Guanfacine Extended Release Research Articles

An Open-Label Study of Guanfacine Extended Release for Traumatic Stress Related Symptoms in Children and Adolescents

The purpose of this open-label pilot study was to investigate the effectiveness and tolerability of guanfacine extended release (GXR) 1-4 mg given in the evening, on the symptoms of traumatic stress (reexperiencing, avoidance, overarousal), generalized anxiety, and functional impairment in children and adolescents with a history of traumatic stress with or without posttraumatic stress disorder (PTSD). As many of our sample had associated attention-deficit/hyperactivity disorder (ADHD) symptoms, we also assessed whether the presence of traumatic stress symptoms impaired the effectiveness of GXR in the treatment of comorbid ADHD symptoms. Participants were 19 children and adolescents 6-18 years of age, with current traumatic stress symptoms. In an 8 week open-label design, each patient's scores on parent-, child-, and clinician-reported symptom rating scales assessing traumatic stress symptoms, generalized anxiety, ADHD symptoms, functional impairment, and global symptom severity and improvement (n=17) were evaluated off and on GXR using χ(2) goodness-of-fit tests, paired t tests, and repeated measures analyses of variance (ANOVAs). To examine patterns of change in outcome measures across treatment, MPlus software was used to conduct linear growth curves modeled with individual-varying times of observation (i.e., random slopes). Using an average GXR daily dose of 1.19 mg±0.35 mg and an average weight-adjusted daily dose of 0.03 mg/kg±0.01 mg/kg, significant differences were found on all symptom severity measures. Parent reported UCLA Reaction Index scores assessing cluster B (reexperiencing), C (avoidant), and D (overarousal) symptoms significantly improved. In the presence of PTSD symptoms, children with ADHD experienced significantly improved ADHD symptom scores, suggesting that comorbidity does not attenuate an ADHD symptom response to GXR therapy. Medication was generally well tolerated. Within the limits of an open-label, hypothesis-generating pilot study, our results suggest that the α2A-adrenoceptor agonist GXR may have therapeutic effects in the treatment of PTSD symptoms in traumatically stressed children and adolescents. The effective dose may be lower than that found for ADHD. Our pilot study supports the need for further controlled research on the effects of GXR and other α2A-adrenoceptor agonists in pediatric disorders of traumatic stress.

Pharmacokinetics of Coadministered Guanfacine Extended Release and Lisdexamfetamine Dimesylate

BackgroundIn clinical practice, α2-adrenoceptor agonists have been adjunctively administered with psychostimulants for the treatment of attention-deficit/hyperactivity disorder (ADHD). Two studies have examined the adjunctive use of guanfacine extended release (GXR, Intuniv®; Shire Development LLC, Wayne, PA, USA) with psychostimulants in children and adolescents with a suboptimal response to psychostimulant treatment. However, the potential for pharmacokinetic drug–drug interactions (DDIs) between GXR and lisdexamfetamine dimesylate (LDX, Vyvanse®; Shire US LLC, Wayne, PA, USA) has not been thoroughly evaluated.ObjectiveThe primary objective of this study was to examine the pharmacokinetics of GXR 4 mg and LDX 50 mg given as single doses alone and in combination.Study DesignThis was an open-label, randomized, three-period crossover, DDI study.SettingThe study was conducted in a single clinical research center.ParticipantsForty-two healthy adults were randomized in this study.InterventionsSubjects were administered single oral doses of GXR 4 mg, LDX 50 mg, or GXR and LDX in combination.Main Outcome MeasuresBlood samples collected predose and up to 72 h postdose assessed guanfacine, LDX, and d-amphetamine levels. Bioequivalence was defined as the 90 % confidence intervals (CIs) of the geometric mean ratios of the area under the plasma concentration–time curve extrapolated to infinity (AUC0–∞) and maximum plasma concentration (C max) falling within the bioequivalence reference interval (0.80–1.25). Safety measures included adverse events, vital signs, and electrocardiograms (ECGs).ResultsForty subjects completed the study. Following administration of LDX alone or in combination with GXR, the statistical comparisons of the AUC0–∞ and C max of d-amphetamine fell entirely within the reference interval. For guanfacine, the 90 % CI of the geometric mean ratio of AUC∞ for the two treatments was within the bioequivalence criteria, but for C max the upper bound of the 90 % CI exceeded the standard range for bioequivalence by 7 %. This relatively small change is unlikely to be clinically meaningful. Treatment-emergent adverse events (TEAEs) were reported by 42.9 % of subjects; the most commonly reported TEAEs included dizziness (5.0, 7.3, and 7.3 %) and headache (7.5, 4.9, and 7.3 %) following administration of GXR, LDX, and GXR and LDX in combination, respectively. Clinically significant ECG abnormalities occurred in one subject following administration of LDX and in one subject following coadministration of GXR and LDX.ConclusionsIn healthy adults, coadministration of GXR and LDX did not result in a clinically meaningful pharmacokinetic DDI compared with either treatment alone. No unique TEAEs were observed with coadministration of GXR and LDX compared with either treatment alone.

Cost Effectiveness of Guanfacine Extended-Release Versus Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder: Application of a Matching-Adjusted Indirect Comparison

Published online: 29 March 2013© Springer International Publishing Switzerland 2013In the November 1, 2012 issue of the Applied Health Economics and Health Policy journal, Erder et al. [1] discussed the cost effectiveness of guanfacine extended- release (GXR) versus atomoxetine (ATX) for the treatment of attention-deficit/hyperactivity disorder using a match- ing-adjusted indirect comparison. We would like to alert you that, after careful review of this article, we noticed a couple of data inaccuracies in the reporting of publicly available ATX data that met the inclusion criteria for trial selection for the indirect comparison.The data that appear to have been reported inaccurately in the Erder et al. [1] article are listed under the ATX column in Table III-'Baseline characteristics before and after matching' (p. 390). Specifically, the mean baseline values for ADHD-RS inattention subscale (16.9) and ADHD-RS hyperactivity/impulsivity subscale (22.2) appear to have been erroneously transposed from the cor- rect original values in the publicly available ATX data. The ATX data were originally presented under the 1.2 mg/kg/ day column in Table 2-'Baseline Symptom Severity' in the article by Michelson et al. [2]. Specifically, the mean baseline value for ADHD-RS inattentive subscale was listed as 22.2 while the mean baseline value for the ADHD- RS hyperactive/impulsive subscale was listed as 16.9. Thus, these correct values appear to have been switched in the article by Erder et al. [1].Importantly, these data inaccuracies may have led to erroneous post-match GXR subpopulations which likely produced results and conclusions that, at a minimum, would be unreliable. Accordingly, we respectfully would like to ask the journal and authors to comment on these inaccuracies and their effects on the research results and conclusions. Should these inaccuracies be confirmed by the journal or authors, we would kindly ask that a revised analysis be conducted and/or that a correction/erratum be published in accordance with ICMJE requirements.

Erratum to: Cost Effectiveness of Guanfacine Extended-Release versus Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder

Background: About 7% of children and adolescents are diagnosed with attention-deficit/hyperactivity disorder (ADHD) in the US. Patients with ADHD who are intolerant of or do not have an optimal response to stimulants often use non-stimulants as alternative therapies. Guanfacine extendedrelease (GXR) and atomoxetine (ATX) are the only non-stimulants approved by the US Food and Drug Administration for once-daily use in the treatment of children and adolescents with ADHD in the US. ATX has been on the market since 2002 while GXR was recently approved in 2009. To date, there is no comparative effectiveness or cost-effectiveness study comparing the two drugs. Objectives: The aim of this study was to assess the cost effectiveness of GXR versus ATX for the treatment of ADHD in children and adolescents, using the comparative efficacy results from a matching-adjusted indirect comparison (MAIC). Methods: The MAIC method was used to compare the efficacy between GXR (target dose and lower doses) and ATX (target dose) in the absence of head-to-head clinical trials. Individual patients in the GXR trials were weighted such that the summary baseline characteristics and the efficacy of the placebo arm of the GXR trials matched exactly with those from published ATX trials. After weighting, the efficacy (i.e. change in the ADHD rating scale, fourth edition [ADHD-RS-IV] total score from baseline) was compared between each GXR dosing group and the ATX group. The results from the MAIC analyses were used to populate a 1-year Markov model that is used to compare the cost effectiveness of GXR versus ATX from a US third-party payer perspective. Effectiveness outcomes for each treatment group were estimated as the proportion of responders, defined as patients with ≥25% reduction in ADHD-RS-IV total score from baseline, and average quality-adjusted life years (QALYs). Utilities associated with response/non-response and disutilities due to adverse events were applied in the model. Costs included drug and medical service costs and were inflated to 2011 US dollars ($US). Incremental cost/QALY and incremental cost/responder were estimated. Univariate sensitivity analyses were conducted by varying all model parameters, including costs, utilities, and response rate. Results: The target dose of GXR was 0.12mg/kg/day. In match-adjusted populations with balanced baseline characteristics, patients receiving GXR at the dose of 0.09–0.12 (p = 0.0009) and 0.075–0.09 mg/kg/day (p = 0.0248) had better efficacy, while those receiving GXR at the dose of 0.046–0.075 mg/kg/day had comparable efficacy (p = 0.0699), compared with patients receiving ATX at the target dose of 1.2 mg/kg/day. In the base case of the cost-effectiveness analysis (CEA), GXR had incremental cost-effectiveness ratios of $US10 637/QALY and $US853/responder, compared with ATX (incremental costs: $US74; incremental effectiveness: 0.007 QALYs and 86 responders per 1000 patients treated). Results of all univariate sensitivity analyses showed that the model results were robust to changes in model inputs. Conclusions: To our knowledge, this is the first application of the novel comparative efficacy method of MAIC to a CEA model. The MAIC results indicate that GXR (0.075–0.12 mg/kg/day) was more effective than ATX (1.2 mg/kg/day) in the trial population. The CEA results indicate that GXR is cost effective compared with ATX for the treatment of ADHD in children and adolescents.

Pharmacokinetics of Coadministration of Guanfacine Extended Release and Methylphenidate Extended Release

Backgroundα2-Adrenoceptor agonists are used adjunctively to psychostimulants in treating attention-deficit/hyperactivity disorder (ADHD) when psychostimulants alone do not sufficiently reduce symptoms. However, data on the pharmacokinetic profiles and safety of combination treatments in ADHD are needed.ObjectiveThe primary objective of this study was to evaluate the pharmacokinetic profiles of guanfacine extended release (GXR) and methylphenidate hydrochloride (MPH) extended release, alone and in combination.Study DesignThis was an open-label, randomized, three-period crossover, drug–drug interaction study.SettingThe study was conducted at a single clinical research center.ParticipantsThirty-eight healthy adults were randomized in this study.InterventionsSubjects were administered single oral doses of GXR (Intuniv®; Shire Development LLC, Wayne, PA, USA) 4 mg, MPH (Concerta®; McNeil Pediatrics, Titusville, NJ, USA) 36 mg, or GXR and MPH combined.Main Outcome MeasuresGuanfacine, dexmethylphenidate (d-MPH), and l-methylphenidate (l-MPH) levels were measured with blood samples collected predose and up to 72 h postdose. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms (ECGs).ResultsThirty-five subjects completed the study. Analyses of the 90 % confidence intervals (CIs) for the geometric mean ratios of the maximum plasma concentration (Cmax) and area under the concentration–time curve extrapolated to infinity (AUC∞) values for guanfacine and d-MPH following administration of GXR or MPH alone or combined met strict bioequivalence criteria (90 % CIs within the interval of 0.80–1.25). Overall, combining GXR and MPH did not alter the pharmacokinetic parameters of either medication. Sixteen subjects (42.1 %) had at least one TEAE. The most commonly reported TEAEs included headache and dizziness following GXR, MPH, and GXR and MPH combined. Two subjects had clinically significant abnormalities in ECG results following coadministration: both events were mild and resolved the same day.ConclusionsIn this short-term, open-label study of healthy adults, coadministration of GXR and MPH did not result in significant pharmacokinetic drug–drug interactions. No unique TEAEs were observed with coadministration of GXR and MPH compared with either treatment alone.

A Controlled Trial of Extended-Release Guanfacine and Psychostimulants for Attention-Deficit/Hyperactivity Disorder

A Controlled Trial of Extended-Release Guanfacine and Psychostimulants for Attention-Deficit/Hyperactivity Disorder

Risk of Serious Cardiovascular Problems with Medications for Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder characterized by persistent symptoms of inattention, hyperactivity and/or impulsivity. The proportion of patients diagnosed with ADHD receiving pharmacological treatments has increased enormously in recent years. Despite the well established efficacy and the good safety and tolerability profile, there is concern about the potential for rare but serious cardiovascular adverse events, as well as sudden cardiac death, with pharmacotherapies used for treating ADHD in children, adolescents and adults. The present paper aims to comprehensively and critically review the published evidence on the controversial association between medications approved for treating patients with ADHD and the risk of serious cardiovascular problems, specifically the risk of corrected QT interval (QTc) prolongation, and the risk of sudden cardiac death. A comprehensive search of relevant databases (PubMed, EMBASE and PsychINFO) was conducted to identify studies published in peer-reviewed journals until 21 July 2012. Clinical reports, as well as retrospective or prospective population-based studies with children, adolescents or adults as participants, of pharmacotherapies for ADHD reporting cardiovascular adverse events were included. Stimulant medications for ADHD, including methylphenidate and amphetamine derivatives, are generally safe and well tolerated. Small but statistically significant increases in blood pressure (BP) and heart rate (HR) are among the adverse events of stimulant treatment in all age groups. Similarly, the non-stimulant medication atomoxetine has also been associated with increased HR and BP, although as is the case with stimulants, these are generally minor, time limited and of minor clinical significance in children, adolescents or adults. Growing evidence suggests that these medications do not cause sudden and unexpected cardiac death or serious cardiovascular problems including statistically or clinically significant increases in QTc, at therapeutic doses in ADHD patients across the lifespan. Small decreases in mean systolic BP, diastolic BP and HR have been observed in studies with guanfacine-extended release (-XR) or clonidine-XR, two α(2)-adrenergic receptor agonists, administered alone or in combination with psychostimulants to children and adolescents with ADHD. There are also no statistically or clinically significant increases in QTc associated with clonidine or guanfacine. There are no reports of torsades de pointes clearly and directly related to medications used for treating ADHD in patients of all age groups. The risk for serious cardiovascular adverse events, including statistically or clinically significant increases in QTc, and sudden cardiac death associated with stimulants, atomoxetine or α(2)-adrenergic agonists prescribed for ADHD is extremely low and the benefits of treating individual patients with ADHD, after an adequate assessment, outweigh the risks. However, great caution is advised when considering stimulant and non-stimulant medications for patients of any age with a diagnosis of ADHD and a personal or family history or other known risk factors for cardiovascular disease.

Cost Effectiveness of Guanfacine Extended-Release versus Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder

About 7% of children and adolescents are diagnosed with attention-deficit/hyperactivity disorder (ADHD) in the US. Patients with ADHD who are intolerant of or do not have an optimal response to stimulants often use non-stimulants as alternative therapies. Guanfacine extended-release (GXR) and atomoxetine (ATX) are the only non-stimulants approved by the US Food and Drug Administration for once-daily use in the treatment of children and adolescents with ADHD in the US. ATX has been on the market since 2002 while GXR was recently approved in 2009. To date, there is no comparative effectiveness or cost-effectiveness study comparing the two drugs. The aim of this study was to assess the cost effectiveness of GXR versus ATX for the treatment of ADHD in children and adolescents, using the comparative efficacy results from a matching-adjusted indirect comparison (MAIC). The MAIC method was used to compare the efficacy between GXR (target dose and lower doses) and ATX (target dose) in the absence of head-to-head clinical trials. Individual patients in the GXR trials were weighted such that the summary baseline characteristics and the efficacy of the placebo arm of the GXR trials matched exactly with those from published ATX trials. After weighting, the efficacy (i.e. change in the ADHD rating scale, fourth edition [ADHD-RS-IV] total score from baseline) was compared between each GXR dosing group and the ATX group. The results from the MAIC analyses were used to populate a 1-year Markov model that is used to compare the cost effectiveness of GXR versus ATX from a US third-party payer perspective. Effectiveness outcomes for each treatment group were estimated as the proportion of responders, defined as patients with ≥25% reduction in ADHD-RS-IV total score from baseline, and average quality-adjusted life years (QALYs). Utilities associated with response/non-response and disutilities due to adverse events were applied in the model. Costs included drug and medical service costs and were inflated to 2011 US dollars ($US). Incremental cost/QALY and incremental cost/responder were estimated. Univariate sensitivity analyses were conducted by varying all model parameters, including costs, utilities, and response rate. The target dose of GXR was 0.12 mg/kg/day. In match-adjusted populations with balanced baseline characteristics, patients receiving GXR at the dose of 0.09-0.12(p = 0.0016) [DOSAGE ERROR CORRECTED] and 0.075-0.09 mg/kg/day (p = 0.0248) had better efficacy, while those receiving GXR at the dose of 0.046-0.075 mg/kg/day had comparable efficacy (p = 0.0699), compared with patients receiving ATX at the target dose of 1.2 mg/kg/day. In the base case of the cost-effectiveness analysis (CEA), GXR had incremental cost-effectiveness ratios of $US10 637/QALY and $US853/responder, compared with ATX (incremental costs: $US74; incremental effectiveness: 0.007 QALYs and 86 responders per 1000 patients treated). Results of all univariate sensitivity analyses showed that the model results were robust to changes in model inputs. To our knowledge, this is the first application of the novel comparative efficacy method of MAIC to a CEA model. The MAIC results indicate that GXR (0.075-0.12 mg/kg/day) was more effective than ATX (1.2 mg/kg/day) in the trial population. The CEA results indicate that GXR is cost effective compared with ATX for the treatment of ADHD in children and adolescents.

Cost Effectiveness of Guanfacine Extended-Release versus Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder

Cost Effectiveness of Guanfacine Extended-Release versus Atomoxetine for the Treatment of Attention-Deficit/Hyperactivity Disorder

Guanfacine ER for the treatment of adolescent attention-deficit/hyperactivity disorder

Introduction: Guanfacine extended release (GXR) is an alpha 1A noradrenergic agonist that has been approved by the FDA for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) as a monotherapy, and as an adjunctive therapy to stimulants for the treatment of ADHD in children and adolescents age 6 – 17.Areas covered: PubMed, the Ovid Medline database, and the PsycInfo database were searched using the term ‘guanfacine'. Results were then limited to criteria such as English and human, from 1990 through December 2011. The resulting yield from the comprehensive literature search was 4391 articles. The titles and abstracts of all articles were reviewed. Studies were selected for full-text review based upon their place in the hierarchy of evidence (e.g., randomized controlled trials), relevance and quality of individual studies, and generalizability to clinical practice. The search was augmented by further search of article reference lists. A total of 15 articles were selected for full-text examination.Expert opinion: Due to the absence of positive evidence for the efficacy of GXR for monotherapy in adolescents, clinicians should be guarded in the use of GXR for monotherapy in adolescents with ADHD. The use of GXR has considerable promise as an adjunct to stimulants for other behavioral conditions associated with ADHD.

Cost Effectiveness of Guanfacine Extended Release as an Adjunctive Therapy to a Stimulant Compared with Stimulant Monotherapy for the Treatment of Attention-Deficit Hyperactivity Disorder in Children and Adolescents

BackgroundAttention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder in childhood, affecting 3–7% of school-age children in the US and imposing substantial economic burden. Stimulants are considered first-line pharmacological treatment and are the most prescribed treatment for ADHD. However, approximately 30% of children with ADHD do not have an optimal response to a single stimulant and may require adjunctive therapy.ObjectiveOur objective was to conduct a cost-effectiveness analysis (CEA) of adding a non-stimulant, guanfacine extended release (GXR), to stimulants versus maintaining existing stimulant monotherapy in the treatment of ADHD in children and adolescents with suboptimal response to stimulant monotherapy.MethodsA 1-year Markov model was developed to estimate costs and effectiveness from a US third-party payer perspective. Effectiveness was measured by the QALY. The model assumed that patients transitioned among four health states (normal, mild, moderate and severe), defined by the Clinical Global Impression-Severity (CGI-S) scale. Transition probabilities were estimated in an ordered logit model using patient-level data from a multicentre, 9-week, double-blind, placebo-controlled, dose-optimization study, where subjects (n=461) continued their stable morning stimulant and were randomized to GXR administered in the morning, GXR administered in the evening, or placebo. The model assumed that patients in moderate/severe health states after week 8 would discontinue ADHD treatment and remain in that state for the rest of the study period. Direct costs included drug wholesale acquisition costs and health state costs, all in $US, year 2010 values. Utility associated with each health state was obtained from the literature and disutilities associated with adverse events were applied for the first 4 weeks. Oneway sensitivity analyses and probabilistic sensitivity analysis (PSA) were conducted by varying costs, utilities, adverse-event duration, and transition probabilities.ResultsCompared with maintaining existing stimulant monotherapy, adding GXR to existing stimulant monotherapy was associated with an incremental drug cost of $US1016 but a lower medical cost of $US124, resulting in a total incremental cost of $US892 at 1 year. The addition of GXR to stimulants led to an incremental QALY of 0.03 and an incremental cost-effectiveness ratio (ICER) of $US31 660/QALY. In one-way sensitivity analysis, ICER values ranged from $US19 723, when 100% of patients were assumed to be severe in their initial health state, to $US46631, when the last observed states from the clinical trial were carried forward to the end of the 1-year analysis period. PSA demonstrated a 94.6% likelihood that the ICER falls below $US50 000/QALY.ConclusionsThe impairment associated with residual ADHD symptoms after stimulant therapy is becoming increasingly recognized. This is the first analysis of the cost effectiveness of stimulants combined with an adjunctive medication. This study suggests that the adjunctive therapy of GXR with stimulants is a cost-effective treatment based on a willingness-to-pay threshold of $US50 000/QALY. This may address an unmet need among patients with suboptimal response to stimulant monotherapy.

Cost Effectiveness of Pharmacotherapies for Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD) is a common psychiatric disorder that impairs the quality of life for patients and their families and is associated with considerable direct and indirect costs. Pharmacotherapies for ADHD, including stimulants and non-stimulants, are often used to treat patients with ADHD. However, the costs, effectiveness and adverse effects of these agents vary. Therefore, information regarding the cost effectiveness of different pharmacological treatments is needed to better inform payers in the allocation of limited resources. The objectives of this study were to conduct a systematic literature review of economic evaluations of pharmacotherapies for ADHD treatments and to assess the cost effectiveness of different interventions based on the existing studies. A systematic literature review of economic evaluations of pharmacotherapies for ADHD was conducted in MEDLINE, the National Health Services (NHS) Economic Evaluation database and EMBASE. For inclusion in this review, studies had to compare two or more ADHD interventions with at least one pharmacotherapy, assess both costs and outcomes, and be conducted between 1990 and 2011 in North America, Europe, Australia or New Zealand. Studies were excluded if they were not original research, were presented only as conference proceedings or abstracts or did not report costs associated with specific interventions. The study quality was assessed using the British Medical Journal (BMJ) health economics checklist. The literature search, data extraction and quality assessment were performed by one author and independently checked for accuracy by a second author. Discrepancies were resolved by consensus and referring to the original article. If necessary, a third reviewer was consulted. The initial search returned 93 citations from MEDLINE, 10 from the NHS Economic Evaluation database and 377 from EMBASE. Thirteen papers met the inclusion/exclusion criteria and were included in the review. Based on the BMJ checklist, all these studies were considered to be of sufficient quality to be included in the literature review, but they varied substantially in target population, methodology and effectiveness measures. Identified pharmacotherapies were cost effective compared with no treatment, placebo, behavioural therapy or community care among children and adolescents with ADHD. Studies comparing non-stimulants with stimulants and amfetamine with methylphenidate stimulants showed inconsistent findings. A limited number of studies indicated that methylphenidate Osmotic-controlled Release Oral delivery System (OROS) was cost effective compared with short-acting methylphenidate. There were no published studies on the cost effectiveness of pharmacotherapy in the adult ADHD population, comparing stimulants, non-stimulants or adjuvant therapy. There is limited evidence on the long-term cost effectiveness of pharmacotherapies. Among children and adolescents with ADHD, there was consistent evidence that pharmacotherapies are cost effective compared with no treatment or behavioural therapy. Adequate data are lacking to draw conclusions regarding the relative cost effectiveness of different pharmacological agents. More economic evaluations with standardized methods, such as effectiveness measures and cost components, are warranted. To better inform payers about the economic value of existing medications, future studies should also consider identifying subgroups that may have heterogeneous responses to different treatments, including analyses of recently approved treatments (e.g. lisdexamfetamine, guanfacine extended-release and clonidine extended-release) and expanding the time horizon to incorporate long-term outcomes.

PMH43 Treatment Patterns, Resource Utilization and Costs Associated with Guanfacine Immediate Release Versus Guanfacine Extended Release among Children and Adolescents with Attention Deficit/Hyperactivity Disorder (ADHD)

PMH43 Treatment Patterns, Resource Utilization and Costs Associated with Guanfacine Immediate Release Versus Guanfacine Extended Release among Children and Adolescents with Attention Deficit/Hyperactivity Disorder (ADHD)

Efficacy of guanfacine extended release in the treatment of combined and inattentive only subtypes of attention-deficit/hyperactivity disorder.

Extended-release guanfacine (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents aged 6-17 years. This post-hoc analysis further examines the effects of GXR on hyperactivity-impulsivity and inattentiveness. Data from two large double-blind placebo-controlled pivotal trials of GXR in the treatment of ADHD were analyzed. Using the pooled population to provide sufficient sample size and associated statistical power, the impact of GXR treatment on core ADHD symptoms was examined by comparing ADHD Rating Scale IV (ADHD-RS-IV) total scores in the overall GXR and placebo groups in subjects with each of the three ADHD subtypes. ADHD-RS-IV Hyperactivity-Impulsivity and Inattentiveness subscale scores in the overall study population by randomized dose group (vs. placebo) were also examined. The full analysis set included 631 subjects aged 6-17 years (GXR: n=490; placebo: n=141). Among subjects with the predominantly inattentive subtype of ADHD, differences in least squares (LS) mean reductions from baseline in ADHD-RS-IV total scores were significantly greater in GXR-treated subjects (n=127) than in placebo-treated subjects (n=38) at treatment weeks 3 through 5 and end point (p≤0.020). Among subjects with combined type ADHD, differences in LS mean ADHD-RS-IV total score reductions from baseline were significantly greater in the GXR group (n=354) than in the placebo group (n=100) at treatment weeks 1 through 5 and end point (p≤0.011). The dearth of predominantly hyperactive-impulsive type subjects (n=12) precluded analysis of this subgroup. Each randomized GXR dose group in each trial demonstrated significantly greater reductions from baseline in ADHD-RS-IV Hyperactivity-Impulsivity and Inattentiveness subscale scores than did the respective placebo group at end point (p≤0.05 for all). The results support the use of GXR in the treatment of core ADHD symptoms as defined in the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision, including hyperactivity, impulsivity, and inattention.

Comparative effectiveness research using matching‐adjusted indirect comparison: an application to treatment with guanfacine extended release or atomoxetine in children with attention‐deficit/hyperactivity disorder and comorbid oppositional defiant disorder

To illustrate a matching-adjusted indirect comparison by comparing the efficacy of guanfacine extended release (GXR) and atomoxetine (ATX) in reducing oppositional symptoms in children with attention-deficit/hyperactivity disorder and comorbid oppositional defiant disorder. Individual patient data were used from a GXR trial; only published summary data were used from ATX trials. In a matching-adjusted indirect comparison, individual patients from the GXR trial were weighted such that their mean baseline characteristics matched those published for ATX trials. Placebo-arm outcomes were then compared to further assess balance between the matched populations. Changes in the Conners' Parent Rating Scale-Revised Short Form Oppositional Subscale from baseline to endpoint among GXR-treated and ATX-treated patients were then compared. Before matching, the GXR (n = 143) and ATX (n = 98) trial populations had significant differences in baseline characteristics and placebo-arm outcomes. After matching, baseline characteristics were well balanced across trials, and placebo-arm outcomes became nearly identical. Comparing active treatment arms across the matched populations, GXR was associated with a significantly greater reduction in mean Conners' Parent Rating Scale-Revised Short form oppositional subscale compared with ATX {-5.0 [95% confidence interval (CI): -6.6 to -3.4] vs. -2.4 [CI: -3.7 to -1.1], p = 0.01, effect size = 0.58}. In the absence of head-to-head randomized trials, matching-adjusted indirect comparisons can provide timely and reliable comparative evidence for decision makers and can be applied even when very few trials are available for the treatments of interest.

Pharmacotherapy of Attention-Deficit Hyperactivity Disorder in Adolescents

Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioural disorder in children and adolescents, consisting of developmentally inappropriate levels of inattention and/or hyperactivity and impulsivity. The majority of children with ADHD will continue to experience significant ADHD symptoms as teens. ADHD in adolescents can result in significant functional impairment and poorer quality of life. Children and adolescents with ADHD are at higher risk of developing other psychiatric illnesses such as mood, conduct and substance abuse disorders. Stimulants (amphetamines and methylphenidates) and nonstimulants (atomoxetine, guanfacine extended-release (XR) and clonidine XR) have been found to be effective and are approved by the US FDA for the treatment of ADHD in adolescents in the US. Of the agents approved in the US, only guanfacine XR and clonidine XR are not approved in any other countries. There is growing evidence that treatment of ADHD with stimulants reduces the risk of development of other psychiatric co-morbidities, including substance abuse disorders. To date, all FDA-approved stimulants and nonstimulants that have been adequately studied have been demonstrated to be safe and effective in treating ADHD in both children and adolescents. Therefore, clinical decisions used in selecting pharmacotherapy to treat ADHD in children aged 6-12 years can be applied in the adolescent population.

Add Extended-Release Guanfacine to a Stimulant for ADHD?

Extended-release guanfacine (GXR) is an effective monotherapy for core symptoms of attention-deficit/hyperactivity disorder (ADHD; JW Pediatr Adolesc Med Mar 26 2008). Is extended-release guanfacine a safe and effective add-on for ADHD patients who have only a partial response to a stimulant medication's maximum dose? Researchers addressed this question in a manufacturer-funded, multicenter study of 461children with ADHD (age range, 6–17 years); all had experienced a suboptimal …

A Controlled Trial of Extended-Release Guanfacine and Psychostimulants for Attention-Deficit/Hyperactivity Disorder

To examine efficacy, tolerability, and safety of guanfacine extended release (GXR; ≤4 mg/d) adjunctive to a long-acting psychostimulant for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents 6 to 17 years of age with suboptimal, but partial, response to psychostimulant alone. In this multicenter, 9-week, double-blind, placebo-controlled, dose-optimization study, subjects (N = 461) continued their stable dose of psychostimulant given in the morning and were randomized to receive GXR in the morning (GXR AM), GXR in the evening (GXR PM), or placebo. Efficacy measures included ADHD Rating Scale IV (ADHD-RS-IV) and Clinical Global Impressions of Severity of Illness (CGI-S) and Improvement (CGI-I) scales. Safety measures included adverse events (AEs), vital signs, electrocardiograms, and laboratory evaluations. At endpoint, GXR treatment groups showed significantly greater improvement from baseline ADHD-RS-IV total scores compared with placebo plus psychostimulant (GXR AM, p = .002; GXR PM, p < .001). Significant benefits of GXR treatment versus placebo plus psychostimulant were observed on the CGI-S (GXR AM, p = .013; GXR PM, p < .001) and CGI-I (GXR AM, p = .024; GXR PM, p = .003). At endpoint, small mean decreases in pulse, systolic, and diastolic blood pressure were observed in GXR treatment groups versus placebo plus psychostimulant. No new safety signals emerged following administration of GXR with psychostimulants versus psychostimulants alone. Most AEs were mild to moderate in severity. Morning or evening GXR administered adjunctively to a psychostimulant showed significantly greater improvement over placebo plus psychostimulant in ADHD symptoms and generated no new safety signals. Clinical trial registration information-Efficacy and Safety of SPD503 in Combination With Psychostimulants; http://www.clinicaltrials.gov; NCT00734578.

Long-Term Outcomes with Medications for Attention-Deficit Hyperactivity Disorder

Attention-deficit hyperactivity disorder (ADHD), a common neurobehavioural disorder characterized by inattention, hyperactivity and impulsivity, is a chronic disorder and often persists into adulthood. CNS stimulants have been the most well known treatment for ADHD for several decades due to their high effectiveness, good safety profiles and relatively minor adverse effects. Non-stimulant agents, including atomoxetine, extended-release guanfacine and extended-release clonidine (US FDA approved), and several non-FDA-approved agents, such as bupropion and tricyclic antidepressants (TCAs), were recently proven to be effective alternatives to the stimulants in several open-label and placebo-controlled trials. However, most medication trials for ADHD have been short term and thus have not provided information on the long-term outcomes of ADHD treatment. Since the medical treatment of many children with ADHD, especially those with more severe symptoms or co-morbid disorders, has to be continued for several years, recent studies have shifted their focus from the acute effectiveness of stimulants or non-stimulant drugs to the long-term outcomes of medications for ADHD. Evidence has shown that stimulants, along with the non-stimulants atomoxetine and extended-release guanfacine, are continuously effective for 24-month treatment periods with few and tolerable adverse effects.

Psychomotor Functioning and Alertness with Guanfacine Extended Release in Subjects with Attention-Deficit/Hyperactivity Disorder

To determine whether treatment with guanfacine extended release (GXR) in subjects with attention-deficit/hyperactivity disorder (ADHD) disrupted psychomotor functioning and alertness, or impacted daytime sleepiness. This was a randomized, double-blind, placebo-controlled, multicenter, phase 2, dose-optimization, noninferiority, laboratory classroom study of GXR (1, 2, and 3 mg/day) in 182 subjects aged 6 to 17 years with ADHD. Psychomotor functioning and alertness were assessed through several measures, including the Choice Reaction Time (CRT) test from the Cambridge Neuropsychological Test Automated Battery. Sedative effects were examined via spontaneously reported adverse events of sedation, somnolence, and hypersomnia as well as fatigue and lethargy, and with two validated subject- and observer-rated sleepiness scales. Standard efficacy measures for ADHD also were included. Cardiovascular and laboratory parameters were assessed. There were no significant differences between the GXR and placebo groups on measures of psychomotor functioning or alertness from the CRT at endpoint (least-square mean difference: 2.5 [95% confidence interval (CI): -22.9, 28.0], p = 0.8 for CRT; 2.5 [95% CI: -21.5, 26.4], p = 0.84 for correct responses; 15.5 [95% CI: -45.1, 14.1], p = 0.30 for movement time; and -8.2 [95% CI: -54.1, 37.6] p = 0.72 for total time). Most sedative adverse events were mild to moderate, occurred during dose titration, decreased with dose maintenance, and resolved during the study period. One subject in the GXR group discontinued due to fatigue and somnolence. GXR was not associated with increased daytime sleepiness. GXR treatment was associated with significant improvement in ADHD symptoms (6.3 [95% CI: 2.7, 9.8], p = 0.001 for ADHD Rating Scale IV total scores at endpoint). At doses that resulted in significant improvement in ADHD symptoms, impairment on cognitive tasks was not observed. Daytime sleepiness did not differ with GXR compared with placebo. Results suggest that the beneficial effects of GXR on ADHD symptoms are independent of sedation.