Intuniv XR: first alpha agonist approved for ADHD

Shire Canada is introducing Intuniv XR (guanfacine 1 mg, 2 mg, 3mg, and 4 mg extended-release tablets), the first selective alpha2A-adrenergic receptor agonist to be approved for the treatment of attention deficit hyperactivity disorder (ADHD) in Canada.Intuniv XR is indicated for use in children six to 12 years of age. It is intended for use as monotherapy, or as adjunctive therapy to psychostimulants in children who have a suboptimal response to psychostimulants. The drug’s effectiveness for long-term use (> 9 weeks) has not been evaluated in controlled trials.(1)The mechanism of action of guanfacine in ADHD is unknown. The drug is a selective alpha2A-adrenergic receptor agonist; it does not have central nervous system (CNS) psychostimulant properties.(1)The recommended starting dosage of guanfacine XR (as monotherapy or as adjunctive therapy to psychostimulants) is 1 mg once daily.(1) Similar clinical response and tolerability are achieved regardless of whether the drug is administered in the morning or evening.(2) The dose should be adjusted in increments of no more than 1 mg per week, based on the patient’s clinical response and tolerability to the drug. The maximum recommended daily dose is 4 mg.(1)Intuniv XR tablets should not be crushed, chewed, or broken because this will increase the rate of guanfacine release. In addition, tablets should not be administered with high-fat meals, as this will increase guanfacine exposure.(1)The most common adverse effects of guanfacine are fatigue, sedation, somnolence (particularly early in treatment or with dose increases), headache, dizziness, nausea, upper abdominal pain, insomnia, and dry mouth. If sedation is concerning or persistent, a reduction in dose or drug discontinuation should be considered.(1)Syncope and dose-dependent reductions in heart rate and blood pressure have been reported. Heart rate and blood pressure should be monitored at baseline, after dose adjustments, periodically during treatment, and following drug discontinuation. Elevations in blood pressure and heart rate above the original baseline (ie, rebound) have been reported upon guanfacine discontinuation.(1)Caution is required if guanfacine is used in patients with pre-existing hypotension, bradycardia, heart block, or other cardiovascular disease (eg, arrhythmia, sick sinus syndrome, ischemic heart disease, congestive heart failure, or congenital long QT syndrome) or a history of syncope.(1)In terms of drug interactions, strong CYP3A4/5 inhibitors (eg, ketoconazole) can significantly increase guanfacine plasma concentrations (by 3-fold), increasing the risk of adverse events such as hypotension, bradycardia, and sedation. An increase in guanfacine dose may be needed when used in combination with a CYP3A4 inducer (eg, rifampin). Guanfacine can increase concentrations of valproic acid; serum valproic acid concentrations should be monitored and patients should be observed for possible additive CNS effects. Guanfacine is not recommended in combination with drugs that can cause bradycardia or QT prolongation. Caution is required when guanfacine is administered with antihypertensives or CNS depressants.(1)A recent review concluded that short-term clinical studies in ADHD have shown guanfacine XR to be effective as a once-daily monotherapy or as an adjunct to psychostimulants. Somnolence, sedation, and hypersomnia are frequent adverse events, although they are typically mild to moderate in severity and tend to diminish with continued treatment. However, a long-term, open-label study noted 22 serious treatment-emergent adverse effects in 16 (6.2%) of 259 subjects, while another study observed that 26% of subjects discontinued therapy due to adverse effects.(3)In a recent comparative trial, guanfacine XR appeared to be more effective than atomoxetine (the other nonstimulant marketed for ADHD), providing significantly greater reductions in hyperactivity/impulsivity, inattention, and mean ADHD scores.(4)References1. Shire Canada Inc. Intuniv XR (guanfacine hydrochloride extended-release tablets) product monograph. Saint-Laurent, QC: July 4, 2013.2. Newcorn JH, Stein MA, Childress AC, et al. Randomized, double-blind trial of guanfacine extended release in children with attention-deficit/hyperactivity disorder: morning or evening administration. J Am Acad Child Adolesc Psychiatry 2013;52:921-30.3. Faraone SV, McBurnett K, Sallee FR, et al. Guanfacine extended release: a novel treatment for attention-deficit/hyperactivity disorder in children and adolescents. Clin Ther 2013 Oct 16. [Epub ahead of print].4. Sikirica V, Findling RL, Signorovitch J, et al. Comparative efficacy of guanfacine extended release versus atomoxetine for the treatment of attention-deficit/hyperactivity disorder in children and adolescents: applying matching-adjusted indirect comparison methodology. CNS Drugs 2013;27:943-53.

Intuniv XR: first alpha agonist approved for ADHD

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