A systematic review of the safety of lisdexamfetamine dimesylate

BACKGROUND: Here we review the safety and tolerability profile of lisdexamfetamine dimesylate (LDX), the first long-acting prodrug stimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD). METHODS: A PubMed search was conducted for English-language articles published up to 16 September 2013 using the following search terms: (lisdexamfetamine OR lisdexamphetamine OR SPD489 OR Vyvanse OR Venvanse OR NRP104 NOT review [publication type]). RESULTS: In short-term, parallel-group, placebo-controlled, phase III trials, treatment-emergent adverse events (TEAEs) in children, adolescents, and adults receiving LDX were typical for those reported for stimulants in general. Decreased appetite was reported by 25-39 % of patients and insomnia by 11-19 %. The most frequently reported TEAEs in long-term studies were similar to those reported in the short-term trials. Most TEAEs were mild or moderate in severity. Literature relating to four specific safety concerns associated with stimulant medications was evaluated in detail in patients receiving LDX. Gains in weight, height, and body mass index were smaller in children and adolescents receiving LDX than in placebo controls or untreated norms. Insomnia was a frequently reported TEAE in patients with ADHD of all ages receiving LDX, although the available data indicated no overall worsening of sleep quality in adults. Post-marketing survey data suggest that the rate of non-medical use of LDX was lower than that for short-acting stimulants and lower than or equivalent to long-acting stimulant formulations. Small mean increases were seen in blood pressure and pulse rate in patients receiving LDX. CONCLUSIONS: The safety and tolerability profile of LDX in individuals with ADHD is similar to that of other stimulants

Growth and Puberty in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

BACKGROUND: Stimulant medications for the treatment of attention-deficit/hyperactivity disorder have a history of safe and effective use; however, concerns exist that they may adversely affect growth trajectories in children and adolescents. OBJECTIVE: The objective of this study was to evaluate the longer-term effects of lisdexamfetamine dimesylate on weight, height, body mass index and pubertal development in children and adolescents with attention-deficit/hyperactivity disorder. METHODS: Children and adolescents aged 6-17 years with attention-deficit/hyperactivity disorder took open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) in this open-label 2-year safety and efficacy study. Safety evaluations included treatment-emergent adverse events, measurement of weight, height and body mass index, and self-reported pubertal status using Tanner staging. RESULTS: The safety analysis population comprised all enrolled participants (N = 314) and 191 (60.8%) completed the study. Weight decrease was reported as a treatment-emergent adverse event in 63 participants (20.1%) and two participants (0.6%) discontinued the study as a result of treatment-emergent adverse events of weight decrease. Growth retardation of moderate intensity was reported as a treatment-emergent adverse event for two participants. From baseline to the last on-treatment assessment, there were increases in mean weight of 2.1 kg (standard deviation 5.83) and height of 6.1 cm (standard deviation 4.90), and a body mass index decrease of 0.5 kg/m2 (standard deviation 1.72). Mean weight, height and body mass index z-scores decreased over the first 36 weeks of the study and then stabilised. Changes from baseline to the last on-treatment assessment in mean z-scores for weight, height and body mass index were significantly less than zero (- 0.51, - 0.24 and - 0.59, respectively; nominal p < 0.0001). The proportion of participants with a z-score of < - 1 ranged from 5.1% (baseline) to 22.1% (week 84) for weight, 8.2% (baseline) to 12.6% (week 96) for height, and 8.3% (baseline) to 28.8% (week 96) for body mass index. Thirteen participants (4.1%) shifted to a weight below the fifth percentile at the last on-treatment assessment from a higher weight category at baseline. At the last on-treatment assessment, most participants remained at their baseline Tanner stage or had shifted higher. CONCLUSIONS: Findings from this comprehensive examination of growth outcomes associated with lisdexamfetamine dimesylate treatment over 2 years were consistent with previous studies of stimulant medications. Whilst mean weight and height increased over the course of the study, there was a small but transient reduction in mean weight, height and body mass index z-scores. A small increase in the proportion of participants in the lowest weight and body mass index categories highlights the importance of the regular monitoring of weight and height. There was no evidence of delayed onset of puberty. CLINICALTRIALS. GOV IDENTIFIER: NCT01328756

Efficacy of lisdexamfetamine dimesylate throughout the day in children and adolescents with attention-deficit/hyperactivity disorder:results from a randomized, controlled trial

Lisdexamfetamine dimesylate (LDX) is a long-acting, prodrug stimulant therapy for patients with attention-deficit/hyperactivity disorder (ADHD). This randomized placebo-controlled trial of an optimized daily dose of LDX (30, 50 or 70 mg) was conducted in children and adolescents (aged 6–17 years) with ADHD. To evaluate the efficacy of LDX throughout the day, symptoms and behaviors of ADHD were evaluated using an abbreviated version of the Conners’ Parent Rating Scale-Revised (CPRS-R) at 1000, 1400 and 1800 hours following early morning dosing (0700 hours). Osmotic-release oral system methylphenidate (OROS-MPH) was included as a reference treatment, but the study was not designed to support a statistical comparison between LDX and OROS-MPH. The full analysis set comprised 317 patients (LDX, n = 104; placebo, n = 106; OROS-MPH, n = 107). At baseline, CPRS-R total scores were similar across treatment groups. At endpoint, differences (active treatment − placebo) in least squares (LS) mean change from baseline CPRS-R total scores were statistically significant (P < 0.001) throughout the day for LDX (effect sizes: 1000 hours, 1.42; 1400 hours, 1.41; 1800 hours, 1.30) and OROS-MPH (effect sizes: 1000 hours, 1.04; 1400 hours, 0.98; 1800 hours, 0.92). Differences in LS mean change from baseline to endpoint were statistically significant (P < 0.001) for both active treatments in all four subscales of the CPRS-R (ADHD index, oppositional, hyperactivity and cognitive). In conclusion, improvements relative to placebo in ADHD-related symptoms and behaviors in children and adolescents receiving a single morning dose of LDX or OROS-MPH were maintained throughout the day and were ongoing at the last measurement in the evening (1800 hours)

An observational study of once-daily modified-release methylphenidate in ADHD: the effect of previous treatment on ADHD symptoms, other externalising symptoms and quality-of-life outcomes

Methylphenidate (MPH) is the most commonly prescribed stimulant for children with ADHD. Data on the effects of different MPH formulations in real-life settings are scarce, and the role of previous therapy on treatment outcome when switching medications has not been well studied. OBSEER was an observational study designed to evaluate the effectiveness and safety of Equasym XL® in routine care. This study assessed whether the improvements reported with Equasym XL® are influenced by the degree of symptom control achieved with the previous medication. Patients enrolled in OBSEER were stratified by prior treatment (none, MPH-immediate release [IR] once daily [o.d.] [MPH-IR o.d.], MPH-IR repeated [MPH-IR >o.d.] and MPH-MR [modified release] excluding Equasym XL®), and changes in ADHD and other externalising symptoms (CGI-S, FBB-ADHD and DAYAS) and quality of life (QoL, KINDL) were evaluated during treatment with Equasym XL®. A total of 782 patients were analysed. Significant group-by-time interactions were found for all symptom variables analysed, indicating that effects varied by previous medication. For CGI-S and FBB-ADHD total scores, the greatest reductions in ADHD symptoms were observed in the treatment-naïve subgroup, followed (in order) by MPH-IR o.d., MPH-IR >o.d. and MPH-MR. A similar profile was seen for DAYAS ratings for all periods of the day except the evening, when there were no significant differences between subgroups. Similarly, the treatment-naïve and MPH-IR o.d. subgroups showed the greatest improvements in KINDL ratings. Although effects were greatest for treatment-naïve patients, improvements were also observed in the prior treatment subgroups for symptoms and QoL. This suggests that a change to Equasym XL® may be beneficial in patients with suboptimal effects on prior medication

Narrative Review: Impairing Emotional Outbursts: What They Are and What We Should Do About Them

Objective: Impairing emotional outbursts, defined by extreme anger or distress in response to relatively ordinary frustrations and disappointments, impact all mental health care systems, emergency departments, schools, and juvenile justice programs. However, the prevalence, outcome, and impact of outbursts are difficult to quantify because they are transdiagnostic and not explicitly defined by current diagnostic nosology. Research variably addresses outbursts under the rubrics of tantrums, anger, irritability, aggression, rage attacks, or emotional and behavioral dysregulation. Consistent methods for identifying and assessing impairing emotional outbursts across development or systems of care are lacking. Method: The American Academy of Child and Adolescent Psychiatry Presidential Task Force (2019-2021) conducted a narrative review addressing impairing emotional outbursts within the limitations of the existing literature and independent of diagnosis. Results: Extrapolating from the existing literature, best estimates suggest that outbursts occur in 4%-10% of community children (preschoolers through adolescents). Impairing emotional outbursts may respond to successful treatment of the primary disorder, especially for some children with attention-deficit/hyperactivity disorder whose medications have been optimized. However, outbursts are generally multi-determined and often represent maladaptive or deficient coping strategies and responses. Conclusion: Evidence-based strategies are necessary to address factors that trigger, reinforce, or excuse the behaviors and to enhance problem-solving skills. Currently available interventions yield only modest effect sizes for treatment effect. More specific definitions and measures are needed to track and quantify outbursts and to design and assess the effectiveness of interventions. Better treatments are clearly needed

An observational study of once-daily modified-release methylphenidate in ADHD: effectiveness on symptoms and impairment, and safety

ADHD affects over 5% of children worldwide. It is typically treated with stimulant medications, and methylphenidate (MPH) is the most commonly prescribed. This study investigated the effectiveness, on symptoms and impairment, and safety of Equasym XL®, a combination of 30% immediate-release and 70% modified-release MPH, in the treatment of ADHD in daily clinical practice. This open-label, observational, post-marketing surveillance study was conducted in 169 centres in Germany. Eligible patients, aged 6–17 years, were diagnosed with ADHD and about to begin treatment with Equasym XL®. Effectiveness was assessed by physicians using the clinical global impression (CGI) severity and improvement scales; teachers and parents completed questionnaires evaluating ADHD symptoms and behavioural problems (DAYAS, FBB-ADHD and SDQ-P). Assessments were carried out at baseline, after 1–3 and 6–12 weeks of treatment. Of 852 enrolled patients, 822 were evaluable; 25.30% were treatment naïve, 69.84% had previously received different MPH formulations, and 4.87% had received other medications. ADHD symptoms improved from baseline to last visit for the majority of patients for all outcome measures. According to physician ratings of core ADHD symptoms, 75.73% of patients showed improvements on the CGI-Improvement scale, 17.77% had no change, and 6.50% worsened. In teacher and parent ratings, the effectiveness of Equasym XL® was rated better than prior therapy at all measured time points across the day, particularly late morning (teachers) and early afternoon (parents). Equasym XL® was generally well tolerated; only 3.16% of patients permanently discontinued treatment due to adverse events. Equasym XL® is effective and well tolerated in daily clinical practice

Cognitive Function of Children and Adolescents with Attention-Deficit/Hyperactivity Disorder in a 2-Year Open-Label Study of Lisdexamfetamine Dimesylate

BACKGROUND: SPD489-404 was the first 2-year safety study of lisdexamfetamine dimesylate in the treatment of attention-deficit/hyperactivity disorder in children and adolescents. In accordance with advice from the European Medicines Agency, assessment of cognitive function was a predefined safety outcome in SPD489-404. OBJECTIVE: The objective of this study was to assess cognitive function over 2 years in study SPD489-404, using the Cambridge Neuropsychological Test Automated Battery (CANTAB). METHODS: Participants aged 6-17 years received dose-optimised open-label lisdexamfetamine dimesylate (30, 50 or 70 mg/day) for 104 weeks. Cognition was assessed using four CANTAB tasks; Delayed Matching to Sample (DMS), Spatial Working Memory (SWM), Stop Signal Task (SST) and Reaction Time (RTI). Key and additional variables were pre-specified for each CANTAB task; groupwise mean percentage changes in key variables from baseline of > 5% were considered potentially clinically significant. RESULTS: All 314 enrolled participants received lisdexamfetamine dimesylate and were included in the safety population, and 191 (60.8%) completed the study. No potentially clinically significant deteriorations from baseline were observed in any key CANTAB variable over the 2 years of the study. Based on predefined thresholds, potentially clinically significant improvements from baseline were observed at 6 months (DMS median reaction time, mean per cent change, - 6.6%; SWM total between-search errors, - 22.8%; SST stop signal reaction time, -18.9%), and at the last on-treatment assessment (DMS median reaction time, - 6.5%; SWM total between-search errors, - 32.6%; SST stop signal reaction time, - 25.7%). CONCLUSIONS: Lisdexamfetamine dimesylate treatment for 2 years was not associated with deterioration of cognitive function in children and adolescents with attention-deficit/hyperactivity disorder. Although improvements in some cognitive measures were observed, lack of a control group makes interpretation of the findings difficult. Further studies of the impact of stimulants on cognition are required

Evaluating movement disorders in pediatric patients receiving risperidone: a comparison of spontaneous reports and research criteria for TD

<p>Abstract</p> <p>Background</p> <p>Movement disorders (MD) in children are relatively common and may be associated with medication use. Objective methods (ie rating scales) and specific research criteria may be helpful in identifying MD-related adverse events that would otherwise not be apparent from spontaneous reports. We assessed whether more stringent and rigorous criteria would provide MD rates similar to those derived subjectively from spontaneous reports.</p> <p>Methods</p> <p>MDs were assessed in children with disruptive behavior disorders (DBDs) and subaverage intelligence receiving risperidone. Data were from three 1-year, open-label studies in subjects 4–14 years old. Dyskinesia severity was rated by the Extrapyramidal Symptom Rating Scale (ESRS) dyskinesia subscale. Tardive dyskinesia (TD) was defined: mild dyskinesia (scores 2, 3) in two anatomical areas; or moderate dyskinesia (score ≥ 4) in one area for ≥ 4 weeks in subjects without dyskinesia at baseline (scores 0, 1).</p> <p>Results</p> <p>The mean (± SD) age of subjects was 9.4 ± 2.4 years, the mean (± SD) risperidone dose was 1.6 ± 0.7 mg/day, and the mean (± SD) exposure was 317.8 ± 104.5 days. ESRS data were available for 668 subjects. Mean ESRS scores were low throughout the study. At baseline, 655 subjects had no dyskinetic symptoms. One subject met predefined TD criteria after a risperidone dose reduction. Symptoms persisted for 4 weeks, resolving with continued treatment and no dosage change. Two different subjects had TD by spontaneous adverse-event reports, with dyskinetic symptoms at 1–2 visits, and symptoms that resolved after treatment discontinuation. Thirteen subjects had dyskinesia at baseline; their mean ESRS dyskinesia scores decreased at endpoint.</p> <p>Conclusion</p> <p>Using objective rating scales and research criteria, low-dose risperidone was associated with low risk of TD and other MDs in children with DBDs in three large 1-year studies. Careful, objective evaluation of emergent MDs during all stages of treatment is essential for identifying treatment-emergent TD.</p