MAS XR Research Articles

P.2.c.009 Epigenetically-induced modulation of the stress axis associated with the progression of bipolar disorder

Lisdexamfetamine dimesylate is a therapeutically inactive prodrug in which d-amphetamine is covalently bound to l-lysine, a naturally occurring amino acid. Pharmacologically active d-amphetamine is released from lisdexamfetamine following oral ingestion.This phase 2, randomized, double-blind, placebo- and active-controlled crossover study compared the efficacy and safety of lisdexamfetamine (LDX: 30, 50, or 70 mg) with placebo, with mixed amphetamine salts extended-release (MAS XR: 10, 20, or 30 mg) included as a reference arm of the study, in 52 children aged 6 to 12 years with attention-deficit/hyperactivity disorder (ADHD) in an analog classroom setting. The primary efficacy measure was the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale; secondary efficacy measures included the Permanent Product Measure of Performance (PERMP) Derived Measures, and the Clinical Global Impression (CGI) Scale.LDX treatment significantly improved scores on SKAMP-deportment, SKAMP-attention, PERMP-attempted, PERMP-correct, and CGI-improvement from baseline. Adverse events were similar for both active treatments.In a laboratory classroom environment, LDX significantly improved ADHD symptoms versus placebo in school-age children with ADHD.

Adderall XR® and Vyvanse™

Adderall XR® (MAS XR) and Vyvanse™ (LDX) are both schedule II amphetamine-based central nervous system stimulants indicated for the treatment of attention-deficit/hyperactivity disorder. Differences among the two primarily involve dosage form, pharmacokinetic profiles, and abuse potential. MAS XR and LDX are both long-acting stimulants with an approximate duration of action of 10 hours. The long-acting property of LDX is secondary to its prodrug formulation, whereas MAS XR utilizes bead filled capsules that mimic twice daily dosing upon administration. MAS XR is a substrate of CYP 2D6 while LDX does not utilize the cytochrome P450 enzymes for metabolism. There are few efficacy studies that directly compare LDX and MAS XR. There are no head to head abuse liability studies for MAS XR and LDX; however, the prodrug formulation of LDX is proposed to have lower abuse potential.

Medication Adherence and Symptom Reduction in Adults Treated with Mixed Amphetamine Salts in a Randomized Crossover Study

Objectives: The study objectives were to 1) evaluate medication adherence for adults with attention-deficit/hyperactivity disorder (ADHD) treated with 3 times daily (TID) mixed amphetamine salts immediate release (MAS IR) versus once-daily (qAM) MAS extended release (MAS XR) in a randomized, crossover study; and 2) to examine the associations between adherence and efficacy for MAS IR and MAS XR. Methods: Sixty-two adults with ADHD were enrolled and 49 completed the study. The treatment condition order (TID-qAM or qAM-TID) was counterbalanced across participants, with an intervening washout period of ≤ 7 days. Adherence was assessed via 3 measures: 1) self-report, 2) pill count, and 3) the Medication Event Monitoring System (MEMS®). The primary efficacy measure was the ADHD Rating Scale (ADHD-RS); secondary measures included the Time-Sensitive ADHD Symptom Scale (TASS) and Clinical Global Impressions-Severity of Illness (CGI-S) scale. Results: Adherence to treatment as measured by self-report and pill count was not significantly different between MAS XR and MAS IR. Adherence was significantly better for MAS XR than MAS IR for all of the MEMS® measures. The mean change in ADHD-RS, TASS, and CGI-S scores at endpoint was significantly improved for both MAS IR and MAS XR and did not differ significantly between groups. There was not a significant adherence by efficacy interaction. Conclusion: Adults with ADHD adhered equally well with MAS IR as with MAS XR when assessed by pill count and self-report, but not by the MEMS® measures. Both treatments significantly reduced ADHD symptoms, and efficacy was not significantly different between groups. Adherence was not associated with treatment outcome.

Physician perception of clinical improvement in children with attention-deficit/hyperactivity disorder: a post hoc comparison of lisdexamfetamine dimesylate and mixed amphetamine salts extended release in a crossover analog classroom study

Objective:To assess effects of lisdexamfetamine dimesylate (LDX) and mixed amphetamine salts extended release (MAS XR) on symptom improvement in children with attention-deficit/hyperactivity disorder (ADHD).Methods:Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover analog-classroom environment was conducted. The primary efficacy outcome was the deportment subscale of the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP-D) rating scale. The secondary efficacy outcome was the investigator-rated Clinical Global Impressions-Improvement (CGI-I), a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), which assesses improvement over time from baseline. McNemar test was used to compare participants’ responses to LDX and MAS XR on CGI-I scores dichotomized into 1 (very much improved) vs all other response scores (2 to 7) in a 2 × 2 table.Results:Fifty-two children (aged 6 to 12 years) were enrolled, titrated, and randomized; 50 completed the study. Investigators rated 74% of LDX participants as either very much improved or much improved on the CGI-I scale relative to 72% of MAS XR participants and 18% of placebo participants. Of the 50 children who completed the study, 32% of LDX participants were very much improved vs 16% of MAS XR, and 2% of placebo participants relative to baseline. McNemar test indicated that 10 participants were very much improved with LDX, but not MAS XR; 2 participants were very much improved with MAS XR, but not LDX; 6 participants were very much improved with both, while 32 were not very much improved with either. Analysis showed that LDX had a significantly higher number of children with a very much improved score on the CGI-I than MAS XR (P = 0.0386).Conclusion:Treatment of children with LDX resulted in a higher number of participants with a very much improved score on the CGI-I than treatment with MAS XR or placebo.

Effects of Omeprazole on the Pharmacokinetic Profiles of Lisdexamfetamine Dimesylate and Extended-Release Mixed Amphetamine Salts in Adults

Objective: To evaluate the pharmacokinetics of lisdexamfetamine dimesylate (LDX), a long-acting prodrug stimulant, and mixed amphetamine salts extended-release (MAS XR), alone or with omeprazole, a proton pump inhibitor (PPI). Methods: This open-label, randomized, 4-period crossover study enrolled healthy adults (18–45 years). Subjects alternately received single doses of LDX 50 mg and MAS XR 20 mg at 4-day intervals. Following washout, subjects received omeprazole (40 mg/day x 14 days), with alternate single doses of LDX 50 mg or MAS XR 20 mg added on days 7 and 11. Blood samples were collected predose and 0 to 96 hours postdose for pharmacokinetic analysis. Safety assessments included adverse events (AEs). Results: Overall, 24 subjects were randomized; 21 completed the study. For LDX monotherapy, d-amphetamine mean (SD) exposure was 45.0 (13.97) ng/mL and 713.0 (134.75) ng · h/mL; when coadministered with omeprazole it was 46.3 (9.71) ng/mL and 761.6 (191.13) ng · h/mL, for Cmax and AUCinf, respectively. The median Tmax was 3 hours with and without omeprazole. For MAS XR monotherapy, total amphetamine mean (SD) exposure was 36.6 (9.19) ng/mL and 640.8 (95.66) ng · h/mL; when coadministered with omeprazole it was 38.1 (7.35) ng/mL and 643.9 (143.16) ng · h/mL, for Cmax and AUCinf, respectively. The median Tmax was 5 hours and 2.75 hours without and with omeprazole, respectively; 57.1% to 61.9% of subjects receiving MAS XR and 25% receiving LDX showed an earlier (≥ 1 hour) Tmax with omeprazole. Both medications had AEs consistent with amphetamine use. Conclusions: Total exposure was unaffected by omeprazole for both compounds. However, ∼50% of subjects receiving MAS XR showed an earlier Tmax while on omeprazole, indicating unpredictable release of active drug by the second bead of MAS XR, most likely related to reduced stomach acid while on a PPI compromising the pulsed delivery of MAS XR. No clear trend was observed for LDX.

Stimulant Dosing for Children With ADHD: A Medical Claims Analysis

Objective To evaluate stimulant dosing patterns in the community treatment of children with attention-deficit/hyperactivity disorder (ADHD). Methods Claims data from U.S. managed care organizations (2000–2004) were analyzed for patients ages 6 to 12 years treated for ADHD with osmotically released oral system (OROS) methylphenidate (MPH; n = 3,815), immediate-release (IR) MPH ( n = 1,960), mixed amphetamine salts extended-release (MAS XR; n = 1,847), or IR MAS ( n = 1,937), and who filled prescriptions covering at least 72 of the first 90 days of treatment. Results The mean initial and maximum dosages were 23.8 and 33.4 mg/day for OROS MPH, 14.8 and 21.8 mg/day for IR MPH, 12.7 and 17.4 mg/day for MAS XR, and 11.2 and 16.5 mg/day for IR MAS. Dose titration occurred in 51.8% (MAS XR) to 61.6% (IR MPH) of patients. Lower initial dose and three or more visits for the treatment of ADHD during the first 90 days of treatment were associated with dose titration. Maximum dose was significantly related to higher initial dose and titration for all four stimulants. For children treated with OROS MPH or IR MAS, treatment by a psychiatrist was significantly related to higher maximum dose. Conclusions Among children with ADHD who continue stimulants through the first 3 months of treatment, dosing in the community treatment of ADHD tends to be lower than doses used in clinical trials. When titration does occur, it is linked to lower initial dosing, clinical monitoring, higher final stimulant doses, and treatment by a psychiatrist.

Simulated Driving Changes in Young Adults With ADHD Receiving Mixed Amphetamine Salts Extended Release and Atomoxetine

Background: Psychostimulant treatment may improve simulated driving performance in young adults with attention-deficit/hyperactivity disorder (ADHD). Method: This was a randomized, double-blind, placebo-controlled, crossover study of simulated driving performance with mixed amphetamine salts—extended release (MAS XR) 50 mg/day (Cohort 1) and atomoxetine 80 mg/day (Cohort 2) in young adults with ADHD. Results: Adults aged 19 to 25 years with AD/HD (N = 19) who were administered MAS XR significantly improved overall simulated driving performance versus placebo up to 12 hours after dosing. In contrast, there were no statistically significant differences in simulated-driving-performance scores between atomoxetine and placebo. At endpoint, MAS XR reduced ADHD Rating Scale scores ≥ 30% in 80% of subjects, whereas atomoxetine achieved this level of improvement for 40%. Limitations: Small sample size and use of simulated driving may limit generalizability of the findings. Conclusion: MAS XR in young adults with ADHD yields significant improvements in simulated driving performance and ADHD symptoms. (J. of Att. Dis. 2009; 12(4) 316-329)

Attention-Deficit/Hyperactivity Disorder in Adults: Evidence-Based Recommendations for Management

Attention-deficit/hyperactivity disorder (ADHD) is associated with impairments in educational, occupational, neuropsychological, and social functioning in adults. Successful diagnosis and treatment of the disorder in adults can be a challenge because recent and integrative clinical guidelines are lacking and diagnostic criteria are based on making a retrospective diagnosis of childhood-onset ADHD. To develop evidence-based recommendations for the treatment of ADHD in adults, the scientific literature was reviewed, including primary clinical studies, meta-analyses, and available clinical guidelines. Studies show that stimulant therapy is highly effective and safe in the management of ADHD in adults, with similar response rates to those reported in children at doses that are equivalent on a mg/kg basis. Long-acting stimulants, such as OROS® methylphenidate (OROS® MPH, Concerta®), dexmethylphenidate (d-MPH, Focalin®), and mixed amphetamine salts extended release (MAS XR, Adderall XR®), have durations of action of up to 10 to 12 hours, which permit once-daily dosing. For adults with ADHD who do not respond to stimulant therapy or who have a comorbid condition in which a stimulant is contraindicated, the nonstimulant atomoxetine (Strattera®) may be an appropriate alternative. For many adults, cognitive-behavioral therapy in addition to pharmacotherapy may improve treatment response. Attention-deficit/hyperactivity disorder medications may increase blood pressure and heart rate in adults, so patients should be monitored.

Special Issues in the Diagnosis and Treatment of ADHD in Adolescents

Attention-deficit/hyperactivity disorder (ADHD) is a common disorder among adolescents but can be a challenge to diagnose in this population for several reasons. Obvious symptoms of hyperactivity and impulsivity are displayed less frequently than in younger children. Direct observation by potential raters is more limited because adolescents spend less time with parents and usually have multiple teachers throughout the day. Also, adolescents often suffer from psychiatric comorbidities, which affect the presentation of ADHD and can confound the diagnosis. Similarly, impaired social skills and academic performance may result from this disorder or for other reasons. These difficulties underscore the importance of a careful and comprehensive assessment that includes parent-, teacher-, and self-reported measures of functioning in several environments, including school, home, and work. Because ADHD is chronic and usually impairing in several domains (eg, social skills, academic performance, family relations, emotional health, driving), adequate treatment is essential. However, there are relatively few treatment studies in adolescents. Stimulant agents are well established as first-line medication treatment for both school-aged children and adults. Existing data support that this is also the case with adolescents. Specifically, both an extended-release formulation of methylphenidate, osmotic-release oral system (OROS® MPH; CONCERTA®) and a mixed amphetamine salts extended-release (MAS XR; Adderall® XR) have demonstrated efficacy and safety in reducing the core symptoms of ADHD in well-designed, multisite, placebo-controlled, double-blind trials. Additional research is needed to further refine diagnostic and assessment tools in the adolescent population.

P.7.a.004 The extent of pupillary fluctuations in the dark correlates with anxiety, depressive and autistic symptoms in ADHD

The ability to recognize and diagnose attention-deficit/hyperactivity disorder (ADHD) has increased in recent years. The persistence of ADHD symptoms puts adolescents with ADHD at risk for long-term adverse psychosocial outcomes.The primary goal of this study was to assess the efficacy and safety of mixed amphetamine salts extended release (MAS XR) in the management of adolescents with ADHD.This was a 4-week, randomized, multicenter, double-blind, placebo-controlled, parallelgroup, forced-dose-titration study. Adolescents aged 13 to 17 years with ADHD were randomized to 1 of 4 active treatments (MAS XR 10, 20, 30 or 40 mg/d) or to placebo. All doses were given in the morning. This study used a forced-dose-titration design in which patients randomized to the 10-mg/d group received 1 dose of 10 mg/d for 4 weeks. Patients randomized to the 20-mg/d group received 1 dose of 10 mg/d for the first week and 1 dose of 20 mg/d for the remaining weeks; patients randomized to the 30-mg/d group received 1 dose of 10 mg/d for the first week, 1 dose of 20 mg/d for the second week, and 1 dose of 30 mg/d for the remaining 2 weeks; and patients randomized to the 40-mg/d group received 1 dose of 10 mg/d for the first week, 1 dose of 20 mg/d for the second week, 1 dose of 30 mg/d for the third week, and 1 dose of 40 mg/d for the fourth week. The primary efficacy measure was change from baseline to end point in the ADHD Rating Scale-IV (ADHD-RS-IV) score. The secondary efficacy measure was the score on the Clinical Global Impressions-Improvement (CGI-I) scale for ADHD. ADHD-RS-IV total scores were analyzed post hoc in patients with low baseline ADHD-RS-IV severity (ie, patients with baseline ADHD-RS-IV total scores less than the median) and high baseline ADHD-RS-IV severity (ie, patients with baseline ADHD-RS-IV total scores greater than the median). Safety was assessed by recording adverse events, vital signs, and body weight at all study visits and 30 days after drug discontinuation.Of the 287 randomized adolescents, 258 completed the study. The intent-to-treat (ITT) population included 278 patients. The majority of patients were male (65.5%) and white (73.7%) The mean weight (57.8 kg [127.1 lb]) at baseline and the mean height (163.8 cm [64.5 in]) at screening were comparable across all MAS XR treatment groups. Patients in the placebo group had a mean weight of 59.8 kg (131.6 lb) and a mean height of 166.1 cm (65.4 in). Most (56.5%) of the patients had ADHD combined inattentive/hyperactive-impulsive subtype. Two hundred nineteen (78.8%) patients were treatment naive, and 59 (21.2%) had received treatment for ADHD within 30 days before screening. ITT analysis of the ADHD-RS-IV revealed statistically significant (P<0.001) improvement in mean ADHD-RS-IV total scores in all 4 MAS XR treatment groups, compared with placebo, at all weeks throughout the 4-week study; the mean change from baseline to end point was −17.8 in the MAS XR 10- to 40-mg/d groups and −9.4 in the placebo group. Significant treatment effects were observed in both the ADHD-RS-IV inattentive (P<0.001) and hyperactive-impulsive (P<0.001) subscales from baseline. In patients with low baseline ADHD-RS-IV severity, statistically significantly (P≤0.01) greater improvements were observed in the MAS XR 20-, 30-, and 40-mg/d groups than in the placebo group; in patients with high baseline ADHD-RS-IV severity, statistically significantly (P≤0.02) greater improvements were observed in all active treatment groups compared with placebo. On the CGI-I scale at end point, a higher percentage of adolescents in all MAS XR treatment groups were considered improved (MAS XR 10 mg/d, 51.9% [P<0.01]; 20 mg/d, 66.0% [P<0.001]; 30 mg/d, 70.7% [P<0.001]; 40 mg/d, 63.9% [P<0.001]) compared with adolescents receiving placebo (26.9%). The most common adverse events in patients receiving MAS XR versus placebo were anorexia/decreased appetite (35.6% vs 1.9%), headache (16.3% vs 22.2%), insomnia (12.0% vs 3.7%), abdominal pain (10.7% vs 1.9%), and weight loss (9.4% vs 0%). Most adverse events were mild or moderate in intensity (97.5%); no serious adverse events were reported.The adolescents with ADHD treated with 10- to 40-mg/d MAS XR up to 4 weeks had significant improvements in ADHD symptoms compared with those who received placebo. Results of this study suggest that once-daily dosing with MAS XR up to 40 mg was effective and well tolerated for the management of ADHD in these adolescents.

Stimulant therapy in the management of ADHD: mixed amphetamine salts (extended release)

The efficacy of amphetamines in the management of attention-deficit/hyperactivity disorder (ADHD) is well established. However, their value in improving the symptoms of ADHD has been compromised by concerns about compliance, abuse potential and adverse events. An extended-release formulation of mixed amphetamine salts (MAS XR) provided the first long-acting amphetamine formulation, and thus, filled an important gap in available treatments for ADHD. MAS XR has been shown to improve ADHD symptoms in children, adolescents and adults in both short- and long-term studies. The drug is generally well tolerated in clinical trials. Although its safety profile in patients with concomitant cardiovascular conditions in a real-world setting has yet to be fully evaluated, a tolerability study of mixed amphetamine salts in adults with ADHD who were being treated for primary essential hypertension showed that these patients can be safely treated with MAS XR.

Lisdexamfetamine Dimesylate and Mixed Amphetamine Salts Extended-Release in Children with ADHD: A Double-Blind, Placebo-Controlled, Crossover Analog Classroom Study

Lisdexamfetamine dimesylate is a therapeutically inactive prodrug in which d-amphetamine is covalently bound to l-lysine, a naturally occurring amino acid. Pharmacologically active d-amphetamine is released from lisdexamfetamine following oral ingestion. This phase 2, randomized, double-blind, placebo- and active-controlled crossover study compared the efficacy and safety of lisdexamfetamine (LDX: 30, 50, or 70 mg) with placebo, with mixed amphetamine salts extended-release (MAS XR: 10, 20, or 30 mg) included as a reference arm of the study, in 52 children aged 6 to 12 years with attention-deficit/hyperactivity disorder (ADHD) in an analog classroom setting. The primary efficacy measure was the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Rating Scale; secondary efficacy measures included the Permanent Product Measure of Performance (PERMP) Derived Measures, and the Clinical Global Impression (CGI) Scale. LDX treatment significantly improved scores on SKAMP-deportment, SKAMP-attention, PERMP-attempted, PERMP-correct, and CGI-improvement from baseline. Adverse events were similar for both active treatments. In a laboratory classroom environment, LDX significantly improved ADHD symptoms versus placebo in school-age children with ADHD.

Cardiovascular Effects of Mixed Amphetamine Salts Extended Release in the Treatment of School-Aged Children with Attention-Deficit/Hyperactivity Disorder

The cardiovascular safety of mixed amphetamine salts extended release (MAS XR) was evaluated in 2968 children 6-12 years of age with attention-deficit/hyperactivity disorder (ADHD). In this prospective, open-label, noncomparative, community-based study, subjects whose symptoms of ADHD were well controlled with stimulant medication maintained their established treatment regimens for 2 weeks before enrollment into the current study. Subjects' regimens were then converted to an approximately equivalent once-daily dose of MAS XR 10, 20, or 30 mg/d according to a medication-conversion algorithm, which could be adjusted to 40 mg/d for optimal efficacy and tolerability. Systolic blood pressure (SBP), diastolic BP (DBP), and pulse were measured at each study visit. Twelve-lead electrocardiography was performed at screening and at the end of the extension phase or early termination. No clinically significant changes in BP or pulse were observed. Although one subject experienced a QT-prolongation interval > 25%, no clinically significant prolongation in the mean QT interval was seen. Approximately 2.5% of subjects demonstrated two consecutive SBP or DBP values > 95th percentile for age, sex, and height, and 3.6% of subjects' pulse increased by > or = 25 to > or = 110 beats per minute. No serious cardiovascular adverse events or deaths occurred. In addition to demonstrated efficacy and safety, the cardiovascular profile of MAS XR showed generally small divergences from age-specific population norms that pose very limited risk in this patient population.

Mixed Amphetamine Salts Extended-Release in the Treatment of Adult ADHD:A Randomized, Controlled Trial

Attention-deficit/hyperactivity disorder (ADHD) is a serious neurobehavioral disorder of childhood onset that often persists into adolescence and adulthood. Functional impairments, underachievement, and difficult interpersonal relationships illustrate the need for effective treatment of ADHD through adulthood. This prospective, multisite, randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study was conducted to assess the efficacy, safety, and duration of action of mixed amphetamine salts extended-release (MAS XR) in adults with ADHD, combined type. Adults > or =18 years of age were given placebo or MAS XR 20, 40, or 60 mg/day for 4 weeks. The main outcome measures were the ADHD Rating Scale and Conners' Adult ADHD Rating Scale Short Version Self-Report (CAARS-S-S). Two hundred fifty-five subjects were randomly assigned to treatment with MAS XR or placebo. MAS XR treatment was associated with statistically and clinically significant ADHD symptom reduction at endpoint; mean ADHD Rating Scale scores were 18.5 for the 20-mg group (P=.001), 18.4 for the 40-mg group (P<.001), and 18.5 for the 60-mg group (P<.001). Adults with severe symptoms (ADHD Rating Scale score >32 at baseline) had significantly greater symptom reduction with the highest MAS XR dose (60 mg/day), however, this dose-response relationship was determined by post-hoc analysis. The mean MAS XR effect size was 0.8. Statistically significant (P<.05) improvements in CAARS-S-S ADHD index scores occurred at 4- and 12-hours postdose for all MAS XR groups, indicating a 12-hour duration of effect. Symptoms improved within the first treatment week. Most adverse events reported were mild or moderate in intensity, and the most commonly reported adverse events were consistent with the known profile of stimulant medications. Vital signs and electrocardiograms showed no clinically significant cardiovascular changes. These results suggest that MAS XR is safe and effective in adults with ADHD and controlled ADHD symptoms for up to 12 hours.

Atomoxetine Versus Stimulants for Treatment of Attention Deficit/Hyperactivity Disorder

To identify, review, and analyze studies comparing atomoxetine with psychostimulants with the intent of determining the role of atomoxetine in the pharmacologic management of attention deficit/hyperactivity disorder (ADHD). Primary, review, and meta-analysis articles were identified by a MEDLINE search (1966-December 2005). MeSH headings used in the search include: attention deficit/hyperactivity disorder, ADHD, atomoxetine, stimulants, psychostimulants, methylphenidate, and amphetamine salts. Relevant data presented at professional meetings that we attended were also identified. All clinical studies comparing atomoxetine with psychostimulants, regardless of study design, were evaluated. Relevant efficacy and safety data from these studies were included in the discussion. At time of writing, 5 head-to-head trials had compared psychostimulants and atomoxetine in the treatment of ADHD. No significant difference between atomoxetine and methylphenidate immediate-release were found on the ADHD Rating Scale total score. Osmotic oral release system (OROS) methylphenidate showed significantly greater improvement at weeks 1 and 2, and significantly more patients treated with OROS methylphenidate were classified as responders. Patients on both atomoxetine and mixed amphetamine salts extended-release (MAS XR) showed significant improvements at endpoint over baseline; however, Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scores were significantly better with MAS XR. Tolerability was similar between atomoxetine and stimulant medications. Based on available evidence, psychostimulants are regarded as first-line pharmacologic treatment for children and adolescents with ADHD, as the efficacy and safety of these agents have been well established based on clinical trials and extensive naturalistic use. Adverse effects in some patients and abuse potential have led to the search for new treatments. Atomoxetine represents an alternative treatment for ADHD and is unlikely to be associated with abuse; however, long-term safety data are needed to further establish its place in therapy.

An Open-Label Study of the Tolerability of Mixed Amphetamine Salts in Adults With Attention-Deficit/Hyperactivity Disorder and Treated Primary Essential Hypertension

To evaluate the short-term tolerability of an extended-release preparation of the stimulant medication mixed amphetamine salts (MAS XR) in adults with attention-deficit/hyperactivity disorder (ADHD) whose hypertension has been successfully treated with antihypertensive medications. An 8-week, 2-phase, open-label study design was implemented. All adults had ADHD (DSM-IV diagnosis) and essential hypertension and were required to be normotensive (blood pressure < 135/85 mm Hg, treated) for at least 4 weeks at entry into the study. MAS XR was given for a 6-week period, titrated once each week to a target maximum dose of 60 mg/day given once daily in the morning (phase 1), and then discontinued for 2 weeks at the end of the study (phase 2). At baseline, subjects underwent a comprehensive clinical assessment, medical history, vital signs assessment, and electrocardiogram (ECG). Rating scales were used throughout the study to assess response to treatment, and blood pressure was measured manually at each study visit. The primary outcome was the effect of MAS XR on blood pressure and the development of hypertension. Thirteen subjects receiving antihypertensive therapy were entered and placed on MAS XR treatment and completed the trial. There were no serious adverse events. No sustained elevated blood pressure (> 140/90 mm Hg at 2 consecutive visits) was observed in the subjects treated with MAS XR. Similar rates of single episodes of hypertension were observed in phases 1 and 2. Similarly, there was no group mean increase in systolic or diastolic blood pressure or pulse during treatment with MAS XR. No clinically significant changes in the ECG were observed. During the 6-week medication phase, significant improvement was found on rating scales assessing ADHD symptoms and severity that reversed with discontinuation of MAS XR. The results of this open study suggest that adults with ADHD and controlled hypertension can be safely treated with MAS XR.

Efficacy and safety of mixed amphetamine salts extended release (adderall XR) in the management of oppositional defiant disorder with or without comorbid attention-deficit/hyperactivity disorder in school-aged children and adolescents: A 4-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled, forced-dose-escalation study

Background: Oppositional defiant disorder (ODD)is associated with a high degree of impairment in social skills, family interaction, and academic functioning. Comorbid ODD is reportedly present in 40% to 70% of children and adolescents with attention-deficit/hyperactivity disorder (ADHD). Objective: The goal of this study was to assess theefficacy and safety of mixed amphetamine salts extended release (MAS XR) for the treatment of ODD in children and adolescents aged 6 to 17 years. Methods: This was a 4-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled, forced-dose-escalation study. Patients were randomized to receive active treatment with MAS XR 10, 20, 30, or 40 mg/d or placebo. The primary efficacy end point was the ODD subscale of the Swanson, Nolan, and Pelham-IV (SNAP-IV) parent rating. Primary safety measures included adverse events recorded at each visit and for 30 days after study drug discontinuation, and changes in vital signs, 12-lead electrocardiographic (ECG) findings, laboratory tests and physical examinations, and body weight. A post hoc efficacy reanalysis was completed based on the results for the per-protocol population. For this analysis, patients were divided into high and low baseline severity categories according to the dichotomized baseline ODD parent or teacher score or dichotomized baseline ADHD parent or teacher score (high defined as scores at the median or greater and low defined as scores less than the median). Results: A total of 308 children and adolescents (age range, 6–17 years; 213 males, 95 females) were randomized to receive active treatment with MAS XR 10 mg/d (n = 60) 20 mg/d (n = 58), 30 mg/d (n = 69), or 40 mg/d (n = 61) or placebo (n = 60). Of the 308 study patients, 244 (79.2%) had comorbid ADHD. A significant change from baseline in the ODD symptoms measured with the SNAP-IV parent rating subscale was found for the MAS XR 30-mg/d (-0.52; P < 0.001) and 40-mg/d (−0.56; P = 0.002) groups in the per-protocol analysis and for the MAS XR 30-mg/d group in the intent-to-treat analysis (−0.42; P < 0.005). Throughout the study, MAS XR was well tolerated in these children and adolescents with ODD, and most adverse events were mild to moderate in intensity. The most frequently reported adverse events occurring in MAS XR-treated patients were anorexia/decreased appetite (25.3%), insomnia (19.5%), headache (18.5%), and abdominal pain (10.7%). Statistically, but not clinically, significant decreases in body weight were seen with MAS XR (range, -1.1 to −3.5 lb; P < 0.001 vs placebo). Changes in laboratory values, ECG measurements, and physical and other vital signs were also not clinically significant. The post hoc reanalysis was based on the per-protocol population (n = 229). An assessment of the high baseline symptom severity subgroups showed a good response to MAS XR treatment for the SNAP-IV parent and teacher rating scales (both, P < 0.05). Conclusion: This study found that higher doses ofMAS XR (30 and 40 mg) were effective and well tolerated in the management of ODD in these schoolaged children and adolescents in the presence or absence of ADHD.

Efficacy and safety of mixed amphetamine salts extended release (adderall XR) in the management of attention-deficit/hyperactivity disorder in adolescent patients: A 4-week, randomized, double-blind, placebo-controlled, parallel-group study

Background: The ability to recognize and diagnose attention-deficit/hyperactivity disorder (ADHD) has increased in recent years. The persistence of ADHD symptoms puts adolescents with ADHD at risk for long-term adverse psychosocial outcomes. Objective: The primary goal of this study was to assess the efficacy and safety of mixed amphetamine salts extended release (MAS XR) in the management of adolescents with ADHD. Methods: This was a 4-week, randomized, multicenter, double-blind, placebo-controlled, parallelgroup, forced-dose-titration study. Adolescents aged 13 to 17 years with ADHD were randomized to 1 of 4 active treatments (MAS XR 10, 20, 30 or 40 mg/d) or to placebo. All doses were given in the morning. This study used a forced-dose-titration design in which patients randomized to the 10-mg/d group received 1 dose of 10 mg/d for 4 weeks. Patients randomized to the 20-mg/d group received 1 dose of 10 mg/d for the first week and 1 dose of 20 mg/d for the remaining weeks; patients randomized to the 30-mg/d group received 1 dose of 10 mg/d for the first week, 1 dose of 20 mg/d for the second week, and 1 dose of 30 mg/d for the remaining 2 weeks; and patients randomized to the 40-mg/d group received 1 dose of 10 mg/d for the first week, 1 dose of 20 mg/d for the second week, 1 dose of 30 mg/d for the third week, and 1 dose of 40 mg/d for the fourth week. The primary efficacy measure was change from baseline to end point in the ADHD Rating Scale-IV (ADHD-RS-IV) score. The secondary efficacy measure was the score on the Clinical Global Impressions-Improvement (CGI-I) scale for ADHD. ADHD-RS-IV total scores were analyzed post hoc in patients with low baseline ADHD-RS-IV severity (ie, patients with baseline ADHD-RS-IV total scores less than the median) and high baseline ADHD-RS-IV severity (ie, patients with baseline ADHD-RS-IV total scores greater than the median). Safety was assessed by recording adverse events, vital signs, and body weight at all study visits and 30 days after drug discontinuation. Results: Of the 287 randomized adolescents, 258 completed the study. The intent-to-treat (ITT) population included 278 patients. The majority of patients were male (65.5%) and white (73.7%) The mean weight (57.8 kg [127.1 lb]) at baseline and the mean height (163.8 cm [64.5 in]) at screening were comparable across all MAS XR treatment groups. Patients in the placebo group had a mean weight of 59.8 kg (131.6 lb) and a mean height of 166.1 cm (65.4 in). Most (56.5%) of the patients had ADHD combined inattentive/hyperactive-impulsive subtype. Two hundred nineteen (78.8%) patients were treatment naive, and 59 (21.2%) had received treatment for ADHD within 30 days before screening. ITT analysis of the ADHD-RS-IV revealed statistically significant ( P<0.001) improvement in mean ADHD-RS-IV total scores in all 4 MAS XR treatment groups, compared with placebo, at all weeks throughout the 4-week study; the mean change from baseline to end point was −17.8 in the MAS XR 10- to 40-mg/d groups and −9.4 in the placebo group. Significant treatment effects were observed in both the ADHD-RS-IV inattentive ( P<0.001) and hyperactive-impulsive ( P<0.001) subscales from baseline. In patients with low baseline ADHD-RS-IV severity, statistically significantly ( P≤0.01) greater improvements were observed in the MAS XR 20-, 30-, and 40-mg/d groups than in the placebo group; in patients with high baseline ADHD-RS-IV severity, statistically significantly ( P≤0.02) greater improvements were observed in all active treatment groups compared with placebo. On the CGI-I scale at end point, a higher percentage of adolescents in all MAS XR treatment groups were considered improved (MAS XR 10 mg/d, 51.9% [ P<0.01]; 20 mg/d, 66.0% [ P<0.001]; 30 mg/d, 70.7% [ P<0.001]; 40 mg/d, 63.9% [ P<0.001]) compared with adolescents receiving placebo (26.9%). The most common adverse events in patients receiving MAS XR versus placebo were anorexia/decreased appetite (35.6% vs 1.9%), headache (16.3% vs 22.2%), insomnia (12.0% vs 3.7%), abdominal pain (10.7% vs 1.9%), and weight loss (9.4% vs 0%). Most adverse events were mild or moderate in intensity (97.5%); no serious adverse events were reported. Conclusions: The adolescents with ADHD treated with 10- to 40-mg/d MAS XR up to 4 weeks had significant improvements in ADHD symptoms compared with those who received placebo. Results of this study suggest that once-daily dosing with MAS XR up to 40 mg was effective and well tolerated for the management of ADHD in these adolescents.

A post hoc subgroup analysis of an 18-day randomized controlled trial comparing the tolerability and efficacy of mixed amphetamine salts extended release and atomoxetine in school-age girls with attention-deficit/hyperactivity disorder

Background: Because the scientific literature on the pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD) is almost entirely based on the results of studies in samples consisting primarily of boys, much is unknown about the treatment response in girls. Objective: This post hoc analysis compared the efficacy, tolerability, and time course of the effect of mixed amphetamine salts extended release (MAS XR) and atomoxetine in school-age girls with ADHD. Methods: This was an intent-to-treat subanalysis of the data from girls enrolled in a multicenter, 18-day, randomized, double-blind, parallel-group, forced dosetitration, laboratory school study enrolling boys and girls aged 6 to 12 years with ADHD. The study compared the efficacy, tolerability, and time course of the effect of increasing doses of MAS XR (10, 20, and 30 mg/d) and atomoxetine (0.5 and 1.2 mg/kg per day). The laboratory school sessions were organized in cycles to include 12 hours of observation. Efficacy measures included the SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham) deportment rating subscale, the SKAMP attention rating subscale, and academic testing (number of math problems attempted and answered correctly). Adverse events were assessed throughout the study period. Tolerability and efficacy measures were assessed during laboratory school visits on days 7, 14, and 21. Results: This subanalysis included 57 girls (median age, 9 years; 49.1% white, 22.8% black, 17.5% Hispanic) with a diagnosis of ADHD, combined subtype. Twenty-six girls were randomized to receive MAS XR and 31 were randomized to receive atomoxetine. Mean SKAMP deportment and attention subscale scores in the 2 groups were similar at baseline. Mean changes from baseline were significantly greater for MAS XR compared with atomoxetine on the SKAMP deportment score (−0.48 vs −0.04, respectively; P<0.001) and SKAMP attention score (−0.45 vs −0.05; P<0.001). The time course of medication effect, based on change from baseline in SKAMP deportment scores, indicated 12-hour efficacy for MAS XR at hours 2, 4.5, 7, 9.5, and 12 (all time points, P<0.01 vs baseline) but not for atomoxetine. At the end of the study, both treatment groups had a significant increase from baseline in the mean number of math problems attempted and answered correctly ( P<0.001). Girls who received MAS XR attempted significantly greater numbers of problems compared with those who received atomoxetine ( P=0.04). Both MAS XR and atomoxetine were well tolerated. The most frequently occurring treatment-related adverse events in girls receiving MAS XR were decreased appetite (40.7%), upper abdominal pain (29.6%), insomnia (25.9%), and headache (14.8%). The most frequently occurring treatment-related adverse events in girls receiving atomoxetine were somnolence (28.1%), upper abdominal pain (15.6%), vomiting (15.6%), nausea (12.5%), and decreased appetite (12.5%). Conclusion: This post hoc analysis in a subpopulation of girls with ADHD, combined subtype, found that 18-day treatment with MAS XR was significantly more effective than atomoxetine in terms of ratings of classroom behavior, attention, and academic productivity.

A community assessment, open-label study of the safety, tolerability, and effectiveness of mixed amphetamine salts extended release in school-age children with ADHD

ABSTRACTObjective: To assess the safety, tolerability, and effectiveness of mixed amphetamine salts extended release (MAS XR) in school-age children with attention-deficit/hyperactivity disorder (ADHD) treated in a community practice setting.Methods: Children aged 6–12 years (N = 2968) with DSM‐IV-defined ADHD entered a 9‐week prospective, open-label, non-comparative study of MAS XR at 386 sites. For at least 2 weeks before enrollment, subjects with well-controlled ADHD received their consistent dose of previously prescribed psychostimulant. Subsequently, this regimen was converted to an equivalent once-daily dose of 10-, 20-, or 30‐mg MAS XR, according to a conversion algorithm. Tolerability and safety were assessed based on reported treatment-emergent adverse events and observed changes in vital signs and body weight. Effectiveness was assessed using a parent-completed Conners’ Global Index Scale (CGIS‐P) measured 8 and 12 h postdose and a clinician-scored Clinical Global Impressions-Improvement (CGI‐I) scale after 1, 3, and 7 weeks of treatment. The dose of study medication could be adjusted at weeks 1 and 3 to a maximum of 40 mg/day. Outcome analyses used an intent-to-treat methodology, with last observations carried forward.Results: Statistically significant improvement in ADHD behavior 8 and 12 h postdose occurred during the first week of treatment and was maintained through study endpoint ( p < 0.0001). Results of the investigator-rated CGI‐I at weeks 1, 3, and 7 were consistent with the parent-rated CGIS‐P results, indicating that MAS XR treatment significantly improved symptoms compared with the baseline stimulant regimen ( p < 0.0001). The incidence of treatment-related adverse events was low, and most AEs were mild in intensity.Conclusion: MAS XR 10–40 mg is a safe and effective once-daily medication for treatment of children with ADHD in a community practice setting. ADHD symptoms may be further reduced by converting from current pharmacotherapy to an optimally titrated dose of MAS XR.