Key points from the evidence

The content of this evidence summary was up-to-date in March 2016. See summaries of product characteristics (SPCs), British national formulary (BNF), BNF for children (BNFc) or the MHRA or NICE websites for up-to-date information.

Summary

Guanfacine prolonged‑release (Intuniv) is a non‑stimulant treatment for children and young people with attention deficit hyperactivity disorder (ADHD). In 3 short‑term, randomised controlled trials (RCTs) it was more effective than placebo at improving ADHD symptoms, although a beneficial effect on social functioning was not consistently shown. The most frequently reported adverse reactions for guanfacine prolonged‑release were somnolence, headache, fatigue, upper abdominal pain and sedation. Serious adverse reactions include hypotension, weight increase, bradycardia and syncope. No studies directly compared the efficacy and safety of guanfacine prolonged‑release with other active treatments for ADHD.

Regulatory status: Guanfacine prolonged‑release (Intuniv) received a European marketing authorisation for use in ADHD in September 2015. It was launched in the UK in February 2016. Guanfacine prolonged‑release is licensed for the treatment of ADHD in children and young people aged 6–17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. It is not licensed for use in combination with stimulants or for adults with ADHD.

Effectiveness

  • In 1 short‑term RCT, dose‑optimised guanfacine prolonged‑release was more effective than placebo at improving ADHD symptoms in children and young people aged 6–17 years (about half of whom had previously been treated with stimulant medication; p<0.001, effect size=0.76; n=338).

  • In 2 other short‑term RCTs, dose‑optimised guanfacine prolonged‑release was more effective than placebo at improving ADHD symptoms in young people aged 13–17 years (p<0.001, effect size=0.52; n=314) and in children aged 6–12 years (p<0.001; n=333).

Safety

Patient factors

Resource implications

  • Guanfacine prolonged‑release tablets (Intuniv) cost £56.00–£141.68 for 28 days treatment at a dose of 1–7 mg daily (excluding VAT; MIMS, February 2016).

  • Atomoxetine capsules (Strattera) cost £62.46–£83.28 for 28 days treatment at a dose of 10–100 mg daily (excluding VAT; Drug Tariff February 2016).

  • Atomoxetine 4 mg/ml oral solution (Strattera) costs £23.33–£233.33 for 28 days treatment at a dose of 10–100 mg daily (excluding VAT; Drug Tariff, February 2016).

Introduction and current guidance

Attention deficit hyperactivity disorder (ADHD) is a heterogeneous behavioural syndrome characterised by the core symptoms of hyperactivity, impulsivity and inattention. The NICE guideline on ADHD (currently being updated, publication expected January 2018) covers diagnosing and managing ADHD in children, young people and adults. Where drug treatment is considered appropriate, the guideline recommends methylphenidate, atomoxetine and dexamfetamine within their licensed indications, as options for the management of ADHD in children and young people. Choice of drug should be guided by comorbidities, adverse effects, specific issues that may affect compliance, the potential for drug diversion or misuse, and the preferences of the child or young person or their parent or carer.

Full text of introduction and current guidance.

Product overview

Guanfacine is a selective alpha2–adrenergic receptor agonist. It is a non‑stimulant.

Guanfacine prolonged‑release (Intuniv) is licensed for the treatment of ADHD in children and young people aged 6–17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective (Intuniv [guanfacine prolonged-release] SPC).

The recommended maintenance dose range for guanfacine prolonged‑release is 0.05–0.12 mg/kg/day, based on the person's response and tolerability. The recommended starting dose is 1 mg once a day. The dose may be adjusted in increments of not more than 1 mg per week. The maximum dose for children aged 6–12 years is 4 mg daily; for young people aged 13–17 years the maximum dose is dependent on weight, with a maximum dose of 7 mg daily for young people weighing 58.5 kg and above. The SPC provides recommended dose titration tables, based on age and weight.

Guanfacine prolonged‑release is not licensed in adults with ADHD.

Guanfacine prolonged‑release is available in 28 tablet packs, costing £56.00 for 28×1 mg; £58.52 for 28×2 mg; £65.52 for 28×3 mg and £76.16 for 28×4 mg (MIMS, February 2016, prices exclude VAT).

Full text of product overview.

Evidence review

This evidence summary is based on 1 randomised controlled trial (RCT) that involved children and young people aged 6–17 years who received dose‑optimised guanfacine prolonged‑release (Hervas et al. 2014). Other RCTs discussed include a study involving young people aged 13–17 years who received dose‑optimised guanfacine; an RCT involving children aged 6–12 years that compared dose‑optimised guanfacine given in the morning and evening; and an RCT involving children aged 6–12 years with ADHD and oppositional symptoms who received dose‑optimised guanfacine. Additional safety and efficacy data from 2 open‑label, long‑term extension studies are discussed, along with results of a phase 2 RCT that assessed the effect of guanfacine on psychomotor functioning and alertness.

  • In a short‑term RCT involving 338 children and young people with ADHD (about half of whom had previously been treated with stimulant medication), dose‑optimised guanfacine prolonged‑release was statistically significantly more effective than placebo at improving ADHD symptoms, measured using the validated ADHD Rating Scale version IV (ADHD‑RS‑IV) score at 10 or 13 weeks (Hervas et al. 2014). The placebo‑adjusted difference in LS mean change from baseline in ADHD‑RS‑IV score for guanfacine was −8.9 points (95% confidence interval [CI] −11.9 to −5.8, p<0.001, effect size 0.76). This study included an atomoxetine arm, but was not powered to test superiority of guanfacine over atomoxetine. The placebo‑adjusted difference in LS mean change from baseline in ADHD‑RS‑IV score for atomoxetine was −3.8 points (95% CI −6.8 to −0.7, p=0.017, effect size 0.32).

  • A 13‑week RCT compared guanfacine prolonged‑release with placebo in 314 young people aged 13–17 years with ADHD (Wilens et al. 2015). At study end there was a statistically significant improvement in ADHD‑RS‑IV score for guanfacine compared with placebo. In the guanfacine group the LS mean change from baseline was −24.6 points compared with −18.5 points for placebo, p<0.001, effect size 0.52.

  • An 8‑week, placebo‑controlled RCT compared morning and evening administration of dose‑optimised guanfacine prolonged‑release in 333 children aged 6–12 years with ADHD (Newcorn et al. 2013). Both morning and evening dosing showed a statistically significant improvement over placebo in mean ADHD‑RS‑IV score from baseline, with no difference between the 2 times of administration (−19.8 points with guanfacine morning dosing, −20.1 with guanfacine evening dosing and −11.0 with placebo; p<0.001 for both guanfacine groups compared with placebo).

  • The efficacy of guanfacine prolonged‑release in children with ADHD and oppositional symptoms was assessed in a 9‑week, flexible‑dose, double‑blind, RCT (Connor et al. 2010, n=217). A statistically significantly greater reduction in the oppositional subscale of the Conners' Parent Rating Scale‑Revised: Long Form (CPRS‑R:L) score was seen for guanfacine compared with placebo (LS mean change from baseline: −10.9 points with guanfacine and −6.8 points with placebo, p<0.001, effect size 0.59).

  • Two open‑label extension studies have reported on the long‑term effectiveness of guanfacine prolonged‑release for up to 2 years (Sallee et al. 2009b and Biederman et al. 2008b). In Sallee et al. 2009b, participants receiving guanfacine monotherapy had a mean ADHD‑RS‑IV score of 40.6 points at baseline, reducing to 19.4 points at study end (mean score reduction 21.2 points, p<0.001). In Biederman et al. 2008b the ADHD‑RS‑IV score reduced by 18.1 points from baseline to study end (p<0.001). Discontinuation rates were high, with approximately 80% of participants across the 2 studies leaving before 24 months.

  • The EPAR for Intuniv (guanfacine prolonged-release) reports that there is uncertainty about the effect of guanfacine on social functioning, with only 1 study (Hervas et al. 2014) showing statistically significant results.

  • The EPAR states that rates of treatment‑emergent adverse events were higher in children and young people treated with guanfacine compared with atomoxetine or placebo. Severe adverse events were reported in 8.8%, 1.8% and 1.7% of those taking guanfacine, atomoxetine and placebo respectively. Adverse events considered to be related to the study drug occurred in 73.2% of people taking guanfacine (1765/2411), 55.4% of those taking atomoxetine (62/112) and 36.7% of those taking placebo (357/973). Discontinuation rates due to adverse events were higher in the guanfacine group (10.8%; 261/2411) compared with the atomoxetine group (4.5%; 5/112) or the placebo group (1.3%; 13/973).

  • The SPC for Intuniv (guanfacine prolonged-release) states that in clinical studies the most frequently reported adverse reactions include somnolence (40.6%), headache (27.4%), fatigue (18.1%), upper abdominal pain (12.0%) and sedation (10.2%). Serious adverse reactions include hypotension (3.2%), weight increase (2.9%), bradycardia (1.5%) and syncope (0.7%). The SPC notes that somnolence and sedation occur predominantly at the start of treatment and may typically last for 2–3 weeks and longer in some cases.

  • The efficacy and safety of guanfacine prolonged‑release has not been directly compared to other active treatments for ADHD. All RCTs discussed in this evidence summary were short‑term, lasting no more than 13 weeks. The beneficial effect of guanfacine on social functioning has not been consistently shown in clinical trials.

Full text of evidence review.

Context

Guanfacine prolonged‑release is licensed specifically for the treatment of ADHD in children and young people aged 6–17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. The only other non‑stimulant drug licensed for ADHD in the UK is atomoxetine (a selective noradrenaline reuptake inhibitor). Unlicensed or off‑label drug treatment options for ADHD include bupropion, clonidine, modafinil and imipramine.

Full text of context.

Estimated impact for the NHS

The NICE guideline on ADHD recommends that drug treatment for children and young people with ADHD should always form part of a comprehensive treatment plan that includes psychological, behavioural and educational advice and interventions. Where drug treatment is considered appropriate, the guideline recommends methylphenidate, atomoxetine and dexamfetamine, within their licensed indications, as options for the management of ADHD in children and young people.

Guanfacine prolonged‑release is licensed for the treatment of ADHD in children and young people aged 6–17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. It must be used as a part of a comprehensive ADHD treatment programme, typically including psychological, educational and social measures (SPC).

The EPAR concluded that treatment with guanfacine prolonged‑release resulted in a clinically meaningful improvement in ADHD symptoms, although an effect on social functioning was not consistently shown. However, the safety profile is characterised by undesirable side effects which are common and limit tolerability. These include (orthostatic) hypotension, bradycardia, sedation, fatigue, and headache. There are no studies that directly compare the efficacy and safety of guanfacine prolonged‑release with other active treatments for ADHD.

Local decision makers will need to consider the available evidence on efficacy and safety, as well as cost and individual patient factors, when making decisions about using guanfacine prolonged‑release or other treatments for ADHD.

Full text of estimated impact for the NHS.

About this evidence summary

'Evidence summaries: new medicines' provide summaries of key evidence for selected new medicines, or for existing medicines with new indications or formulations, that are considered to be of significance to the NHS. The strengths and weaknesses of the relevant evidence are critically reviewed within this summary to provide useful information for those working on the managed entry of new medicines for the NHS, but this summary is not NICE guidance.