Guanfacine Hydrochloride Extended Release: Therapeutic area: Attention-deficit/hyperactivity disorder: Reimbursement Review

WHAT IS ATTENTION-DEFICIT/HYPERACTIVITY DISORDER? • Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder most commonly identified in children and adolescents that often continues into adulthood. It is an impairment of the ability to regulate attention or focus. ADHD can present differently in different people. Some symptoms may include forgetfulness, impulsivity, disorganization, distracted behaviour, and restlessness. People with ADHD can also experience emotional dysregulation. These factors may contribute to learning challenges, problems with self-esteem, and difficulties with relationships. • In Canada, the prevalence of ADHD in children and adolescents combined is estimated to range from 2.6% to 8.6%. The prevalence is thought to be higher in males (range, 3.7% to 13.3%) than in females (range, 1.5% to 7.0%). WHAT ARE THE TREATMENT GOALS AND CURRENT TREATMENT OPTIONS FOR ADHD? • The treatment goals for children and adolescents with ADHD are to reduce hyperactivity, impulsivity (including aggressive impulsive actions), inattention, oppositional behaviours, and emotional dysregulation to improve their development (e.g., learning, social development, cognitive outcomes, and health-related quality of life [HRQoL]). • Methylphenidate and dextroamphetamine (or mixed amphetamine salts) preparations are common psychostimulant (PST) medications used as first-line treatment to target symptoms. • However, PST treatment is not helpful to all patients, particularly those with certain medical conditions. This includes those who cannot tolerate PSTs due to their adverse effects; those whose disease does not have a clinical response to PSTs; those for whom optimized PST use results in only a partial disease response; and those whose families may feel strongly that PST medications are not a good option for them. • Guanfacine hydrochloride extended release (GXR), a nonstimulant medication, could be used as a second-line treatment as monotherapy or as adjunctive therapy to a PST for patients whose disease responds suboptimally to PSTs alone. WHAT IS GXR AND WHY DID CANADA’S DRUG AGENCY CONDUCT THIS REVIEW? • GXR, an alpha-2a agonist, is available as an oral tablet. Health Canada has approved GXR as monotherapy for the treatment of ADHD in children and adolescents aged 6 years to 17 years, and as adjunctive therapy to PSTs for the treatment of ADHD in children and adolescents aged 6 years to 17 years, with a sub-optimal response to PSTs. • In 2015, the Canadian Drug Expert Committee recommended that GXR not be listed for the treatment of ADHD in children aged 6 years to 12 years as monotherapy (due to insufficient evidence to assess the comparative clinical benefit of GXR as monotherapy relative to other less costly treatments) or as adjunctive therapy (due to limited evidence from 1 randomized controlled trial [RCT] of only 9 weeks’ duration). • At the request of the participating public drug programs in 2025, Canada’s Drug Agency (CDA-AMC) reviewed GXR used as monotherapy and as an adjunctive therapy to a PST to inform a recommendation on whether it should be reimbursed for the treatment of ADHD in children and adolescents aged 6 years to 17 years. HOW DID CDA-AMC EVALUATE GXR? • CDA-AMC reviewed the clinical evidence on the beneficial and harmful effects of GXR and compared its costs versus those of other treatments used in Canada for ADHD in children and adolescents aged 6 years to 17 years. PSTs (e.g., amphetamine and methylphenidate, both short- and long-acting formulations) and other nonstimulants (e.g., atomoxetine and clonidine) were considered relevant treatments to compare with GXR. • The clinical evidence was identified through systematic searches for available studies. The objectives of this review are 2-fold: to review the benefits and harms of GXR as monotherapy and to review the benefits and harms of GXR as adjunctive therapy to a PST. For the use of GXR as monotherapy, evidence from indirect treatment comparisons was sought due to limited direct evidence for GXR and active comparators found during evidence scoping. • The review received no inputs from patient groups, clinician groups, or industry. • Two clinical experts in the diagnosis and management of children and adolescents with ADHD were consulted as part of the review process, with representation from Ontario and British Columbia. WHAT WERE THE FINDINGS? CDA-AMC reviewed the following clinical evidence: • 1 systematic review with network meta-analysis (NMA) comparing monotherapy oral medications (i.e., amphetamines, methylphenidate, modafinil, atomoxetine, clonidine, guanfacine, or bupropion) and placebo for the treatment of ADHD in children and adolescents. • 3 long-term extension (LTE) studies of GXR as monotherapy (1 of which also included evidence for GXR as an adjunctive therapy to a PST) for the treatment of ADHD in children and adolescents. • 2 RCTs with 4 reports comparing GXR versus placebo as adjunctive therapy to a PST for the treatment of ADHD in children and adolescents. CLINICAL EVIDENCE OF MONOTHERAPY: • NMA results showed: o.. GXR may result in decreases in ADHD core symptoms and an increase in clinical global functioning rated by clinicians compared with placebo. o.. Compared with amphetamines, GXR may result in an increase (i.e., less improvement) in ADHD core symptoms and a decrease (i.e., less improvement) in clinical global functioning as rated by clinicians. o.. Compared with atomoxetine or methylphenidate, GXR may result in little to no difference in ADHD core symptoms and an uncertainty in clinical global functioning as rated by clinicians. o.. The effects of GXR compared with clonidine on the improvement of ADHD core symptoms and clinical global functioning are uncertain. o.. GXR may result in an increase in study discontinuations due to adverse events (AEs) compared with placebo, but the effect of GXR compared with active comparators is very uncertain. o.. GXR may result in smaller decreases in weight compared with amphetamines, atomoxetine, or methylphenidate. The effect of GXR on weight compared with placebo or clonidine is uncertain. o.. GXR may result in a decrease in systolic blood pressure, but little to no difference in diastolic blood pressure compared with placebo. o.. In the absence of evidence, the effects of GXR compared with placebo or active comparators for other AEs, illness severity, or HRQoL are not known. o.. Limitations of the NMA included the potential for intransitivity (differences in patient and study characteristics across comparisons in the network), which would bias the effect estimates, affect study-level risks of bias, and result in imprecision in the effect estimates. Evidence of all comparisons to active treatments were of low or very low certainty. The NMA also risks being out of date, resulting in risk of bias due to missing evidence in the synthesis. • LTE studies showed: o.. Patients treated with GXR in 3 LTE studies for 24 months experienced clinically important decreases in ADHD core symptoms (3 studies), decreases in illness severity (2 studies), and clinically important improvements in psychosocial aspects of HRQoL (2 studies). o.. Somnolence, headache, fatigue, upper respiratory tract infection, sedation, dizziness, abdominal pain, insomnia, and irritability are common AEs associated with GXR use. o.. Although changes in vital signs, blood pressure, and cardiovascular events were not commonly observed in long-term treatment with GXR, these potential harms should be closely monitored as per suggestion of the clinical experts. o.. Due to the single-arm design of the LTE studies, it is uncertain to what extent the observed effects can be attributed to GXR. Other limitations include risk of bias in the measurement of the outcomes and due to missing outcomes data. The studies could not inform about the long-term effects of GXR relative to active comparators used in clinical practice. ECONOMIC EVIDENCE OF MONOTHERAPY: • Reimbursing GXR as monotherapy for the treatment of ADHD in children and adolescents aged 6 years to 17 years is expected to increase costs to public drug programs. CLINICAL EVIDENCE OF ADJUNCTIVE THERAPY: • Evidence from 2 RCTs comparing GXR + PST therapy versus placebo plus PST therapy suggests GXR + PST treatment may result in greater improvement in ADHD core symptoms in children and adolescents. • GXR adjunctive therapy may also improve executive function (1 RCT), severity of illness (2 RCTs), clinical global functioning (2 RCTs), overall psychopathology (1 RCT), disease response and remission (1 RCT), and ADHD symptomatology and functioning (1 RCT) in children and adolescents. • Common AEs such as headache, abdominal pain, fatigue, somnolence, dizziness, insomnia, and affective lability occurred more frequently in the GXR + PST group than in the placebo plus PST group. • The findings were limited by short-term follow-up and various sources of bias. Long-term follow-up of a single-arm adjunctive therapy in a small subgroup suggested that the long-term safety and efficacy of GXR adjunctive therapy were consistent with the findings from short-term blinded studies. Due to the single-arm design of the LTE study, it is uncertain to what extent the observed effects can be attributed to GXR + PST therapy. ECONOMIC EVIDENCE OF ADJUNCTIVE THERAPY: • Reimbursing GXR as adjunctive therapy to a PST for the treatment of ADHD in children and adolescents aged 6 years to 17 years is expected to increase costs to public drug programs.