Profile of guanfacine extended release and its potential in the treatment of attention-deficit hyperactivity disorder

Abstract

The α2-adrenergic receptor agonist guanfacine, in its extended-release formulation (GXR), is the most recent nonstimulant medication approved in several countries for the treatment of attention-deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive pharmacotherapy to stimulants in children and adolescents. The present paper aims to review comprehensively and critically the pharmacodynamic and pharmacokinetic characteristics and the published evidence on the efficacy and safety profile of GXR in the treatment of ADHD. A comprehensive search of relevant databases (PubMed, Embase, and PsycInfo) was conducted to identify studies published in peer-reviewed journals until January 15, 2015. Though the precise mechanism of action of guanfacine in the treatment of ADHD is not fully understood, it is thought to act directly by enhancing noradrenaline functioning via α2A-adrenoceptors in the prefrontal cortex. Weight-adjusted doses should be used, with a dosing regime on a milligram per kilogram basis, starting at doses in the range 0.05–0.08 mg/kg/day, up to 0.12 mg/kg/day. As evidenced in short-term randomized controlled trials and in long-term open-label extension studies, GXR has been shown to be effective as monotherapy in the treatment of ADHD. Furthermore, GXR has also been found to be effective as adjunctive therapy to stimulant medications in patients with suboptimal responses to stimulants. Many of the adverse reactions associated with GXR, particularly sedation-related effects, were dose-related, transient, mild to moderate in severity, and did not interfere with attention or overall efficacy. There are no reports of serious cardiovascular adverse events associated with GXR alone or in combination with psychostimulants.

Attention-deficit hyperactivity disorder medication use: factors involved in prescribing, safety aspects and outcomes

“…While, atomoxetine overall is less likely than stimulants to worsen sleep problems, initial somnolence can be observed, particularly if the dosage is increased too rapidly [Wolraich et al 2007]; however insomnia may also be experienced by adult patients taking atomoxetine [Wietecha et al 2013]. Likewise, the most common TEAEs associated with the α2-adrenergic receptor agonists guanfacine-XR (GXR) and clonidine-XR (CLON-XR) are somnolence, headache, upper abdominal pain, fatigue, and sedation [Hirota et al 2014;Martinez-Raga et al 2015;Ruggiero et al 2014]. In the long-term prospective trials of GXR and CLON-XR the most commonly reported TEAEs are somnolence, headache, fatigue and abdominal pain [Martinez-Raga et al 2015].…”

“…Likewise, the most common TEAEs associated with the α2-adrenergic receptor agonists guanfacine-XR (GXR) and clonidine-XR (CLON-XR) are somnolence, headache, upper abdominal pain, fatigue, and sedation [Hirota et al 2014;Martinez-Raga et al 2015;Ruggiero et al 2014]. In the long-term prospective trials of GXR and CLON-XR the most commonly reported TEAEs are somnolence, headache, fatigue and abdominal pain [Martinez-Raga et al 2015].…”

“…The increases in HR and BP, reported with stimulants and atomoxetine, generally are observed early in treatment, more commonly during the initial titration phase, and stabilize over time [Hammerness et al 2009;Martinez-Raga et al 2013c;Upadhyaya et al 2015]. In contrast, treatment with the α2adrenergic receptor agonists guanfacine and clonidine, either as monotherapy or as add-on to psychostimulants, can induce small-to-modest and dose-dependent decreases in diastolic and systolic BP and HR, ranging between −3 and −5 mmHg and −3 to −6 bpm, respectively [Martinez-Raga et al 2015]. Nonetheless, in some instances these drugs, particularly in their immediate release (IR) formulations, may be associated with significant hypotension, including the risk of orthostatic hypotension, and marked bradycardia [Connor et al 1999].…”

“…It has been hypothesized that nonmedical use and diversion of prescription stimulants may be associated with unrecognized or untreated ADHD [Poulin, 2007]. While methylphenidate and amphetamines may be self-administered by laboratory animals and have shown subjective and reinforcing effects in humans [Kollins et al 2009], nonstimulant medications approved for the treatment of ADHD, including, atomoxetine, guanfacine or clonidine, lack any reinforcing effects and consequently any abuse potential [Jasinski et al 2008;Martinez-Raga et al 2015]. However, a recent report suggested that, although to a lesser extent than methylphenidate, atomoxetine is used by adults for nonmedical purposes, including recreational use [Jensen et al 2015].…”

A randomized, placebo-controlled trial of extended-release guanfacine in children with autism spectrum disorder and ADHD symptoms: an analysis of secondary outcome measures

“…Guanfacine is a selective alpha 2A adrenergic receptor agonist that stimulates postsynaptic alpha 2A receptors in the prefrontal cortex (PFC), potentiating noradrenergic transmission and strengthening the connectivity of PFC networks [12,13]. This mechanism of action likely mediates the therapeutic effects of guanfacine on working memory, attention, and behavioral control [13].…”