is the dextrorotary stereoisomer of the amphetamine molecule and is approximately twice as potent as methylphenidate. LDX is not an encapsulated matrix or a bead formulation, as are other currently approved long-acting stimulant formulations. 46 All LDX doses are available as capsules only. The amino acid L-lysine is covalently bound to the d-amphetamine molecule, which is the active portion of the drug, through creation of a peptide bond. Because peptide bonds are cleaved by peptidases, one peptidase, trypsin, has been shown in vitro to convert LDX to d-amphetamine. Trypsin, which is found in abundance in the gastrointestinal tract, is believed to be the primary enzyme that converts LDX to d-amphetamine when taken orally. The exact mechanism of action of amphetamines in treating the symptoms of ADHD has not been established. LDX shares substantial pharmacologic effects with amphetamines, which, being noncatecholamine sympathomimetic amines with central nervous system (CNS)-stimulant activity, are thought to inhibit the reuptake of norepinephrine and dopamine into pre147

Clinical Therapeutics

+ Lisdexamfetamme dlmesylate

L-Iysme

d-Amphetamme

Figure. The chemical structure oflisdexamfetamine dimesylate. 45 Dextroamphetamine (d-amphetamine) is covalently bonded to L-Iysine (prodrug) and is inactive until metabolized to d-amphetamine (active drug moiety).

synaptic neurons, increase the release of these neurotransmitters into the extraneuronal space, and inhibit the catabolic activity of monoamine oxidase. 45 ,47 In vitro, the parent drug, LDX, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine. 45

Toxicity The toxicity profile of oral LDX has been evaluated in rats in 3 studies: a single-dose acute toxicology study and 2 repeated-dose toxicology studies. 48 The acute study used a dose of LDX ranging from 0.1 to 1000 mg/kg and was designed to assess the potential toxicity and lethal dose of oral LDX. Doses up to 10 mg/kg were well tolerated, while doses ::::60 mg/kg were associated with increased motor activity. The median lethal dose (LD 50 ) for single oral doses of LDX in rats was >1000 mg/kg (equivalent to 548 mg/kg of d-amphetamine). The oral LD 50 of d-amphetamine sulfate in rats was 96.8 mg/kg,4 9 suggesting that LDX may have a wider therapeutic index compared with d-amphetamine. The decreased observed toxicity of LDX in rats may be due to saturation of either oral absorption and/or metabolism of the inactive prodrug to the active d-amphetamine compound. Thus, there may be a possible ceiling effect for the intact prodrug, in which larger doses of LDX do not correspond to higher plasma levels of d-amphetamine relative to those noted by equivalent d-amphetamine doses. Thus, a prodrug that releases 148

relatively less stimulant at higher doses may be less likely to be abused, as larger doses would not be expected to produce a corresponding increase in pharmacodynamic effects. PHARMACOKINETICS Several studies have evaluated the pharmacokinetic profile of LDX in healthy adults and pediatric patients (6-12 years of age) with ADHD; 4 of these studies have been fully published,50-53 while the others appear as abstracts and/or poster presentations. 54-57 Additional pharmacokinetic information is presented in Table III53 and Table Iv. 51 ,52 After oral administration, LDX is rapidly absorbed from the gastrointestinal tract and is converted to d-amphetamine and L-lysine. This process occurs via first-pass intestinal and/or hepatic metabolism; however, the exact nature of this process, including its extent and duration, has not been determined. 45 ,58 Preclinical studies suggest that blood is the primary site of conversion, accounting for the majority of this process (~90%).45 This is also evident from the concentration-time profile of LDX. After oral administration of LDX, its plasma concentration peaks rapidly (T max' ~ 1 hour). Simultaneously, d-amphetamine concentrations rise slowly, and peak levels are observed 3.5 hours postdose. These observations suggest that the contribution of the gastrointestinal tract to the enzymatic conversion of LDX is low and that the majority of conversion occurs in the systemic circulation. Volume 31 Number 1

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Table III. Pharmacokinetic parameters for dextroamphetamine (d-amphetamine) and intact lisdexamfetamine dimesylate (LDX) after oral administration of LDX 70 mg/d in fasting and fed healthy adult volunteers and in solution. Values are given as mean (SD). d-Amphetamine

Intact LDX

LDX Fasted

LDX Fed

LDX Solution

3.78 (1.01)*

4.72 (1.07)*

3.33 (1.19)*

1.15 (0.28)*

2.08 (0.65)*

0.97 (0.27)*

9.69 (1.96)

9.59 (1.89)

9.37 (2.06)

0.41 (0.07)*

0.63 (0.20)*

0.44 (0.10)*

Cmax ' ng/mL

69.3 (14.3)

65.3 (13.4)

68.4 (14.6)

48.0 (23.8)*

26.2 (11.9)*

45.6 (17.0)*

AUC O_t ' ng . h/mL

1020 (319.8)

59.47 (24.85) 53.68 (17.72)

53.07 (16.56)

AUCo_oJ:" ng . h/mL

1110 (314.2) 1038 (238.6)

66.84 (23.6)

55.10 (17.0)

Parameter Tmax ' h ty"

h

972 (228.3) 1007 (223.5) 1074 (220.8)

LDX Fasted

LDX Fed

58.81 (15.3)

LDX Solution

*Dlfferences among the 3 treatment groups were significant (P < 0.001) as reported for the mean. Adapted from Krishnan and Zhang. 53

Additionally, IV administration of LDX leads to a pharmacokinetic profile of amphetamine which is similar to that after oral administration. The prodrug is not metabolized by cytochrome P450 (CYP) enzymes, while the ability of d-amphetamine, and its metabolites, to inhibit various CYP isozymes and other enzymes has not been adequately reported. d-Amphetamine is a known inhibitor of monoamine oxidase, and the active drug and its metabolites also produce minor inhibition of CYP1A2, CYP2D6, and CYP3A4 subsets in vitro; however, there are no in vivo studies of CYP enzyme inhibition. 45 After oral administration of a single 70-mg dose of radiolabeled LDX in 6 healthy adults, 96% of the oral dose radioactivity was recovered in the urine over a period of 120 hours; 42% was related to amphetamine, 25% to hippuric acid, and 2% to intact LDX. Only 0.3 % of the dose was recovered in the feces. Plasma levels of unconverted LDX are low and transient; after 8 hours of administration, levels become generally nonquantifiable. 45 A Phase I, open-label, crossover study was undertaken in 18 children (aged 6-12 years) with ADHD who received a single oral 30-,50-, or 70-mg dose of LDX after an 8-hour overnight fast. 45 The T max of d-amphetamine was ~3.5 hours and the T max of LDX was ~ 1 hour. Linear pharmacokinetics of d-amphetamine were noted with once-daily dosing of LDX over a dose range of 30 to 70 mg in this age group. January 2009

A Phase I, single-dose, randomized, open-label, 3-treatment, 3-period, crossover study was conducted in 18 healthy volunteers (age range, 18-55 years; mean age, 31.6 years).53 The 9 females and 9 males were administered a single 70-mg LDX dose under 3 dosing conditions: fasting with intact capsule only, intact capsule after a high-fat meal, and solution containing the capsule contents. This study comprised three 1-week study periods with a 7-day washout period between doses. Data from this study (Table III) suggest that when LDX was administered under the fasted, fed, or solution conditions, the d-amphetamine systemic exposure bioavailability was equivalent for all dosing conditions, as seen by C max and AUCo~J:'. However, for d-amphetamine, significant differences (P < 0.001) in T max values (mean [SD] hours) were noted between the fasted and fed conditions; for intact LDX, significant differences (P < 0.001) in T max ' C max ' and tl/2 were noted between the fasted, fed, and solution conditions, respectively. The results suggest that LDX may be administered with or without food, or its capsule contents dissolved in water and consumed immediately, without affecting the extent of the absorption. 53 In contrast, food prolonged the T max of d-amphetamine from extended-release mixed amphetamine salts (MAS XR) by 2.5 hours compared with the fasted state. 59 The t 1/ 2 values of intact LDX in this single-dose pharmacokinetic study in healthy adults ranged from 0.41 to 0.63 hour, and the t 1/ 2 of 149

Clinical Therapeutics

Table IV. Steady-state pharmacokinetic parameters for dextroamphetamine (d-amphetamine) and intact lisdexamfetamine dimesylate (LDX) after 7 days of oral administration of LDX 70 mg/d in fasting healthy adult volunteers and after 7 days of oral administration of LDX 70 mg/d and 30 mg/d of extended-release mixed amphetamine salts (MAS XR) in pediatric patients with attention-deficit/ hyperactivity disorder. 51 ,52 Intact LDX (from LDX)

d-Amphetamine (from 30 mg MASXR)

Pediatric Mean (SD) [CV%]

Adults Mean (SD) [CV%]

Pediatric Mean (SD) [CV%]

5.06 (0.78) [15.33]

6.56 (3.46) [52.77]

d-Amphetamine (from LDX)

Parameter

Adults Mean (SD) [CV%]

Tmax ' h ty,> h Cmax, 55' ng/mL Cavg , 55' ng/mL Cm1n , 55' ng/mL AUC O_24' ng . h/mL AUCo_'J:" ng . h/mL

3.0 10.1 90.1 46.4 18.2 1110 1453

CV% ~

state; state.

(1.4) [38.5] (2.8) (29.6) [32.8] (16.5) [35.7] (14.2) [78.1] (397) [35.7] (646)

NA

NA

155 (31.4) [20.34]

119 (52.5) [43.96]

NA NA NA

NA NA NA

1326 (285.8) [21.56]

1019 (436.2) [42.83]

(0.3) [28.5] (0.1) (18.6) [38.8] (0.9) [34.6] o (0) 60.7 (21.0) [34.6] 61.1 (20.1)

percent coefficient ofvariation; NA ~ data not available; C max. ~ maximum observed drug concentration at steady average observed drug concentration at steady state; C mln . ~ minimum observed drug concentration at steady

C avg . 55 ~

d-amphetamine after LDX administration ranged from 9.37 to 9.69 hours. 53 A Phase II, randomized, multicenter, double-blind, 3-treatment, 3-period, crossover study was conducted in 52 children (aged 6-12 years) with a primary diagnosis of ADHD, as defined by the DSM-IV-TR criteria. 51 Doses of LDX (30, 50, or 70 mg/d) were compared with MAS XR at equivalent total d-amphetamine base content (10, 20, and 30 mg/d, respectively). The pharmacokinetic data were reported at the last visit for the largest patient cohort as a secondary trial objective and included 8 patients who received LDX 70 mg/d and 9 patients who received MAS XR 30 mg/d, deemed equivalent to d-amphetamine base content, for 1 week (Table IV). Once-daily dosing of LDX, MAS XR, or placebo showed low intersubject (patientto-patient) pharmacokinetic variability in those taking LDX, as measured by coefficients of variation in the following pharmacokinetic parameters: Tmax' Cmax ' and AUCo_'J:" This differed from previous research with MAS XR, which found considerable intersubject variability in serum plasma d-amphetamine levels (CmaJ over time. 6o The T max was 3.5 times less vari150

1.0 0.4 47.9 2.5

55

55

able with LDX than with MAS XR, as noted by the corresponding percent coefficients of variation: 15.33% for LDX and 52.77% for MAS XR. The mean (SD) AUCo~J:' of d-amphetamine after LDX administration compared with MAS XR was 1326 (285.8) and 1019 (436.2) ng . h/mL, with percent coefficients of variation of 21.56% and 42.83%, respectively. Thus, in patients who took 70-mg LDX, release of d-amphetamine was more predictable than in those who took 30-mg MAS XR, and this more consistent exposure of d-amphetamine from patient to patient observed with LDX was noted (as measured by T max and C maJ.51 Also, because the solubility profile of LDX is not affected by the environmental pH within the biological pH range, variation in gastric pH will not affect the absorption of LDX.60 Steady-state concentrations of d-amphetamine were obtained in a Phase I, open-label study of 12 healthy adult volunteers (8 females, 4 males; 6 white, 6 Hispanic/Latino) after 5 days of consecutive dosing with once-daily LDX 70-mg (Table IV).52 This multipledose, single-arm, pharmacokinetics study of oral LDX did not find any unexpected accumulation in the acVolume 31 Number 1

J. tive drug systemic exposure (AUC) at steady state and no accumulation of LDX after once-daily dosing for 7 consecutive days. On days 5 through 8 (with day 8 being 24 hours after the final oral 70-mg dose), mean (SD) predose trough d-amphetamine levels did not differ significantly (20.6 [11.8], 18.7 [10.7], 21.9 [17.2], and 18.2 [10.7] ng/mL, respectively). Also, predose plasma levels of intact LDX for each of these predose time points measured was 0 ng/mL, suggesting that accumulation of the prodrug does not occur. In these healthy adult volunteers, the mean t 1/2 values for d-amphetamine and LDX were 10.1 and 0.4 hours, respectively. Both the prodrug and its metabolite were completely eliminated from plasma within 5 and 72 hours, respectively (d-amphetamine was 95% eliminated within 48 hours), after the final dose of LDX on day 7. 52 The effect of patient gender on LDX pharmacokinetics was assessed, and systemic exposure to d-amphetamine was similar in both genders when administered the same dose in milligrams per kilogram, according to the prescribing information. 45 Weight!dosenormalized AUC and Cmax on day 7 after once-daily dosing of 70-mg LDX for 1 week were 22% and 12% lower, respectively, in adult females than in males. Weight! dose-normalized AUC and Cmax were the same for girls and boys after single-dose administration of LDX 30 to 70 mg. 45 Also, the pharmacokinetics of d-amphetamine were reportedly similar in pediatric (aged 6-12 years) and adolescent (aged 13-17 years) ADHD patients compared with healthy adult volunteers, and any differences noted in kinetics after oral administration were due to differences in milligram/kilogram dosing. 45 The pharmacokinetics and bioavailability of intranasal oral and IV single-dose LDX administration were compared with d-amphetamine sulfate in rats. 56 The study data suggest that, irrespective of the route of administration, LDX decreased and delayed the bioavailability of d-amphetamine, even at oral doses higher than the therapeutically equivalent human doses. Intact LDX, after oral administration, was associated with a nonlinear increase in bioavailability in relation to escalating doses from 1.5 to 12 mg/kg (2.6% and 24.6%, respectively); however, at 60 mg/kg, the bioavailability of intact LDX decreased to 9.3 %. The bioavailability of d-amphetamine from LDX increased from 52% to 82% across the full range of doses (1.5-60 mg/kg); however, with d-amphetamine sulfate, the bioavailability increased from 62% to 84% at therapeutic doses and then disproportionately January 2009

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to 101 % and 223% at higher doses (12 and 60 mg/kg, respectively).56 For the intranasal doses of LDX compared with d-amphetamine, the d-amphetamine AUC O_ 1 value with the prodrug was 95% less, while Tmax was ~12 times longer and Cmax was 96% less. Pooled plasma pharmacokinetic parameters of d-amphetamine after IV administration of LDX compared with d-amphetamine also noted the d-amphetamineAUCo~J:' value with the prodrug was 50% less, while Tmax was ~6 times longer and Cmax was 75% less. Results from 12 healthy adults with a history of stimulant abuse suggest that the systemic exposure of d-amphetamine (AUC and CmaJ was dose proportional in these subjects after a single administration of LDX in doses between 30 and 130 mg but was attenuated at doses between 130 and 150 mg. 54 Thus, LDX, as it undergoes rate-limited hydrolysis, is gradually converted to d-amphetamine, which may be associated with a reduced potential for abuse. A single oral 100-mg dose of LDX was compared with a 40-mg dose of d-amphetamine sulfate (which contain approximately equal amounts of d-amphetamine base). The results showed that the d-amphetamine AUC for the first 4 hours after administration of LDX was 165.3 to 231.1 ng . hlmL compared with 245.5 to 316.8 ng . hlmL after administration of d-amphetamine sulfate. Cmax values of d-amphetamine with LDX and d-amphetamine sulfate were achieved at a Tmax of 3.78 to 4.25 hours and 1.88 to 2.74 hours, respectively. The prodrug was rapidly cleared, with a t 1/2 reported as 0.44 to 0.77 hour. 54 Another study in 12 healthy stimulant abusers noted that 50-mg LDX administered intravenously compared with a molar weight-basis equivalent amount of 20-mg IV d-amphetamine sulfate was associated with a lesser degree of euphoria or amphetamine-like subjective effects. 57 After administration of 50 mg of IV LDX, a mean d-amphetamine Cmax of 38.9 ng/mL occurred at 2.5 hours and was maintained during the 4-hour observation period, compared with a mean d-amphetamine Cmax of 105 ng/mL, which occurred at 0.82 hour and rapidly subsided in patients who were administered IV d-amphetamine sulfate. LDX has not been studied in the geriatric population or in patients with hepatic and/or renal impairment; thus, no data are available regarding the use of this agent in those patient populations. An in vitro study using a high-pressure liquid chromatographic assay specific for LDX was used to de151

Clinical Therapeutics

termine the pH solubility profile of LDX in saturated buffer aqueous solutions with pH levels of 1 to 13. 61 The solubility profile of LDX was not affected by the pH of the solution within a physiologically relevant pH range of 1 to 8, and modest reductions in LDX solubility were noted when the pH was increased from 8 to 13. Thus, the conversion of LDX to d-amphetamine should not be affected by gastrointestinal pH, and alkalinizing agents (eg, sodium bicarbonate, antacids) should not influence the absorption of LDX. Additionally, because LDX is a prodrug, and not a controlledrelease delivery vehicle, it is unlikely to be affected by alterations in normal gastrointestinal transit times. No published pharmacokinetic studies have determined if LDX crosses the blood-brain barrier in humans. Pharmacokinetic studies in rats did not detect LDX in rat brain tissue after oral administration of intact LDX.45 PHARMACODYNAMICS As an isomer, d-amphetamine is twice as potent a CNS stimulator on a weight basis than racemic amphetamine, and peak d-amphetamine concentrations in adults occur 3 to 4 hours after ingestion. 45 With LDX, the washout period of d-amphetamine is delayed, as might be expected from the rate-limited hydrolysis of the prodrug, and may contribute to the higher level of insomnia reported with LDX.45,62 Toxicology studies in rats have noted that higher doses of LDX do not result in correspondingly higher plasma levels of the active drug moiety, d-amphetamine, relative to those produced by equivalent d-amphetamine doses. 48 A prodrug stimulant that releases relatively less stimulant drug at higher doses may be less abused, as escalating doses would not be expected to yield a corresponding increase in pharmacodynamic effects. 48 DRUG INTERACTIONS Krishnan and Moncrief5o evaluated the CYP inhibition potential of LDX in pooled human liver microsomes from males and females. In vitro testing for LDX, at concentrations ranging from 0.01 to 100 rM, found that none of the 7 CYP isoforms (CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) showed any concentration-dependent or mechanism-based inhibition caused by time-dependent inactivation of human CYP isoforms. This suggests that LDX has a low potential for drug-drug interactions or initiation of drug-drug interactions; however, any 152

interactions would likely be caused by d-amphetamine and its metabolites. More studies are needed to better determine the precise mechanism of lysine hydrolysis and to fully appreciate the potential for unique drug interactions associated with LDX. Amphetamines, including LDX, have been implicated in various drug interactions (Table V).45,58 Amphetamines can cause a substantial increase in plasma corticosteroid levels, and this increase is greatest in the evening. They may also interfere with urinary steroid determinations. 45 LDX's urinary amphetamine concentration after its therapeutic use has not been reported; however, it is possible and expected that patients taking LDX would test positive for amphetamines during routine urinary drug-screening tests. 45 TH ERAPEUTIC EFFICACY Table VI summarizes results from clinical trials of LDX in patients with ADHD.51,63-67 Clinical Trials in Children Two randomized, double-blind, multicenter, clinical trials in school-aged children who met DSM-IV-TR criteria for ADHD (either the combined or the hyperactiveimpulsive subtype) were undertaken to evaluate the efficacy and safety profile of once-daily oral LDX,51,63 followed by an open-label extension study.64 A placebocontrolled Phase II trial with an active reference arm conducted in an analog classroom setting51 and a placebo-controlled Phase III trial conducted in a naturalistic setting63 included children aged 6 to 12 years. Some 63 or all 51 of these subjects had previously received treatment for ADHD. A long-term, open-label, multicenter, extension study was undertaken in children aged 6 to 12 years meeting DSM-IV-TR criteria for ADHD (majority had the combined subtype) who mayor may not have received prior LDX treatment 64 (Table VI).

Phase /I Trial: Analog Classroom Setting Biederman et a15 1 conducted a Phase II, multicenter, double-blind, placebo- and active-controlled, 3-treatment, 3-period,crossover study (Study NRP104201) in 52 children aged 6 to 12 years (mean [SD] age, 9.1 [1. 7] years), in whom the mean (SD) time since ADHD diagnosis was 3.3 (2.3) years. The study was conducted in a controlled classroom environment. Key inclusion criteria included treatment with a stable regimen of stimulant medications for::::1 month within Volume 31 Number 1

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Table V. Drug interactions with amphetamines and lisdexamfetamine dimesylate. Medication

Clinical Effect

Therapeutic Management

Monoamine oxidase inhibitors 45 .58

Slow amphetamine metabolism and potentiate effect; may lead to hypertensive crisis and fatal resu Its.

Contraindicated together. Do not use within 2 weeks of each other.

Sympathomimetics 45

Sustained increases in amphetamine; potential cardiovascular effects.

Lower the dose of sympathomimetics; monitor cardiovascular function.

Tricyclic antidepressants 45

Sustained increases in amphetamine; potential cardiovascular effects.

Lower dose of tricyclic antidepressants; mon itor cardiovascular function.

Meperidine 45

Potentiate analgesic effect of meperidine; CNS excitation; seizures.

Lower dose of analgesics or use alternative agents.

Propoxyphene overdose 45

Potentiate amphetamine CNS stimulation; fatal convulsions may occur.

Supportive management; monitor closely.

Veratrum alkaloids 45

Antagonize the hypotensive effects ofveratrum alkaloids.

Monitor blood pressure.

Antihypertensive agents (eg, adrenergic blockers)45

Antagonize or reduce the effects of antihypertensive agents.

Monitor blood pressure; make adjustments accordingly.

Nonselective ~-blockers58

Lead to unopposed alpha stimulation (tachycardia, hypertension).

Monitor blood pressure; make adjustments accordingly.

Urinary acidifiers (ammonium chloride, sodium acid phosphate)45.58

Increase urinary excretion of amphetamines; efficacy reduced.

Cautiously increase amphetamine dose and monitor for efficacy accordingly.

Alkalinizing agents (bicarbonate, carbonic anhydrase inhibitors)45.58

Delay urinary excretion of amphetamines; increased levels of amphetamines.

Decrease amphetamine dose and monitor for toxicity accordingly.

Methenamine 45

Increase urinary excretion of amphetamines; efficacy reduced.

Cautiously increase amphetamine dose and monitor for efficacy accordingly.

Ethosuximide, phenytoin, phenobarbital 45

Delayed intestinal absorption of the antiepileptic agents.

Space medications apart, monitor levels of antiepileptic agents, and make dosage adjustments accordingly.

Haloperidol 45

The neuroleptic agent blocks dopamine, inhibiting the central stimulant effects of amphetamines.

Use cautiously, as amphetamines may exacerbate psychosis; monitor patient for adverse effects and efficacy. (continued)

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153

Clinical Therapeutics

Table V (continued). Medication

Clinical Effect

Therapeutic Management

Chlorpromazine 45

The neuroleptic agent blocks dopamine and norepinephrine, inhibiting the central stimulant effects of amphetamines.

Use cautiously, as amphetamines may exacerbate psychosis; monitor patient for adverse effects and efficacy.

Norepinephrine 45

Enhanced adrenergic effect of norepinephrine.

Avoid concomitant use; monitor patient for enhanced effect of amphetamines and toxicity.

Lithium carbonate 45

Inhibit the stimulatory and anorectic effects of amphetamines.

Make dosage adjustments accordingly; monitor therapeutic response and weight.

eNS

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central nervous system.

the past 6 months with adequate response, capacity to follow classroom instructions, and ability to function at age-appropriate academic levels. Exclusion criteria included comorbid medical and psychiatric disorders that could interfere with study participation or affect the efficacy or tolerability of the stimulants used in the study; allergy or intolerance to MAS XR; history of drug abuse; use of concomitant medications that affect the CNS; seizures within the past 2 years; tic disorders, hyperthyroidism, or cardiac disorders; and significant laboratory abnormalities. This Phase II trial compared the efficacy and safety profile of LDX (30, 50, or 70 mg) with placebo; MAS XR (10,20, or 30 mg) was included as a reference arm of the study. A 3-week, open-label, dose-titration period with MAS XR was initiated at 10 mg/d; depending on therapeutic response (evaluated by using the Clinical Global Impression [CGI] score, interview with parents, and safety data), the dose was titrated upward at 10-mg increments or remained the same during each subsequent weekly visit. 51 It could also be decreased by 10-mg increments to a minimum dose of 10 mg/d. Patients were assigned to 1 of 3 cohorts based on the optimal dosage of MAS XR determined during the 3-week titration phase. The dose of LDX in each cohort was determined to be comparable to the corresponding optimal MAS XR dosage based on approximately equivalent amphetamine base content (ie, LDX doses of 30, 50, and 70 mg/d were deemed equivalent 154

to MAS XR doses of 10, 20, and 30 mg/d, respectively). Each cohort received LDX (dose equivalent to participant's optimal MAS XR dose), MAS XR (participant's optimal dosage), and placebo once daily for 1 week each. The 3 cohorts were as follows: cohort A (n = 10 [19%]) received LDX 30 mg/d, MAS XR 10 mg/d, and placebo; cohort B (n = 17 [33%]) received LDX 50 mg/d, MAS XR 20 mg/d, and placebo; and cohort C (n = 25 [48%]) received LDX 70 mg/d, MAS XR 30 mg/d, and placebo. After the dosetitration period, patients entered the double-blind crossover portion of the trial, and the order of the treatments was randomized. All 52 patients were diagnosed with combined ADHD subtype (both hyperactive-impulsive and inattentive). The majority of the patients were male (64%); 29 (56%) were white, 12 (23%) were black, 8 (15%) were Hispanic, and 3 (6%) were classified as other. Patients had previously been treated with amphetamines, methylphenidate, stimulants not otherwise specified, stimulants with atomoxetine, and other agents (46%, 26%, 12%, 10%, and 4%, respectively), while the rest did not have their prior medication listed. Using baseline CGI-Severity (CGI-S) scores, 62% were "moderately ill," 21 % were "markedly ill," and 17% were "severely ill." Of the 52 patients enrolled in the study, 2 of the 10 patients in cohort A terminated the study during the first double-blind treatment week while on placebo; the intent-to-treat (ITT) population therefore consisted of 50 children. Volume 31 Number 1

J. The primary efficacy measure was the least squares (LS) mean of the average scores for LDX versus placebo from the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) rating scale across a treatment day (measured at 1,2,3,4.5,6,8, 10, and 12 hours postdose).51 SKAMP is a standardized, validated classroom assessment tool used for evaluating the behavioral symptoms of ADHD via an independent observer rating of subject impairment in classroom behavior. 68 Comprising 2 subscales (deportment [SKAMP-DS] and attention [SKAMP-AS]), SKAMP is scored on a 7-point impairment scale ranging from 0 to 6, with higher ratings reflecting greater impairment. Secondary efficacy outcome measures included changes in SKAMP-AS, Permanent Product Measure of Performance (PERMP)-Attempted (PERMP-A) and PERMPCorrect (PERMP-C) scores, and changes from baseline on the CGI scale scores. PERMP is a validated 10-minute test used to evaluate response to stimulant medication by objectively measuring the number of attempted and correct age-adjusted collection of math problems. 69 Patients were administered a pretest during the practice visit, which-based on patients' ability-determined the level of the math test they would undertake. Both SKAMP and PERMP are considered to be sensitive to dosage and time effects of stimulant medications. 69 The CGI rating scale is used to assess global improvement in symptoms over time. 7o The CGI-S scale was conducted at baseline, with scores ranging from 1 to 7 (1 = no symptoms to 7 = very severe symptoms). After each postbaseline visit, the clinician assessed symptom improvements for each patient utilizing the CGI-Improvement (CGI-I) scale, with scores ranging from 1 to 7 (1 = very much improved to 7 = very much worse). For each measure of efficacy (SKAMP, PERMP, and CGI-I scales), both LDX and MAS XR produced similar improvements in children at each time point over 12 hours, and each treatment was significantly superior at all doses compared with placebo (P < 0.001).51 SKAMP-DS scores were significantly lower with LDX or MAS XR than with placebo in all 3 cohorts (cohort A, P < 0.05; cohorts Band C, P < 0.001 each [for both active treatments compared with placebo]), with no significant differences noted between the active treatment groups in any of the cohorts. At end point, LS mean SKAMP-DS scores were significantly lower with LDX (30, 50, and 70 mg) or MAS XR (10,20, and 30 mg) compared with placebo (0.8 each for LDX and January 2009

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MAS XR vs 1. 7 for placebo [P < 0.001 for both active treatment groups vs placebo]). Additionally, significant improvement in secondary outcome measures was noted on the LS mean SKAMP-AS score for both LDX and MAS XR (1.2 for combined doses for both agents) compared with placebo (1.8; P < 0.001 for both active treatments vs placebo). A post hoc analysis of SKAMP-DS, the duration as assessed by the change in score at each hour from first measurement at 1 hour postdose, favored both LDX and MAS XR in the ITT population (n = 50) at all time points beginning 2 hours postdose (P < 0.05 vs placebo). The duration of therapeutic efficacy lasted across the 8 sessions of a 12-hour treatment day for both active treatment groups, as noted 12 hours postdose (the last time point measured), and the drug effect was similar for all 8 sessions. A post hoc analysis of SKAMP-AS, the duration as assessed by the change in score at each hour from first measurement at 1-hour postdose, noted significant improvement from baseline beginning at 2 hours for LDX-treated patients and at 3 hours for MAS XR-treated patients. The number of math problems attempted and correct, as assessed by PERMP, was significantly greater in both active treatment groupS.51 Combined dosage analyses revealed significantly higher LS mean PERMP-A (LDX, 133.3; MAS XR, 133.6; placebo, 88.2 [both, P < 0.001]) and LS mean PERMP-C (LDX, 129.6; MAS XR, 129.4; placebo, 84.1 [both, P < 0.001]) scores with both active treatments compared with placebo. A post hoc analysis of PERMP-A and PERMP-C ratings, the duration as assessed by the change in score at each hour from first measurement at 1 hour postdose, favored both LDX and MAS XR in the ITT population (n = 50) at all time points beginning 2 hours postdose (P < 0.001 vs placebo). On the CGI-I scale, the LS mean (SE) for LDX was 2.2 (0.2) and for MAS XR it was 2.3 (0.2), a significant improvement compared with placebo (4.2 [0.2]; P < 0.001). The difference in LS mean (95% CI) of LDX versus placebo was -2.0 (-2.4 to -1.5 [P < 0.001]) and the difference in LS mean (95% CI) of MAS XR versus placebo was -1.8 (-2.3 to -1.3 [P < 0.001]). Investigators noted ratings of "very much improved" or "much improved" in 74% of patients who received LDX (P < 0.001) and 72% of those who received MAS XR (P < 0.001), compared with 18% of patients who received placebo. A total of 32 % of patients who received LDX were rated as "very much improved" versus 16% of patients who 155

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Table VI. Summary of clinical trials of lisdexamfetamine dimesylate (LDX) in patients with attention-deficit/hyperactivity disorder (ADHD)"

Reference/ Population Biederman et al S1 (6-12 y)

Study Design/ Duration

Regimens/ No. of Patients (ITT)

Cohort A, n = 8 Phase II, MC, DB, R, PC and LDX 30 mg/d activeMASXR controlled, 10 mg/d 3-treatment, Placebo Cohort B, n = 17 3-period, crossover study LDX 50 mg/d in a controlled MASXR classroom 20 mg/d environment. Placebo Cohort C, n = 25 Three cohorts (each cohort LDX 70 mg/d received LDX, MASXR MASXR, and 30 mg/d placebo, once Placebo daily for 1 week each).

Results

LS mean of the From baseline, average scores sign ificant from SKAMPimprovement noted DS across a for LDX (30-, 50-, treatment day and 70-mg combined doses) and MAS XR (10-, 20-, and 30-mg combined doses) in mean (SD) SKAMPDS score (both, 0.8 [0.1]) vs placebo (1.7 [0.1]) (P < 0.001 for both activetreatment groups vs placebo).

AEs Reported During the OL dose titration with MAS XR: headache (15%), decreased appetite (14%), insomnia (10%), abdominal pain (6%), upper abdominal pain (6%), upper respiratory tract infection (4%), affect lability (4%), vomiting (2%), and anorexia (2%). During the double-blind part of the study, AEs reported for LDX, MAS XR, and placebo, respectively: insomnia (8%,2%,2%), decreased appetite (6%, 4%,0), anorexia (4%,0,0), upper respiratory tract infection (2%, 2%, 0), vomiting (0, 2%,4%), and upper abdominal pain (0,4%,2%). Reports of abdominal pain, headache, and affect lability were reported as 0 for all 3 treatment groups.

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Reference/ Population

Study Design/ Duration

Biederman et al 63 (6-12y)

Phase III, MC, DB, R, FD, PC, PG; 4 weeks' duration

Regimens/ No. of Patients (ITT) LOX 30 mg/d (n = 56) LOX 50 mg/d (n = 60) LOX 70 mg/d (n = 60) Placebo (n = 54)

Primary Efficacy Measurements Change from baseline in ADHD-RS-IV total score

Results

AEs Reported

Sign ificant improvements in ADHD-RS-IV noted with all doses of LOX (30, 50, and 70 mg) vs placebo (-21.8, -23.4, -26.7, -6.2 points, respectively; all, P < 0.001). Significant improvement noted in weekly ADHD-RSIV total score change from baseline starting at week 1 (P < 0.001).

For LOX 30 mg, LOX 50 mg, LOX 70 mg, and placebo, respectively: decreased appetite (37%, 31%,49%,4%), insomnia (16%,16%,25%,3%), upper abdominal pain (14%, 7%,15%,6%), headache (10%, 10%, 16%, 10%), irritability (11 %, 8%, 10%, 0), vomiting (7%, 5%, 14%,4%), weight loss (6%, 3%,19%,1%), nausea (4%, 3%,11%,3%), dizziness (7%, 5%, 3%, 0), nasopharyngitis (6%, 4%, 6%, 6%), nasal congestion (4%, 0, 0, 6%), cough (3%, 1%,0,6%), and dry mouth (3%,3%,8%,0).

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Reference/ Population Findling et al 64 (6-12y)

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Study Design/ Duration Phase III, longterm, Me, OL, single-arm study; patients were previously enrolled in a DB study and mayor may not have received prior treatment with LOX (except for 1 newly enrolled patient).

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Regimens/ No. of Patients (ITT) All patients titrated in an OL fash ion to oncedaily 30-, 50-, or 70-mg LOX during weekly visits for first 4 weeks; then maintained for up to an additional 11 months. N = 272; 201 (74%) treated with LOX for at least 6 months and 146 (54%) for at least 12 months.

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Results

AEs Reported

At end point (last observation), LOX 30 mg, 50 mg, and 70 mg showed a 60% improvement in ADHD symptoms by decreasing ADHDRS-IV total mean (SO) scores (-27.2 [13.0]) compared with baseline (for all comparisons, P < 0.001); improvement in decreasing ADHDRS-IV inattentive and hyperactivityimpulsivity subscale scores (-13.4 [7.0] points and -13.8 [7.0] points, respectively) compared with baseline (both, P < 0.001). Reduction in ADHDRS-IV was consistent from week 4 and onwards.

With all doses of LOX: decreased appetite (33%), weight loss (18%), headache (18%), insomn ia (17%), upper abdominal pain (11%), upper respiratory tract infection (11 %), irritability (10%), nasopharyngitis (10%), vomiting (9%), cough (7%), and influenza (6%).

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Reference/ Population

Study Design/ Duration

Adler et al 65 Niebler et al 66 Goodman et al 67 (18-55 y)

Phase III, FD, DB, R, PC, PG; 4-week study with dose escalation

Regimens/ No. of Patients (ITT)

Primary Efficacy Measurements

LOX 30 mg/d (n = 115) LOX 50 mg/d (n = 117) LOX 70 mg/d (n = 120) Placebo (n = 62)

Change from baseline to end point of the ADHD-RS (using adult prompts) total score

Results

AEs Reported

Changes in ADHDRS sign ificantly greater for each LOX dose (30, 50, and 70 mg) vs placebo (-16.2 [1.06], -17.4 [1.05], -18.6 [1.03], and -8.2 [1.43], respectively; all 3 LOX groups, P < 0.001). Significant changes for each LOX dose (30, 50, and 70 mg) vs placebo (-12.2, -11.5, -13.4, and -5.7, respectively; all, P < 0.001) were observed within 1 week.

Treatment-emergent AEs with incidence >5% in any treatment group and twice that of placebo for LOX 30 mg, LOX 50 mg, LOX 70 mg, and placebo, respectively: decreased appetite (29%, 28%, 23%, 2%), dry mouth (21%, 25%, 31%, 3%), insomnia (19%,17%,21%,5%), nausea (8%,6%,7%,0), diarrhea (7%, 10%, 3%, 0), anxiety (4%, 5%, 7%, 0), anorexia (3%, 7%, 5%, 0), and feeling jittery (2%, 3%,7%,0). Cardiac-related treatment-emergent AEs with an overall incidence >2% for LOX 30 mg, LOX 50 mg, LOX 70 mg, and placebo, respectively: palpitations (1.7%, 0.9%, 2.5%, 0), tachycardia (0.8%, 2.6%, 0, 0), increase in blood pressure (0.8%, 3.4%, 4.1%,0), increased heart rate (0.8%, 2.6%, 2.5%, 0), and dyspnea (2.5%, 1.7%, 2.5%, 0). Sleep-related treatment-emergent AEs with an overall incidence >2% for LOX 30 mg, LOX 50 mg, LOX 70 mg, and placebo, respectively: initial insomnia (3%,6%,6%,3%), insomnia (19%,17%, 21%,5%), middle insomnia (4%,2%,5%,0), somnolence (1%, 0, 0, 3%), and sleep disorder (0, 2%, 0, 3%).

ITT ~ Intent-to-treat population; AEs ~ adverse events; MC ~ multicenter; DB ~ double-blind; R ~ randomized; PC ~ placebo-controlled; MAS XR ~ extendedrelease mixed amphetamine salts; LS ~ least squares; SKAMP-DS ~ Swanson, Kotkm, Agler, M-Flynn, and Pelham deportment ratmg subscale; OL ~ open-label; FD ~ forced dose; PG ~ parallel-group; ADHD-RS-IV ~ ADHD Ratmg Scale Version IV; ADHD-RS ~ ADHD Rating Scale.

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Clinical Therapeutics

received MAS XR and 2% of patients who received placebo. Secondary end points in this Phase II study included safety, as assessed by adverse events at every visit; physical examination (at screening and final visit); vital signs (recorded at each visit); laboratory findings (at screening and at final visit); and electrocardiogram (ECG) findings (at screening, last visit of titration period, every visit during the double-blind period, and final visit).51 At the last classroom visit, participants had an indwelling catheter inserted into a vein for repeated plasma sampling to be obtained at 1,2,3,4.5, 6, 8, 10, and 12 hours postdose. Twenty-nine of the 52 patients (56%) reported a total of 89 adverse events (56 were mild, 33 were moderate) during the study; 52 were reported during dose titration with MAS XR and 37 during the double-blind treatment period. During the double-blind phase, 16% of LDXtreated patients, 18% of MAS XR-treated patients, and 15% of patients receiving placebo reported adverse events (Table VI). The most common adverse events for LDX were insomnia (8%), decreased appetite (6%), and anorexia (4%). Although this Phase II study used validated efficacy measures in an analog classroom setting previously described in treatment research, as well as evaluations in the classroom setting and nonclassroom setting, severaI limitations exist.51 Patients with comorbid medical or psychiatric disorders were excluded, which could potentially influence the efficacy and/or tolerability of the study stimulants if used concomitantly with medications that affect the CNS. Because approximately one half of all children with ADHD have ::::1 other comorbidity, and because treatment of these comorbid disorders with other psychoactive agents may affect the responsiveness and tolerability of LDX in these patients,23 a key inclusion criterion included a history of treatment with a stable regimen of stimulant medication; hence, the results from this trial may not necessarily be generalizable to treatment-naive patients. Although the study population was diverse, the subgroups were insufficient in size to determine relative benefit regarding patient age, gender, or ethnicity. Additionally, the objective of the study was not designed to compare the efficacy or safety profile of LDX with MAS XR, an agent already used for the management of ADHD. Improved tolerability in the double-blind period of the study may have occurred during the open-label dose optimization of MAS XR 160

and limited the conclusions regarding the tolerability of LDX during that part of the study. Insomnia was observed in 10% of patients during the titration period with MAS XR, but during the double-blind period, only 2% of patients receiving MAS XR or placebo experienced insomnia compared with 8 % of patients treated with LDX. The short duration of the trial limits extrapolation of the efficacy and tolerability data to the long-term treatment that is generally required in the management of ADHD symptoms. Phase 11/ Trials: Naturalistic Setting Study NRP104-301, conducted by Biederman et al,63 was a Phase III, double-blind, randomized, placebocontrolled, parallel-group study in 290 children (201 boys, 89 girls) aged 6 to 12 years (mean [SD] age, 9 [1.8] years) with a primary diagnosis of ADHD using DSM-IV-TR criteria (either combined or hyperactive-impulsive subtypes) conducted in 40 centers in the United States. After a 1-week washout period, treatment-naive or previously treated patients were randomly assigned for 4 weeks to 1 of 4 fixed-dose treatment arms of once-daily LDX 30 mg (n = 71), LDX 50 mg (n = 74), LDX 70 mg (n = 73), or placebo (n = 72). To assess the efficacy and tolerability of each individual dose of LDX, a forced-dose design was used: 30 mg for 4 weeks, 50 mg (30 mg/d for week 1, with forced-dose escalation to 50 mg/d for weeks 2-4), or 70 mg (30 mg/d for week 1, with forced-dose escalation to 50 mg/d for week 2, and 70 mg/d for weeks 3 and 4). The primary efficacy end point was the change from baseline in the ADHD Rating Scale Version IV (ADHDRS-IV) total score. 63 This scale comprises 18 items, which correspond to 1 item for each of the 18 symptoms contained in the DSM-IV-TR diagnosis of ADHD. The 18 items are grouped into 2 subscales (hyperactivityimpulsivity and inattentiveness) each consisting of 9 items, with each item scored on a 4-point scale ranging from 0 to 3 (0 = no symptoms, 1 = mild symptoms, 2 = moderate symptoms, and 3 = severe symptoms).71,72 Children were required to have an ADHD-RS-IV score ::::28 to be eligible for randomization into this study. Secondary efficacy outcome measures were the changes from baseline on the Conners' Parent Rating Scale-Revised Short Form (CPRS-R),73 a parent-rated scale that assessed ADHD symptomatic behavior at 3 time points throughout the day (morning [~10 AM], noon [~2 PM], and evening [~6 PM]); the changes from Volume 31 Number 1

J. baseline in CGI-I scores; and safety parameters. 63 Independent clinician raters were not used for outcome measures and tolerability assessments. Of the 290 randomized patients, 285 were included in the lIT population and 230 completed the study (LDX 30 mg, n = 56; LDX 50 mg, n = 60; LDX 70 mg, n = 60; and placebo, n = 54).63 There were no notable demographic differences between treatment groups, but patients were primarily white (53 %), male (69%), and were previously treated for ADHD (36%). Significantly greater improvements in ADHD-RS-IV total scores (mean change from baseline to end point) were noted in recipients of daily doses of LDX 30 mg, 50 mg, and 70 mg compared with placebo recipients (-21.8, -23.4,-26.7,and-6.2 points, respectively; all,P < 0.001). Additionally, mean ADHD-RS-IV scores were significantly improved from week 1 in all LDX-treated patients compared with placebo recipients and continued over the course of the 4-week treatment period (P < 0.001). All patients treated with LDX had significantly greater improvement in both the ADHD-RS-IV hyperactivity-impulsivity and inattention subtypes from baseline to end point compared with placebo recipients (all, P < 0.001). The effect sizes (measured to determine the magnitude of treatment effect and calculated by dividing the difference in means over the pooled SD) with LDX were 1.21, 1.34, and 1.60 in the 30-,50-, and 70-mg groups, respectively, based on the ADHD-RS-IV scores at treatment end point, determined by the corresponding between-group differences and the model-based SD of 12.84. 63 Notably, these effect sizes were greater than those reported with other stimulants.74 Comparisons between the 30- and 70-mg doses of LDX were statistically significant, and the difference in LS mean ADHD-RS-IV change from baseline scores between these 2 dosage groups was -4.91 (P < 0.05), with the greatest improvements observed in the 70-mg group. Assessment of symptomatic behaviors of ADHD using the CPRS-R found significant improvements from baseline in LS mean scores, as observed at each time point with all LDX daily doses compared with placebo (P < 0.001 for each time point and dosage).63 CPRS-R scores in the morning (~10 AM), afternoon (~2 PM), and evening (~6 PM) reflected significantly greater improvements in symptom control throughout the day in each LDX dose group compared with placebo (P < 0.01); median time of LDX administration was between 7:30 and 8 AM. CGI-I scores were signifiJanuary 2009

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cantly improved with all 3 doses of LDX, as ratings of "very much improved" or "much improved" were observed in >70% of patients in the active treatment groups, compared with 18% observed with placebo (P < 0.001). A post hoc responder analysis found that patients who received LDX at any dose, compared with those who received placebo, were more likely to meet the responder criteria of a >30% decrease in ADHD-RS-IV total score and a CGI rating of 1 or 2 ("very much improved" or "much improved").63 At study end point, responders for the daily oral LDX doses of 30, 50, and 70 mg were 66%, 72%, and 80%, respectively, compared with an 18 % response in the placebo cohort. 75 In this Phase III trial, tolerability was assessed by adverse-event identification (using patient interview and observation), physical examination (including vital signs, and laboratory and biochemistry tests), and ECG measurements, all performed at screening and final study visits only.63 Nonserious adverse events were collected throughout the study, while serious adverse events were collected throughout the study and ~30 days after the last dose of study medication. The observed results of these outlier analyses revealed no apparent trends. Treatment-emergent adverse events for all doses of LDX were greatest during the first week of treatment; >95% of events were mild or moderate in intensity and the majority resolved within 4 weeks of continued therapy.63 No serious adverse events or deaths were reported. Adverse events were experienced in 72 % of LDX 30-mg recipients, 68% of LDX 50-mg recipients, and 84% of LDX 60-mg recipients compared with 47% of placebo recipients. These adverse events were consistent with those associated with amphetamines and were very similar to those reported in an earlier clinical trial involving 584 school-aged children with ADHD treated with MAS XR using the same study design. 76 Although a large sample size and several validated efficacy measures were used in the evaluation of ADHD with parent- and clinician-completed rating scales, there are several methodologic limitations to this Phase III trial. 63 Parental assessments (CPRS-R) were used in the secondary efficacy measures, and although parents are good reporters of ADHD symptoms in their children, having classroom assessments performed by teachers would provide additional sup161

Clinical Therapeutics

port and a more objective evaluation of the benefits of the stimulant. Patients assigned to the LDX 50-mg and 70-mg groups underwent dose escalation quickly, regardless of efficacy and tolerability, contrary to standard practice; this may have led to an increase in the adverse events reported in these groups. As in the previous study, 51 limitations included that patients with comorbid psychiatric disorders were excluded from the study, and the short duration of the trial did not provide the ability to extrapolate efficacy and safety findings required for the chronic long-term management of symptoms associated with ADHD. Long-Term Data Study NRP104-302 was a Phase III, single-arm, longterm, multicenter, open-label study that assessed safety, tolerability, and efficacy of LDX for up to 12 months in 272 children aged 6 to 12 years (mean age, 9.2 years) with DSM-IV-TR criteria for ADHD.64 A total of 55% of patients were 6 to 9 years old and 44% were 10 to 12 years old; 96% had a subtype diagnosis of combined ADHD. The majority of the patients were white (53%), followed by black (26%), Hispanic (17%), Asian (1 %), and other (2%); Native Americans and Native HawaiianJPacific Islanders each made up <1 %. Mean (SD) age at onset of ADHD was 6.9 (2.3) years, with a reported mean (SD) length of disease present of 2.3 (2.5) years. The 272 patients (189 boys, 83 girls) were previously enrolled in a double-blind clinical study and mayor may not have received prior treatment with LDX, except for one newly enrolled subject. After a 1-week washout period, a once-daily dose of LDX 30 mg was initiated, and patients were either maintained on this dose or had their dose titrated to 50 or 70 mg once daily over a 4-week period, based on clinical response and tolerability. Patients were treated for up to an additional 11 months, with dose adjustments permitted at monthly maintenance visits based on optimal efficacy and tolerability; however, most dosage adjustments were made early in the study, suggesting that tolerance to LDX did not occur. Primary efficacy measures included ADHD-RS-IV scores at end point and from baseline over the course of the treatment, while secondary assessment measures included CGI-S and CGI-I scores, which were completed at every visit. Safety was evaluated by assessment of adverse events, vital signs, physical examinations, ECGs performed at baseline and every 3 months, and laboratory evalua162

tions performed at screening, 6 months, and the final visit. The findings from this study included, at end point (last observation), a >60% (P < 0.001, for all comparisons) improvement in ADHD symptoms based on a decrease in ADHD-RS-IV total scores (-27.2 [13.0] points [mean (SD)]) compared with baseline. 64 Mean (SD) ADHD-RS-IV inattentive and hyperactivityimpulsivity subscale scores at end point changed -13.4 (7.0) points (>60%) and -13.8 (7.0) points (66%), respectively (both, P < 0.001) from baseline. Changes from baseline in ADHD-RS-IV scores were observed at each postbaseline visit (P < 0.001); beginning at week 4, the reduction in ADHD-RS-IV scores was noted and continued onward throughout the subsequent 11 months of the study period. More than 80% of patients were rated as "very much improved" or "much improved" by study end point using the CGI-I rating scale, and the percentage of patients rated as improved was consistent at each visit, starting at week 4 and continuing throughout the study.64 In this long-term trial, Findling et a1 64 noted that mean exposure to LDX at any dose was 259 days, with a final dose of 30, 50, and 70 mg in 28%,34%, and 38% of children, respectively. LDX was generally well tolerated, and without adjusting the length of exposure to a daily dose, 42%, 63%, and 67% of patients reported ;::: 1 adverse event while receiving daily doses of LDX 30, 50, and 70 mg, respectively. Treatment-emergent adverse events were reported by 78% of patients, with decreased appetite, weight loss, headache, and insomnia the most frequently reported (Table VI).64 Most treatment-emergent adverse events occurred during the first 2 months of treatment, and after 4 months, the incidence of these adverse events were all generally :C:;5%; only decreased appetite and weight loss occurred in >5% of patients. Of the 272 patients treated with LDX, 125 (46%) discontinued treatment before completing the study, with 25 patients (9%) discontinuing due to adverse events; the most common adverse events were aggression, irritability, and loss of appetite (n = 3 each; 1%). This is the only long-term safety and tolerability trial with LDX published in children with ADHD; however, as with the previous trials, patients with comorbid psychiatric disorders or general medical conditions were excluded from the study.64 Collection of adverse events was obtained from observation and Volume 31 Number 1

J. open-ended inquiry and did not utilize a structured adverse-event assessment, thus leading to the potential for underreporting of adverse events. Additionally, because the majority of the patients had received the study drug in a previous trial and chose to continue in a long-term, open-label study, it is likely that those who had experienced an acute adverse event due to LDX had already discontinued treatment, leading to a lower reported rate of adverse events. Because the majority of the patients were white (53%) and male (69%), more trials are needed to determine the relative benefit of LDX concerning gender and ethnic background, as well as the use of this agent in patients with comorbid medical conditions and psychiatric disorders. Clinical Trials in Adults

The efficacy of once-daily LDX in the treatment of adult ADHD was established on the basis of 1 doubleblind, randomized, placebo-controlled, parallel-group, Phase III clinical trial (NRP104-303) in adults diagnosed with moderate to severe ADHD.65 In a poster presentation, the efficacy and safety profile of LDX were compared with placebo in 420 adults (aged 18-55 years) with a primary diagnosis of ADHD by DSM-IV-TR criteria and as confirmed by the Adult ADHD Clinical Diagnostic Scale version 1.2. Patients were required to have a baseline ADHD-RS score ::::28, including ::::6 of the 9 DSM-IV-TR subtype criteria using adult prompts. Exclusion criteria included nonresponsiveness to stimulant medications, comorbid psychiatric diagnosis with significant symptoms, or concurrent chronic or acute illness that the investigator deemed could interfere with results of tolerability or efficacy. After a washout period (7 days for stimulants, 28 days for atomoxetine), patients were randomized 2:2:2: 1 to LDX 30 mg (n = 119), LDX 50 mg (n = 117), LDX 70 mg (n = 122), or placebo (n = 62). Patients assigned to receive 50- and 70-mg LDX underwent forced-dose titration, receiving LDX 50 mg at week 2, while those randomized to LDX 70 mg were increased to 50 mg at week 2 and to 70 mg at week 3. This 4-week, dose-escalation study used a primary efficacy analysis of change from baseline to end point of the ADHD-RS (revised for adults) total score, using a 2-way analysis of covariance model for the ITT population. 65 Secondary efficacy measures included LDX dose response, as measured by subgroup ADHD-RS January 2009

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at each weekly study VISIt, and CGI-I and CGI-S scores. Percent improved included patients with a CGI-I score of 1 (very much improved) or 2 (much improved), compared with patients with a CGI-I score >3. Safety assessments included adverse events, physical examinations, vital signs, clinical laboratory tests, ECG findings, and the Pittsburgh Sleep Quality Index ([PSQI] with 18 self-reported items). The PSQI includes 7 components (sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleep medications, and daytime functioning), which are rated from 0 (no difficulty) to 3 (severe difficulty).77 A global PSQI score >5 of 21 is indicative of poor sleepers and associated with poor sleep quality. A decrease in PSQI scores indicates improvement in sleep quality, and scores :c:;5 are indicative of good sleepers. Across treatment groups, males accounted for 52% to 56% of the patients and whites for 77% to 89%; the ITT population included 414 patients. 65 The mean (SD) ADHD-RS score at baseline ranged from 39.4 (6.4) to 41.0 (6.0). At end point, the primary efficacy analysis for the ITT population found significant changes in ADHD-RS scores for each LDX dose compared with placebo (for each active dose, P < 0.001).65 The LS mean change from baseline for each LDX dose and placebo was as follows: LDX 30 mg, -16.2 (1.06); LDX 50 mg, -17.4 (1.05); LDX 70 mg, -18.6 (1.03); and placebo, -8.2 (1.43) (all 3 LDX groups, P < 0.001). Significant improvements for each LDX dose were observed within 1 week (LDX 30 mg, -12.2; LDX 50 mg, -11.5; LDX 70 mg, -13.4; placebo, -5.7 [all, P < 0.001]). At end point, recipients of LDX 70 mg reported an apparent reduction in ADHD-RS scores compared with recipients of LDX 30 mg; however, this did not reach statistical significance. At treatment end point, significantly more patients were rated as either "very much improved" or "much improved" on the CGI-I scale for LDX 30, 50, and 70 mg (57%, 65%, and 61 %, respectively; all, P < 0.001) compared with placebo (29%). The difference in proportion of patients improved between all active-treatment groups was significant (P < 0.001) compared with placebo. In this study of adults, adverse events were reported by 79% (282/358) of patients who received active treatment compared with 58% of patients (36/62) who received placebo. 65 Twenty-three treatmentemergent severe adverse events were reported in 15 LDX163

Clinical Therapeutics

treated patients (4%) compared with 3 severe adverse events in 2 patients receiving placebo (3 %). The most common treatment-emergent adverse events reported with an incidence >5% and more than twice that of placebo in any treatment group were decreased appetite, dry mouth, insomnia, nausea, diarrhea, anxiety, anorexia, and feeling jittery (Table VI). The incidence of adverse events was highest in the first week of treatment and subsequently decreased in each subsequent treatment week. Patients who were randomized and met all inclusion! exclusion criteria in the Phase III adult study presented by Adler et al 65 were eligible for participation in a nonrandomized, multicenter, open-label, singlearm study in adults with ADHD to assess the longterm (ie, for up to 1 year) safety and efficacy of 30, 50, and 70 mg of LDX.78 Data from this trial are not yet available. This pivotal ADHD study by Adler et al 65 was the basis on which the FDA approved LDX for adults with ADHD. Although >400 patients were enrolled in this study, the trial only lasted 4 weeks and thus did not provide the ability to extrapolate efficacy and safety findings to the chronic treatment generally required in managing the symptoms of ADHD. This trial was not prospectively designed or powered to detect differences between the subgroups. Additionally, patients with comorbid psychiatric conditions, or on medications that affected the CNS or blood pressure, were excluded; thus, more studies are needed to assess the efficacy and tolerability of LDX in such patients. TOLERABILITY AND SAFETY PROFILE Tolerability data for LDX were obtained from Phase 1,52 Phase 11,51 and Phase III63 trials; 1 long-term study in children 64; a study of adult stimulant abusers 54; 1 adult study 65; and from the manufacturer's prescribing information. 45 The majority of the treatmentemergent adverse events reported with LDX were mild to moderate in intensity, with no reports of serious adverse events or deaths reported during the trials. The first open-label, multiple-dose, Phase I study52 undertaken in 12 healthy adults noted that the most frequently reported treatment-emergent adverse events were consistent with those commonly observed with amphetamines: anorexia (58%), insomnia (50%), tachycardia (42%), and hyperkinesias (33 %). Addi164

tionally, headache, euphoria, abdominal pain, and upper respiratory tract infection were all reported at an incidence of 25 % each. Eleven of the participants (92 %) reported > 1 adverse event during the study period. One participant with a baseline pulse ~2 SDs higher than the mean obtained in this study withdrew due to tachycardia after receiving 1 dose of LDX 70 mg. Ten of the 64 treatment-emergent adverse events (16%) were deemed unrelated to the study drug, while 8 (13 %) were rated as possibly related and 46 (72 %) were rated as probably related to the study medication. Thirty-one of the 64 adverse events (48 %) were mild in severity, 32 (50%) were moderate, and 1 (2% [anorexia]) was severe. The majority of these adverse events (81 %) occurred during the dosing period. No laboratory abnormalities were noted as adverse events by the investigators, and there were no visible trends in ECG abnormalities. 52 Mean increases in systolic blood pressure (SBP) ranged from 7 to 9 mm Hg between 2 and 4 hours postdose; diastolic blood pressure (DBP) had a maximum mean increase of 4 to 8 mm Hg from 1 to 4 hours postdose, compared with predose measurements on the morning of the last day (day 7). During the MAS XR dose-titration period of the Phase II trial, 8 of 52 patients (15%) reported 9 psychiatric events (all mild or moderate in severity), including affect lability, early morning awakening, insomnia, and tearfulness. 51 During the double-blind phase of the study, for patients on LDX, 4 of 50 (8 %) reported a total of 6 psychiatric adverse events that included depression, insomnia, and altered mood. All events were mild or moderate in severity, and no discontinuations resulted from these events. During the crossover phase, there were 2 psychiatric adverse events in patients on placebo (insomnia and mood swings), and 3 psychiatric adverse events in patients on MAS XR (bruxism, insomnia, and tearfulness). Changes in vital signs during the double-blind phase of the study were also recorded. 51 In patients treated with LDX and MAS XR, DBP was higher (~5 and 3 mm Hg, respectively) at 2.5 to 5 hours after morning dosing compared with placebo (both active treatment groups vs placebo, P < 0.05). At 2.5 hours postdose, pulse was higher in both LDX and MAS XR recipients by ~ 7 and 5 beats/min, respectively, as compared with placebo (both active-treatment groups vs placebo, P < 0.05). Analysis of outliers revealed no apparent trends, and the small postdose increases in Volume 31 Number 1

J. DBP and pulse associated with LDX were deemed not clinically meaningful by the investigators. ECG parameters were measured during the doubleblind treatment period. At 2.5 hours postdose, the corrected QT (QTc) interval was greater than that of placebo by ~6 and 5 milliseconds for LDX and MAS XR, respectively (compared with placebo, both P < 0.05).51 Similarly, at 10.5 hours postdose, the QTc interval was greater than that of placebo by ~8 and 5 milliseconds for LDX and MAS XR, respectively (compared with placebo, both P < 0.05). The QRS interval at 10.5 hours postdose was greater with LDX and MAS XR compared with placebo by ~2.4 and 3.1 milliseconds, respectively (both, P < 0.05). No prolonged QT or QT c interval changes, defined as ::::60 milliseconds from baseline, were observed in patients administered LDX. For the QT c interval determined using Fridericia's formula (QT c-F), no change from a baseline value of 30 to 59 milliseconds was noted in any patient in the LDX group at 2.5 and 5 hours postdose, although such changes were noted in 3 patients at 10.5 hours postdose. The corresponding values for MAS XR were 1 patient each at 2.5 hours postdose and 5 hours postdose, and 2 patients at 10.5 hours postdose. For the group receiving placebo, the corresponding numbers were no patients at 2.5 and 5 hours postdose, and 1 patient at 10.5 hours postdose. In the Phase III short-term trial, 21 patients withdrew from the study due to adverse events: 6 (8 %) in the LDX 30-mg group, 4 (5%) in the LDX 50-mg group, 10 (14%) in the LDX 70-mg group, and 1 (1 %) in the placebo group.63 Six of the 218 actively treated patients discontinued LDX due to psychiatric adverse events, which included tics, insomnia, anger, and hyperactivity with logorrhea (excessive/rapid speech). Three (4%) of these psychiatric adverse events occurred with the 30-mg dose, 2 (3%) with the 50-mg dose, and 1 (1 %) with the 70-mg dose. Of the 486 treatmentemergent adverse events reported during treatment with LDX, 130 events in 78 patients were classified as psychiatric disorders; 3 reports of insomnia were rated as severe. The majority (97%) of psychiatric adverse events were considered possibly (34%) or probably (63 %) related to LDX treatment. Treatment with LDX was not associated with statistically significant changes in laboratory values, mean ECG values (including QTc intervals), and SBP or DBP. 63 A significant increase in mean heart rate and January 2009

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ECG heart rate relative to placebo recipients was noted across all LDX doses at end point, with each active-treatment group showing an increase from baseline (P < 0.022). The highest placebo-adjusted mean increase of ~4 to 5 beats/min was noted in the LDX 70-mg group at end point, although no differences were noted at each treatment week. No statistically significant changes in SBP or DBP readings were noted in change from baseline to either end point or to each treatment week. On ECG, the QRS interval indicated a statistically significant difference (P = 0.049) in change from baseline at end point among all active doses relative to placebo, with the greatest placebo-adjusted mean increase of ~2 to 3 milliseconds observed for the 70-mg LDX group.63 No significant changes were noted from baseline to either end point or to each treatment week for PR interval, QT interval, QTc-F interval, and QTc interval corrected using Bazett's formula (QTc-B). Additionally, during any ECG assessment, no patients had a QT, QTc-F, or QTc-B interval >500 milliseconds. In the long-term, open-label, safety and tolerability study of LDX in children, psychiatric adverse events were reported in 13%,23%, and 35% of those who received LDX 30 mg, 50 mg, and 70 mg, respectively.64 Insomnia and irritability, respectively, were the only psychiatric adverse events reported by >5% of patients treated with daily doses of LDX 30 mg (4% and 2%, respectively), 50 mg (9% and 7%), and 70 mg (17% and 5%). Only one serious psychiatric adverse event was reported, an episode of mania, which was deemed not related to the study drug. During the study period, no statistically or clinically significant changes in ECG or blood pressure were noted. 64 The magnitude of mean changes in vital signs from baseline to end point were small and not clinically meaningful, ranging from 0.3 to 3.5 beats/ min for pulse, -1.8 to 1.0 mm Hg for SBP, -1.0 to 0.7 mm Hg for DBP, 1.8 to 5.2 beats/min for ECG heart rate, -4.7 to -1.8 milliseconds for QT interval, -0.4 to 2.2 milliseconds for QTc-F interval, and 1.1 to 6.4 milliseconds for QTc-B interval. Although at end point patient height increased a mean of 1.5 inches (P < 0.05) and patient weight increased a mean of 0.6 pound (P = NS vs baseline), there was a slowing in growth rate measured by body weight compared with age and sex controls. 64 Taking expected growth rate into consideration, the mean changes in z scores for height and weight at end point 165

Clinical Therapeutics

were -0.08 (P < 0.05) and -0.40 (P = NS), respectively, compared with baseline. The age- and sex-normalized mean change in weight was -13.4 pounds (from a baseline of 60.6 to 47.2 pounds) after 12 months. According to data from the adult study with LDX, reasons for discontinuation of LDX and placebo, respectively, included adverse events (6% vs 2 %), protocol violation (4 % vs 3 %), lack of efficacy (1 % vs 6%), physician decision (1 % vs 0), loss to follow-up (2% vs 2%), withdrawal of consent (3% vs 3%), and "other" (1 % vs 0).65 Insomnia was the most common treatment-emergent adverse event that led to treatment discontinuation in 8 patients (LDX 30 mg, 2 patients; LDX 50 mg, 3 patients; LDX 70 mg, 3 patients); none of the patients receiving placebo withdrew due to this adverse event. Seven patients (LDX 30 mg, 1 patient; LDX 50 mg, 2 patients; LDX 70 mg, 4 patients) withdrew from the study due to 11 cardiovascular treatmentemergent adverse events, including palpitations, sinus tachycardia, increased blood pressure, hypertension, and dyspnea; none of the placebo recipients withdrew due to these adverse events. 66 No deaths were reported, and 2 events were reported as serious, although neither was considered related to study medication (metatarsal fracture and postoperative knee pain). LS mean change (95% CIs) in pulse (beats/min) from baseline to end point for patients treated with LDX 30 mg, LDX 50 mg, and LDX 70 mg, respectively, were reported as follows: 2.8 (1.2 to 4.4), 4.2 (2.6 to 5.9), and 5.2 (3.6 to 6.8) (all, P < 0.05) compared with placebo (0 [-2.2 to 2.2]). In the LDX 30-, 50-, and 70-mg groups, there were 31, 43, and 26 pulse outliers, respectively (defined as mean change ::::2 SDs or mean change <2 SDs) at any time point during the study) compared with 4 pulse outliers for placebo. Distributions of pulse outliers indicated that treatment with LDX was associated with an increase in pulse (P < 0.002), although it was not clinically meaningful (3-6 beats/min). No meaningful changes in SBP and DBP were observed at end point (LS mean change, -0.5 to 1.3 mm Hg for SBP and 0.8 to 1.6 mm Hg for DBP).66 For ECG parameters, heart rate (LS mean change from baseline [95% CIs]) was elevated from baseline to end point in the active-treatment groups (LDX 30 mg, 4.3 beats/min [2.6 to 5.9]; LDX 50 mg, 5.3 beats/min [3.6 to 6.9]; LDX 70 mg, 5.3 beats/min [3.7 to 6.9]; all, P < 0.05) compared with placebo (1.1 beats/min 166

[-1.2 to 3.3]).66 No clinically meaningful changes in QRS interval and no ECG readings with QT, QTc-F, or QTc-B intervals >480 milliseconds across all treatment weeks were observed. At end point, the number of patients with a QTc-F interval change between 30 and 59 milliseconds were 2 (3.2%),5 (4.2%), and 1 (0.9%) for LDX 30, 50, and 70 mg, respectively, and 3 (2.5%) for placebo. Statistically significant changes in weight from baseline to end point were noted across treatment groups (-2.8 to -4.3 pounds) compared with placebo (P < 0.001).66 The PSQI was used to assess sleep quality over the I-month period, as sleep problems (eg, insomnia, sleep apnea, nocturnal motor activity) are common in adults with ADHD. 79 Goodman et a1 67 reported that when each dose of LDX (30, 50, and 70 mg) was compared with placebo for baseline, end point, or LS mean change, there was no significant impact on sleep-related quality according to global PSQI scores. The mean baseline PSQI score in these adult ADHD patients was 5.77 for LDX and 6.27 for placebo, indicating an overall poor baseline quality in this study population. At end point, LS mean change from baseline global PSQI scores did not differ significantly between LDX (all doses, -0.8) and placebo (-0.5). In terms of the 7 PSQI components, baseline scores ranged from 0.1 to 1.3 and did not differ significantly between patients who received LDX and patients who received placebo. Components of the PSQI showed no significant differences (or worsening) with LDX compared with placebo (LS mean changes from baseline to end point ranged from -0.2 to 0). The exception was the daytime functioning component (trouble staying awake/loss of enthusiasm), which showed a significant improvement in LS mean change from baseline to end point for LDX (30 mg, -0.3 [0.06]; 50 mg, -0.3 [0.06]; 70 mg, -0.5 [0.06]) compared with placebo (0 [0.08]) (P < 0.005). Sleep aids were used during the trial (zolpidem tartrate [1 patient on LDX 30 mg], melatonin [1 patient taking placebo], diphenhydramine hydrochloride [total of 12 patients: 2 taking placebo, 6 on LDX 30 mg, 3 on LDX 50 mg, and 1 on LDX 70 mg]), and there were no reported meaningful differences between the dosage groupS.67 Using patient-reported time measures, LDX was not associated with worsening in measures of sleep duration (LDX, all doses, LS mean change of -0.2 hour; placebo, LS mean change of -0.1 hour) or sleep onset (LDX, all doses, LS mean Volume 31 Number 1

J. change of 0.4 minute; placebo, LS mean change of -1.2 minutes). However, sleep onset was delayed in the LDX 70-mg group compared with the 30- and 50-mg groups (4.0 minutes, -3.5 minutes, and 0.4 minute, respectively). Sleep-related treatment-emergent adverse events reported with an overall incidence >2% were initial insomnia, insomnia, middle insomnia, somnolence, and sleep disorder (Table VI).67 There was no discernible pattern with increasing doses, and they generally decreased after the first week of treatment. A majority of the insomnia cases were reported as mild (16%) to moderate (12 %) in severity; 8 patients (2 %) reported the insomnia as severe. Eight patients (LDX 30 mg, n = 2; LDX 50 mg, n = 3; LDX 70 mg, n = 3) discontinued LDX due to insomnia, and 1 patient who received LDX 50 mg discontinued treatment because of a sleep disorder. 67

Postmarketing Data A review of 5 poison centers, covering 8 states, for all human cases involving LDX from June 1, 2007, through March 31, 2008, noted 81 cases of LDX ingestion, with adverse reactions reported in 28 patients (35%).80 This rate was significantly greater than rates previously reported to poison centers, which are ~2 % of all exposures, with 3.1 % specifically for amphetamines. During this 10-month period after postmarketing of the stimulant, adverse reactions occurred with initial usage of LDX in 22 of the 28 patients (79%) and within the first 7 days of therapy in 24 patients (86%). The mean and median ages were 11 and 8 years, respectively, and 13 (46%) of the patients had received stimulants as prior therapy in managing their ADHD. Twenty-five of the cases involved single drug exposure (LDX); 3 involved therapeutic polydrug exposure. The majority of the cases (54%) received direct medical care; 3 required hospitalization. In patients experiencing adverse effects to LDX, the most common clinical events reported by patients and by the examining health care provider, respectively, included agitation (43%, 53%), tachycardia (39%, 73%), insomnia (29%,20%), dystonia (29%,47%), vomiting (18%, 13%), chest pain (14%, 13%), hallucination (11 %,20%), new-onset jitters (11 %, 7%), fasciculation (7%, 13 %), fever (7%, 13 %), dizziness (7%,0), abdominal pain (7%, 7%), tremor (7%, 7%), confusion (4%, 7%), seizure (4%, 7%), and blurred vision (4%, 0). Although the latter 2 adverse events January 2009

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were not reported in clinical trials, stimulants may lower the convulsive threshold even in those patients without a history of seizures, and visual disturbances (described as difficulties with accommodation and blurring of vision) have been reported with stimulant treatment. 8l

Abuse Liability Data LDX, including its salts, isomers, and salts of isomers, is classified as a Schedule II Controlled Substance according to the United States Drug Enforcement Administration. 82 It is also the only medication currently approved for the treatment of ADHD that includes abuse liability data in the package insert labeling. Two placebo-controlled oral abuse liability clinical studies 54 ,83 and 1 placebo-controlled IV abuse liability study57 in adult patients meeting DSM-IV-TR criteria for the diagnosis of stimulant abuse were used to evaluate the abuse liability of LDX. Results from these studies support the reduced abuse potential of LDX relative to immediate-release d-amphetamine sulfate. 54 ,57,83 The first oral abuse liability study was a singleblind, placebo- and active-controlled, single-dose, escalation study in 12 healthy adult volunteers with a history of stimulant abuse as defined according to the DSM-IV-TR.54 LDX was administered in single oral doses (30-150 mg), as were placebo and immediaterelease d-amphetamine sulfate 40 mg in all treatment cohorts. All doses were administered as single morning doses, separated by a 48-hour washout period; patients were blinded to treatment sequence. The amphetamine-free base of LDX 100 mg was compared with a molecular weight-basis equivalent amount of d-amphetamine sulfate 40 mg. Abuse liability assessment tools included the visual analog scales of the Drug Rating Questionnaire-Subjects (DRQS) and the Drug Rating Questionnaire-Observer (DRQO), with each measure rated on a scale of 1 ("not at all") to 29 ("an awful lot"). LDX at doses equivalent or higher in d-amphetamine base content apparently caused less euphoria, expressed as dmg liking, and more dysphoria, expressed as dmg disliking, with a later peak effect compared with immediate-release d-amphetamine sulfate 40 mg. 54 The expected subjective euphoric (drug-liking) effects that were distinguishable from placebo were observed in subjects who received d-amphetamine sulfate 40 mg. 167

Clinical Therapeutics

The second oral abuse liability study was a randomized, double-blind, 6-period, crossover study in 36 healthy adult non-ADHD subjects with a DSM-IV-TR diagnosis of stimulant abuse. 83 The study assessed the abuse potential of oral LDX 50, 100, and 150 mg (approximately equivalent to 20-, 40-, and 60-mg d-amphetamine sulfate, respectively) compared with d-amphetamine 40 mg (a Schedule II stimulant), diethylpropion 200 mg (a Schedule IV stimulant), and placebo. The single oral doses were administered after an overnight fast with each dose separated by 48 hours. For the primary measure of subjective response on the DRQS drug-liking effects, the maximum postdose change in score from baseline was significantly greater in subjects who received d-amphetamine 40 mg (2.4 units) versus the equivalent LDX 100 mg (P < 0.04) compared with placebo. 83 The drug-liking response was significantly greater with LDX 150 mg than with LDX 50 or 100 mg (-4.1 and -3.9 units, respectively; both, P < 0.01). Compared with d-amphetamine 40 mg, the maximum drug-liking effect was apparently indistinguishable for both diethylpropion 200 mg and LDX 150 mg but was significantly less for the 50- and 100-mg doses of LDX (P < 0.05), suggesting the abuse potential of oral LDX is dose dependent. Thus, after the 150-mg LDX dose, the maximum drug-liking scores were similar after the d-amphetamine 40-mg dose, even though the amphetamine content in LDX 150 mg was equivalent to ~ 1.5 times the dose of d-amphetamine used in the study. The mean drug-liking scores peaked between 1.5 and 2 hours postdose in subjects who received d-amphetamine 40 mg and diethylpropion 200 mg, and between 3 and 4 hours postdose in subjects who received LDX, irrespective of dose, supporting the rate-limited hydrolysis of LDX to active d-amphetamine. Observer assessments of the subject response were secondary measures as assessed by the DRQO scores, and results from these scores were generally consistent with those observed with the DRQS scores; however, LDX 100 mg significantly differed in maximum drugliking response compared with placebo and did not differ from d-amphetamine 40 mg (LS mean, 2.9, 0.6, and 4.2, respectively).83 On the DRQO score, LDX 150 mg was noted to have the highest maximum drug-liking response and was significantly higher than d-amphetamine 40 mg and diethylpropion 200 mg (LS mean, 6.8, 4.2, and 3.0, respectively). 168

Overall, oral LDX at doses from 30 to 150 mg were well tolerated in these healthy adults with a history of stimulant abuse. 54 ,83 No serious adverse events were observed; of the total number of adverse events reported, 95% were treatment emergent and mild to moderate in intensity. No subjects withdrew from the study due to adverse events. The percentage of patients reporting adverse events for LDX 50 mg, LDX 100 mg, LDX 150 mg, d-amphetamine 40 mg, diethylpropion 200 mg, and placebo were 24%, 30%, 41%,24%,32%, and 17%, respectively. The most frequently reported adverse event was headache, which was observed with LDX 50 mg (11 %), LDX 100 mg (11 %), LDX 150 mg (16%), d-amphetamine 40 mg (8%), and diethylpropion 200 mg (14%). The mean change in SBP and DBP from baseline was less intense for the 50-mg dose (P < 0.01) and 100-mg dose (P = NS) of LDX but slightly more intense for the 150-mg LDX dose (P < 0.05) compared with d-amphetamine 40 mg (Table VII).83 The peak blood pressure response to LDX was delayed by ~ 1 hour compared with d-amphetamine 40 mg and by ~90 minutes compared with diethylpropion 200 mg. No clinically significant abnormalities on ECGs were reported. 83 The abuse liability of IV LDX 25 or 50 mg was compared with a molecular weight-basis equivalent amount of IV d-amphetamine sulfate 10 or 20 mg, respectively, and with placebo, in 12 healthy, nonADHD adult volunteers with a diagnosis of stimulant abuse based on DSM-IV-TR criteria. 57 In this randomized, single-center, double-blind, 3-way crossover study, the drugs were administered intravenously over 1 minute at 48-hour intervals. The 12 subjects were assigned to 2 cohorts: cohort 1 included 3 subjects who received randomized single IV doses of placebo, d-amphetamine sulfate 10 mg, or LDX 25 mg; cohort 2 included 9 subjects who received IV placebo, d-amphetamine sulfate 20 mg, or LDX 50 mg. The primary measure of abuse potential was the drug likability scale of the DRQS, and cohort 2 was the primary cohort for assessing abuse liability. All active doses were compared with placebo, but no comparison was made across active doses. Subjects reported no amphetamine-like subjective or behavioral effects with IV LDX 25 mg. 57 Compared with placebo, d-amphetamine sulfate 20 mg displayed significant drug-liking scores on the DRQS (P = 0.01); LDX 50 mg did not produce significantly Volume 31 Number 1

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Table VII. Mean maximum postdose changes in blood pressure and pulse in adult stimulant abusers. 83

Measure SBP, mm Hg OBP, mm Hg Pulse, beats/min

Placebo

LOX 50 mg

LOX 100 mg

LOX 150 mg

Oiethylpropion 200 mg

d-Amphetamine 40 mg

11 * 7* 1St

17* 11 * 17

30 16 21

41t 19t 22

20* 10* 18

33 16 19

LDX ~ Iisdexamfetamme dlmesylate; SBP ~ systolic blood pressure; DBP *P < 0.01 compared with d-amphetamme 40 mg. tp < 0.05 compared with d-amphetamlne 40 mg.

different drug-liking scores compared with placebo. Peak plasma d-amphetamine levels after IV d-amphetamine sulfate 10 and 20 mg occurred within 0.23 and 0.82 hour, respectively; peak plasma d-amphetamine levels were achieved in 2.48 and 2.51 hours after administration of LDX 20 and 50 mg, respectively, reflecting a slow rise in serum level, as in the previous study of oral LDX.54 In cohort 2, which assessed scores on the Treatment Enjoyment Assessment Questionnaire, participants were asked to choose which drug they would like to take again; 6 participants chose IV d-amphetamine sulfate, 2 chose none of the treatments, and 1 chose LDX. Thus, the majority (89%) of the subjects in cohort 2 reported that they would not choose to take LDX again.

Black Box Warning The prescribing information for LDX contains many of the same precautions and warnings as other stimulants used to treat ADHD, including a black box warning alerting prescribers to the possibility of drug dependence, the abuse liability of amphetamines, and the potential to cause sudden cardiac death or serious cardiovascular adverse events when misused. 45 The warning section also states that sudden death has occurred with stimulant medications at usual doses in children and adolescents with structural cardiac abnormalities or other serious cardiac problems, which may place them at increased vulnerability to the sympathomimetic effects of the stimulants. Use in Pregnancy Amphetamine use during pregnancy may increase the risk of premature birth, low birth weight, and January 2009

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diastolic blood pressure.

neonatal withdrawal associated with dysphoria, agitation, and lassitude. 45 Amphetamines are excreted in human milk and should not be consumed by breastfeeding women. 45 LDX has not been studied in pregnancy in humans and is Pregnancy Category C. A case report describes severe congenital bony deformity, tracheoesophageal fistula, and anal atresia associated with use of d-amphetamine sulfate and lovastatin during the first trimester of pregnancy.45 Amphetamines should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Contraindications LDX is contraindicated in patients with known hypersensitivity or idiosyncrasy to sympathomimetic amines, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, and glaucoma, as well as in patients in an agitated state or who have a history of drug abuse. It is also contraindicated during or within 14 days of monoamine oxidase inhibitor administration. 45 DOSAGE AND ADMINISTRATION The dosage of LDX should be individualized according to the therapeutic needs and response of the patient. The recommended starting dose of LDX in children (aged 6-12 years) or adults with ADHD is 30 mg daily, in the morning, with or without food. All patients start at this dose, regardless if they have received previous ADHD medications. 45 The dose may be increased at weekly intervals by 10 or 20 mg/d, to a maximum daily dose of 70 mg. Amphetamines are not recommended in children aged <3 years, and LDX 169

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has not been evaluated in children <6 years or >12 years of age. Dosing in the afternoon should be avoided because this may increase the risk of insomnia. 45 LDX should be administered whole, or the capsule may be opened and the entire contents dissolved in a glass of water and consumed immediately. The dose of a single capsule should not be divided, and the contents of an entire capsule should be consumed. When possible, it is advised that drug administration should occasionally be interrupted to determine if there is a recurrence of behavioral symptoms sufficient to warrant continued therapy. 76 COST The average wholesale price (AWP) for all doses of LDX (20,30,40,50, 60, and 70 mg) is approximately US $4.57 per capsule (as of July 2008).84 All the dosages are available in bottles of 100 capsules. This translates to a monthly expenditure of approximately US $13 7.00, regardless of the dosage, based on the AWP. To date, there are no published pharmacoeconomic studies evaluating the utility of LDX. DISCUSSION Because ADHD is a chronic condition, more studies of LDX in long-term treatment are necessary, as are comparison studies with other stimulants and nonstimulant agents used in the management of ADHD. The 1 long-term study64 that evaluated the safety profile and efficacy of LDX treatment in school-aged children for up to 12 months may not be sufficient because patients with comorbid psychiatric and/or general medical disorders were excluded from the clinical trial, as in the short-term trials 63 ,76 and the 1 adult study.65 Comorbidities occur frequently in patients with ADHD and include depression, bipolar disorder, dysthymia, and drug dependence. 23 Stimulants may exacerbate symptoms of behavior disturbance and thought disorder in patients with a preexisting psychotic disorder, and in patients with comorbid bipolar disorder, they can induce a mixed/manic episode. Excluding ADHD patients with comorbid psychiatric and medical disorders may not reflect the real-world population of ADHD patients, and may affect the efficacy and tolerability of LDX. Although no significant changes were noted in various cardiovascular parameters, even in the 1 longterm trial published,64 clinicians should exercise good clinical judgment when prescribing stimulants to chil170

dren and adults with ADHD. Stimulants may cause a modest increase in mean blood pressure (~2-4 mm Hg) and mean heart rate (~3-6 beats/min), and while the mean changes alone may not be expected to have short-term consequences, patients must be monitored. Greater caution should be exercised in those whose underlying medical conditions (eg, hypertension, heart failure, arrhythmia) might be compromised by increases in blood pressure or heart rate. As a class, stimulants carry a label warning of serious cardiovascular adverse events and sudden death, which has been reported at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems in association with CNS stimulant treatments. 85 Additionally, sudden death, cerebral vascular accident, and myocardial infarction have been reported in adults taking stimulants at usual doses for ADHD. Because adults have a greater likelihood than children of having serious structural cardiac abnormalities, cardiomyopathy, severe heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems,86 they should generally not be treated with stimulants. Analysis of cardiovascular effects of LDX in the adult study noted small increases in LS mean pulse with LDX in a dose-dependent fashion while no clinically meaningful effects on SBP and DBP or ECG parameters were observed. 66 Regarding ECG parameters, LS mean change from baseline to end point was significantly different for heart rate but not for QRS or QTc-F interval when compared with placebo. 66 As always, a thorough medical and family history and physical examination, including blood pressure and pulse monitoring, to assess the presence of cardiovascular disease should be performed before stimulant use. In August 2008, the AAP issued a new policy recommendation which stated that routine use of ECGs in children receiving medications for ADHD is not warranted. 87 This was after the American Heart Association (AHA) had offered their own recommendation earlier in 2008 that physicians should obtain an ECG to aid them in deciding whether underlying heart disease was present before prescribing ADHD drugs. 85 To clarify this situation, the AAP and the AHA issued a joint advisory statement that an ECG should be performed at the physician's discretion and is not mandatory. 88 Decreased appetite, abdominal pain, and anorexia have been reported with amphetamines and LDX, and Volume 31 Number 1

J. patients receiving stimulants should have their weight monitored regularly. Mean weight loss from baseline after 4 weeks of treatment was reported as -0.9, -1.9, and -2.5 pounds in a controlled trial of LDX in children aged 6 to 12 years who received 30,50, and 70 mg of LDX, respectively, compared with a gain of 1 pound in patients receiving placebo. 45 Consistent with findings regarding other stimulants,8 9,90 there was a slowing in growth rate (measured by body weight) compared with age and sex controls in the long-term trial with LDX involving school-aged children. 64 Thus, as with other stimulants, growth should be monitored during treatment with LDX, and patients who are not growing or gaining weight as expected may need to have their treatment interrupted. Because insomnia is a common adverse event associated with LDX45 and other stimulants,4 9,5 9 clinical assessments of lower and higher doses would be helpful in evaluating the tolerability profile of LDX. In the Phase III trial in children with ADHD, insomnia was reported in 25%, 16%, and 16% of patients treated with LDX 70, 50, and 30 mg, respectively, compared with 3 % in patients who received placebo. 63 Even in the long-term trial with school-aged children, 41 % treated with LDX experienced psychiatric adverse events, with insomnia and irritability being the only psychiatric adverse events reported by >5% of patients. 64 Treatment-emergent psychotic or manic symptoms (eg, hallucinations, delusions, mania) in children and adolescents with no history of psychotic illness or mania can be caused by stimulants at usual doses. The topic has not been closely examined, although anecdotal reports have addressed the relationship between therapeutic doses of stimulants and mania or psychosis. 91 The FDA recently reviewed several trials sponsored by pharmaceutical companies involving amphetamine salts, methylphenidate formulations, modafinil, and atomoxetine. 81 ,92-94 In identifying psychotic-like and manic-like symptoms, it was estimated that toxicosis will occur in ~0.25% of children treated with stimulants (~1 in 400), compared with zero episodes in patients receiving placebo. This proportion suggests an infrequent but not rare effect of therapeutic dosing. Additionally, aggressive behavior or hostility has been reported in the postmarketing surveillance of some medications indicated for the management of ADHD.81 Although no systematic evidence exists that stimulants cause hostile or aggressive behavior, patients January 2009

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initiating treatment for ADHD should be monitored for the appearance-or worsening-of aggressive behavior or hostility. Pharmacokinetic studies with LDX have noted consistent bioavailability across fed and fasted states, and T max for d-amphetamine was similar whether LDX was administered as an intact capsule, without food, or in solution, and was ~ 1 hour longer when taken as a capsule in a fed state. 53 Additionally, LDX has shown low interpatient variability in pharmacokinetic parameters, as measured by coefficients of variation indicating that LDX may provide more consistent d-amphetamine plasma levels from patient to patient. 51 ,52 Because LDX is a prodrug rather than a formulation, no active drug (d-amphetamine) is found in the commercially available capsule formulations. Thus, d-amphetamine does not become available through mechanical manipulation, such as crushing, but rather LDX undergoes a biochemical process in the body to be converted to d-amphetamine, making tampering with LDX difficult and impractical. Also, because the solubility profile of LDX is not affected by the environmental pH within the biological pH range, variation in gastric pH will not affect the absorption of LDX.61 LDX may be less "likable" than immediate-release d-amphetamine sulfate and hence may be less likely to be misused or abused. Additionally, findings from an abuse liability trial noted that IV LDX containing equivalent d-amphetamine base was associated with a lower abuse potential than immediate-release d-amphetamine sulfate.57 Thus, LDX may be advantageous for treating those patients where there are concerns about IV or intranasal abuse, or for children with ADHD who live with parents or family members with substance abuse issues and require pharmacotherapy with efficacy similar to that of stimulants. 95 Unfortunately, the biggest problem with stimulants is not parenteral or intranasal abuse, but rather diversion (ie, the oral ingestion by someone other than the patient for whom the medication was prescribed). Approximately 11 % of US youth with ADHD admit to selling their medications, while another 22 % with comorbid substance use disorder or conduct disorders admit to misusing their medications. 96 Likewise, an undergraduate and graduate student sample of 1025 students at a US university noted that 16% reported abusing or misusing stimulant medications. 97 Others have reported illicit use among US college stu171

Clinical Therapeutics

dents ranging from 8% to 24% 98; improving alertness and concentration were the most popular motives, although one third 98 to one half of the students 97 also reported use in experimentation and "to get high." Illicit use of amphetamine or d-amphetamine was 3 times higher than methylphenidate preparations (76% vs 25%, respectively) among US college students. 98 Thus, the reduced potential for abuse is beneficial for patients at risk for substance abuse or for those who are in an environment with high rates of misuse or diversion, such as high school and university settings. Data from the 5 poison centers noted that in the first 10 months after its immediate release, adverse reactions from LDX were reported at a 10-fold higher rate compared with the previously reported mean rate for amphetamines. 8o Additionally, these reported cases occurred within the first week of therapy in a majority of patients, suggesting a close association with the use of the stimulant. Thus, health care providers should be aware of the potential for the increased risk of adverse events, as this agent is now marketed for children and adults and will thus be used in diverse patients with ADHD, necessitating greater patient selection and education. No data are currently available regarding the use of LDX in patients with hepatic and/or renal impairment; until more research and clinical experience with LDX become available, caution should be used in patients with coexisting medical conditions and those receiving concomitant therapy, especially with psychoactive agents, as this may also affect the pharmacokinetic and pharmacodynamic disposition of the stimulant. CONCLUSIONS LDX is the first amphetamine prodrug stimulant approved by the FDA for the treatment of ADHD in children (aged 6-12 years) and adults. LDX was developed with the goal of providing an extended duration of effect consistent throughout the day, with a reduced potential for abuse, overdose toxicity, and drug tampering or diversion. The extended duration of effect and lower abuse potential compared with d-amphetamine make it another option for the management of ADHD when used at recommended doses. LDX may thus be an integral part of a total treatment program for ADHD that can include other measures such as psychological, educational, and social interventions. 172

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lates of dentin and bone lead levels In adolescents. Arch Environ Health. 1994;49:98-105. 20. Needleman HL. Childhood lead pOisoning. CurrOptn Neural. 1994;7: 187-190. 21. M Ick E, Biederman J, Faraone SV, et al. Case-control study of attentlondeficit hyperactivity disorder and maternal smoking, alcohol use, and drug use dUring pregnancy. J Am Acad Chtld Adolesc Psychiatry. 2002; 41:378-385. 22. Linnet KM, Dalsgaard 5, Obel C, et al. Maternal lifestyle factors In pregnancy risk of attention hyperactivity disorder and associated behaviors: Review ofthe current eVidence. AmJ Psychiatry. 2003; 160: 1028-1 040. 23. Pllszka 5, for the AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment ofchildren and adolescents with attention-deficit/hyperactivity

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Address correspondence to: Jadwiga Najib, PharmD, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Division of Pharmacy Practice, Long Island University, 5th Floor, 75 DeKalb Avenue, Brooklyn, NY 11201. E-mail: [email protected] 176

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