Guanfacine (Intuniv) for attention deficit hyperactivity disorder

• A new non-stimulant medicine for people aged 6–17 years with ADHD
  Guanfacine (Intuniv) is PBS listed for people with contraindications or intolerance to stimulants, or as an adjunctive treatment to stimulants.
• Stimulants remain the first-line ADHD medicine for children and adolescents
  Guanfacine is a second-line ADHD medicine. It should be used alongside a treatment program including psychological, educational and social measures.
• Guanfacine or atomoxetine can be used when stimulants are inappropriate
  Both are PBS listed for patients with contraindications or intolerance to stimulants. Only guanfacine is listed as an adjunctive treatment.
• Adjunctive guanfacine can lead to incremental symptom improvements
  Compared with placebo, response and remission rates were greater in patients who had guanfacine added to their stimulant medicine.
• Careful dose titration is required when commencing or discontinuing treatment
  Guanfacine can cause hypotension, bradycardia, sedation, somnolence, fatigue and headache.
• Syncope has been reported with guanfacine
  Heart rate and blood pressure monitoring are recommended prior to initiation of guanfacine, following dose increases, and periodically during treatment.

Authority Required (Streamlined)

On 1 March 2019, guanfacine (Intuniv) was listed on the PBS as an Authority Required (Streamlined) listing. It was listed as an adjunctive treatment to stimulant medicines in patients with attention deficit hyperactivity disorder (ADHD).^1,2

To receive subsidised treatment, patients must have residual moderate to severe symptoms despite receiving a maximum tolerated dose (MTD) of dexamfetamine, methylphenidate or lisdexamfetamine (‘stimulant’ medicines).^1,2

Symptoms must be severe enough to impair social, academic or occupational functioning in at least one setting.¹

On 1 September 2018, guanfacine was first listed as monotherapy for patients with ADHD and contraindications or intolerance to dexamfetamine, methylphenidate or lisdexamfetamine.^1,3,4

For this listing, patients must meet one of the following criteria:¹

• have a contraindication to dexamfetamine, methylphenidate or lisdexamfetamine as specified in the TGA-approved product information
• have a comorbid mood disorder that has developed or worsened as a result of dexamfetamine, methylphenidate or lisdexamfetamine, and is severe enough to necessitate treatment withdrawal
• be at unacceptable risk of a drug interaction severe enough to necessitate permanent stimulant withdrawal
• have experienced adverse reactions severe enough to necessitate permanent treatment withdrawal following treatment with dexamfetamine, methylphenidate and lisdexamfetamine (not simultaneously).

To be eligible for PBS-subsidised guanfacine (for either listing), patients must be treated by a paediatrician or psychiatrist and diagnosed with ADHD according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 criteria.¹

To receive initialtreatment, patients must have been diagnosed with ADHD between the ages of 6 and 17 years (inclusive).¹

Patients qualify for continuing treatment if they have previously received PBS-subsidised guanfacine for ADHD.¹

There are no age restrictions for continuing treatment.¹

See the PBS website for more information and PBS restrictions on guanfacine prescribing.

Guanfacine is a selective α2A adrenergic receptor agonist. It is not a stimulant medicine.^5,6

Guanfacine’s mechanism of action in ADHD is uncertain, but nonclinical data suggest it may stimulate postsynaptic α2A adrenoceptors in the midbrain and pyramidal cells of the prefrontal cortex. These regions are known to play a major role in attention, organisation, planning, and impulse control.^5,7

Guanfacine is available on the PBS as 1 mg, 2 mg, 3 mg and 4 mg modified-release tablets.¹

Guanfacine is an option for people who are contraindicated to stimulant medicines, cannot tolerate them or don’t fully respond to stimulants at a dose they are able to tolerate.^1,5

See PBS Listing and Where does it fit? for further information.

Approved indications

In 2009, guanfacine was approved in the United States for the treatment of ADHD as monotherapy and as adjunctive therapy to stimulant medications. Approvals in Canada and Europe followed in 2015, with greater restrictions.⁷

In Europe, guanfacine was approved for the treatment of ADHD in people aged 6–17 years for whom stimulants are not suitable, not tolerated or have been shown to be ineffective.⁷

Guanfacine has to be used as part of a comprehensive ADHD treatment program, typically including psychological, educational and social measures.⁷

In Australia, guanfacine was submitted for approval and reimbursement under the TGA/PBAC parallel process.⁴

Guanfacine was registered in Australia in August 2017.^5,7

In Australia it is indicated for people aged 6–17 years as monotherapy (when stimulants or atomoxetine are not suitable, not tolerated or have been shown to be ineffective) or as adjunctive therapy to stimulants (where there has been suboptimal response to stimulants).^5,7

Its approved Australian indications also specify that guanfacine should be used as part of a comprehensive ADHD management program.^5,7

Stimulant medicines are the first-line pharmacological treatment for children and adolescents with ADHD.^8-10

Guanfacine is a second-line ADHD medicine.^1,5,9,11It is an alternative to atomoxetine for children and adolescents with contraindications or intolerance to stimulant medicines.⁸

Atomoxetine is indicated for the treatment of ADHD (defined by DSM-IV criteria) in children aged 6 years and older, adolescents and adults.¹²

Like guanfacine, atomoxetine is listed on the PBS General Schedule for patients with ADHD and contraindications or intolerance to dexamfetamine, methylphenidate or lisdexamfetamine.^1,13

However, only guanfacine is PBS listed as an adjunctive treatment for patients with a suboptimal response to stimulants.^1,13

In the sponsor’s submission, the PBAC considered that up to 20% of patients taking stimulants may be eligible for add-on therapy with guanfacine.¹⁴

Another α2A adrenergic receptor agonist, clonidine, has been used for ADHD complicated by comorbid tics, aggression or sleep disturbance. However, it is not TGA-approved for ADHD in Australia and there are concerns regarding its safety when used in combination with stimulants.^8,15

Background to ADHD

ADHD is a heterogeneous disorder characterised by the core symptoms of hyperactivity, impulsivity and inattention.^8,9

International studies using DSM-IV criteria suggest a childhood prevalence of around 5% to 7%.^8,10

Similarly, in a national household survey conducted in Australia in 2013–14 an estimated 7.4% (312,000) of children and adolescents aged 14–17 years were assessed as having ADHD (using the Diagnostic Interview Schedule for Children Version IV).^16,17

ADHD was the most common mental disorder in this age group.¹⁶

A diagnosis of ADHD should only be made after a comprehensive assessment by an experienced child behaviour specialist (such as a paediatrician or child/adolescent psychiatrist).^8,10

To meet DSM-5 diagnostic criteria for ADHD, symptoms must be accompanied by clear evidence that they interfere with social, academic or occupational functioning.¹⁸

When evaluating children and adolescents for ADHD, health professionals should also assess for other conditions that might coexist, including oppositional defiant disorder, conduct disorder, anxiety, depression, tics, sleep disturbance, substance abuse, and learning and language difficulties.^8,10,19

They should also look for other explanations for ADHD symptoms, including family conflict or evidence of a traumatic family environment (abuse, neglect, domestic violence or parental illness, for example).¹⁰

Pharmacological and non-pharmacological interventions (primarily behaviour-based methods) can reduce the core symptoms of ADHD in the short-term, although their effects on long-term outcomes (such as academic performance) is not established.^10,19

Stimulants remain first-line medicines for ADHD

Improved efficacy and acceptability of stimulants compared with non-stimulants has been demonstrated in meta-analyses.^20,21

In a 2017 systematic review and network meta-analysis of 190 randomised controlled trials and people with ADHD aged 3–16 years, treatment response (improvement in ADHD symptoms or global functioning) with stimulant monotherapy was reported to be superior to non-stimulant monotherapy (including guanfacine or atomoxetine).²⁰

Low quality evidence showed improved treatment response with methylphenidate and amphetamine compared with atomoxetine and guanfacine, and improved discontinuation rates with methylphenidate compared with atomoxetine.²⁰

In a 2017 systematic review and Bayesian network analysis of 36 randomised controlled trials (funded by Shire), lisdexamfetamine was found to be more effective than methylphenidate, guanfacine or atomoxetine at improving ADHD symptoms in people aged 8.5–14.6 years, although 95% confidence intervals overlapped on several analyses.²¹

Discontinuation rates were lower with methylphenidate than the other medicines.²¹

Australian Therapeutic Guidelines (published in 2013) advise that either dexamphetamine or methylphenidate could be used to treat a child with ADHD. Failure to tolerate or respond to one medicine does not imply the other will not be effective or tolerated.⁸

An adequate trial of both medicines is recommended before trialling alternative less efficacious options.⁸

More recent guidelines from the National Institute for Health and Care Excellence (NICE, UK), recommend methylphenidate as the first-line medicine for young people and children aged 5 years and over.⁹

They recommend switching to lisdexamfetamine if there is a suboptimal response to a 6-week trial of methylphenidate at an adequate dose, and considering dexamphetamine if patients are responding to lisdexamfetamine but cannot tolerate it.⁹

Guanfacine or atomoxetine are recommended if patients cannot tolerate or do not respond to methylphenidate or lisdexamfetamine.⁹

Monotherapy in patients with contraindications or intolerance to stimulants

In their PBS submission, guanfacine’s sponsor nominated atomoxetine as the comparator for this indication. The PBAC agreed this was appropriate.⁴

To support their submission for this indication, the sponsor identified a double-blind, randomised controlled trial comparing guanfacine and atomoxetine with placebo in 338 participants with ADHD aged 6–17 years.^4,23

The trial duration was 10 weeks in children and 13 weeks in adolescents to allow time for dose optimisation with guanfacine (6–12 years: 1–4 mg/day; 13–17 years: 1–7 mg/day) and atomoxetine (10–100 mg/day).²³

Exclusion criteria included serious cardiac and psychiatric illness (except oppositional defiant disorder), tic disorders, and a history of alcohol or substance abuse. Approximately 50% of participants reported prior use of stimulants.²³

Improvements in ADHD-RS-IV scores were greater with guanfacine and atomoxetine than placebo.²³

For the primary analysis, mean (standard deviation [SD]) changes from baseline in ADHD-RS-IV total scores at Week 15 were –23.9 (12.41) for guanfacine and –15.0 (13.07) for placebo (LS mean difference –8.9, 95% confidence interval [CI] –11.9 to ­­–5.8, p < 0.001).²³

In a post-hoc analysis, mean (SD) changes from baseline in ADHD-RS-IV total scores at Week 15 were –18.6 (11.91) with atomoxetine (LS mean difference versus placebo –3.8, 95% CI –6.8 to ­–0.7, p = 0.017]).²³

The response rate (≥ 30% reduction in ADHD-RS-IV total score and CGI-I score 1 or 2) was 64.3% for guanfacine, 55.4% for atomoxetine and 42.3% for placebo.⁴

Treatment-emergent adverse events (TEAEs) leading to study discontinuation occurred more frequently with guanfacine (7.9%) than atomoxetine (4.5%) or placebo (0.9%).²³

The most commonly reported TEAEs with guanfacine were somnolence, headache and fatigue, whereas with atomoxetine they were decreases in appetite, nausea and fatigue.²³

In the July 2017 submission, the PBAC advised that the sponsor’s claim of guanfacine’s superior effectiveness versus atomoxetine based on this study was questionable, because the study did not recruit patients intolerant or contraindicated to stimulants, and because the comparison versus atomoxetine was post‐hoc.⁴

Adjunctive therapy to stimulants

To support their submission for this indication, guanfacine’s sponsor identified a 9-week, double-blind, randomised controlled trial comparing guanfacine with placebo as an adjunct to stimulant medicines in participants with ADHD aged 6–17 years.^4,24

Participants were required to have suboptimal response to methylphenidate or amphetamine and need additional treatment in the opinion of the study investigator.²⁴

Suboptimal response was defined as at least 4 weeks of treatment with a stable dose of an extended-release stimulant, with improvement but mild to moderate ADHD symptoms, ADHD-RS-IV score ≥ 24 and CGI-S score ≥ 3.²⁴

A total of 461 participants were randomised to placebo, or guanfacine 1–4 mg taken in the morning or evening. Participants continued to take their stable dose of stimulant medicine.²⁴

Exclusion criteria included lack of response to current stimulant medicine, cardiovascular abnormalities, body weight below 25 kg or above 80 kg, or any current psychiatric diagnosis (except oppositional defiant disorder).²⁴

The primary outcome was again improvement in ADHD-RS-IV total score from baseline.²⁴

At endpoint, the mean (SD) ADHD-RS-IV total score was 21.7 (12.98) for placebo, 17.3 (12.86) for guanfacine morning administration and 16.1 (11.84) for guanfacine evening administration.²⁴

For both morning and evening administration, there were greater improvements from baseline in ADHD-RS-IV total scores for guanfacine versus placebo.²⁴

Placebo-adjusted LS mean reductions were –4.5 (95% confidence interval [CI] –7.5 to –1.4, p < 0.002) for guanfacine morning administration and –5.3 (95% CI –8.3 to –2.3, p < 0.001) for guanfacine evening administration.²⁴

While a 4-point between-treatment difference in ADHD-RS-IV total scores was pre-specified by the investigators as being clinically meaningful, the PBAC regarded the clinical significance as uncertain.^4,24

However, a higher proportion of participants achieved a response or remission with guanfacine and long-acting stimulants compared with placebo and long-acting stimulants (see Table 1).¹⁴

Treatment-emergent adverse events were more common with guanfacine morning administration (n = 116, 77.3%) and evening administration (n = 116, 76.3%) than placebo (n = 97, 63.4%).²⁴

The most common TEAEs with guanfacine were headache (21%) and somnolence (13.2% to 14%). Small mean decreases in pulse and systolic and diastolic blood pressure were observed with guanfacine compared with placebo.²⁴

Guanfacine’s only contraindication is use in patients with a history of hypersensitivity to guanfacine.⁵

However, there are precautions for guanfacine’s use. Guanfacine can cause hypotension, bradycardia, sedation, somnolence, fatigue and headache.⁵

The impact of hepatic and renal impairment on the pharmacokinetics of guanfacine in people aged 6–17 years has not been investigated, but dose reductions may be required in patients with hepatic impairment, severe renal impairment and end stage renal disease.⁵

Dose-dependent decreases in mean heart rate (6–9 bpm) and blood pressure (systolic 4–5 mmHg, diastolic 3 mmHg) have also been observed in short-term trials.⁵

As guanfacine can cause hypotension, bradycardia and syncope, the product information recommends checking heart rate and blood pressure prior to starting guanfacine, following dose increases, and periodically while on therapy.⁵

Tapered withdrawal is required to minimise the risk of rebound hypertension upon discontinuation.⁵

Significant QTc prolongation concerns were not identified in guanfacine Phase II and III trials, but the studies did not include people with a history of cardiac conduction problems or people taking medicines known to prolong the QTc interval.⁷

No adverse psychiatric changes were identified in pre-registration trials. However, people with comorbid psychiatric disorders (except oppositional defiant disorder) were excluded from enrolment.⁷

Guanfacine appears to have a low potential for abuse and dependence and this is reflected in its Schedule 4 listing on the Poisons Schedule.^1,6

However, cases of intentional and accidental overdose have been reported with guanfacine.²⁵

Signs and symptoms of overdose may include hypotension, initial hypertension, bradycardia, lethargy, and respiratory depression. Management should include monitoring for and treatment of these signs and symptoms.⁵

Children and adolescents who develop lethargy should be observed for up to 24 hours for the development of more serious toxicity (including coma, bradycardia, and hypotension) due to the possibility of delayed onset of these symptoms.⁵

For information about reporting adverse reactions to the TGA, or to report suspected adverse reactions online, see the TGA website.

Drug interactions

Guanfacine is a substrate of CYP3A4/3A5 and caution is required if it is co-administered with CYP3A4/3A5 inducers (such as rifampicin) and inhibitors (such as ketoconazole). Co-administration with valproic acid can lead to increased levels of valproate.⁵

Sedative effects may be increased if guanfacine is taken at the same time as other CNS depressants.⁵

Long-term safety

In a 2-year, open-label extension of two guanfacine Phase III randomised controlled trials in 214 participants with ADHD aged 6–17 years, TEAEs leading to discontinuation were reported in seven (3.3%) participants.²⁶

These were somnolence (two participants), aggression, first-degree atrioventricular block, dizziness, drug abuse and increased weight. All of these, except drug abuse, were considered by the investigator to be related to guanfacine and resolved with dose tapering or discontinuation.²⁶

While some children and adolescents treated with guanfacine may show an increase in their BMI,⁵ most participants in this trial (163/207) remained in their baseline BMI percentile category at the final study assessment.²⁶

At the July 2017 PBAC meeting, guanfacine was recommended on a cost-minimisation basis with atomoxetine for the treatment of patients diagnosed with ADHD between ages 6–17 years who are contraindicated or intolerant to stimulant therapy.⁴

The PBAC considered that the sponsor’s claim of superior comparative effectiveness over atomoxetine was questionable, but a claim of non-inferiority was reasonable.⁴

The PBAC did not recommend the listing of guanfacine as an adjunctive treatment to stimulants at this meeting due to ‘uncertain clinical significance of the trial outcomes and the uncertain cost-effectiveness’.⁴

Guanfacine is registered for use as monotherapy in patients who have an inadequate response to stimulant therapy.⁵ However, the PBAC also rejected an application for this indication at the July 2017 meeting because evidence presented by the sponsor did not support a listing in this population.⁴

At the July 2018 meeting, the PBAC considered a minor resubmission, seeking the listing of guanfacine as an adjunctive treatment at a lower price, to address concerns about uncertain cost-effectiveness.¹⁴

The PBAC recommended the listing of guanfacine as an adjunctive treatment in conjunction with optimised stimulant therapy, for ADHD in children and adolescents experiencing residual moderate to severe symptoms.¹⁴

Continuing treatment

At the 2017 PBAC meeting, the sponsor requested that guanfacine be restricted to patients aged 17 years and younger.⁴

The PBAC noted clinician comments that restricting guanfacine in such a way may force patients to discontinue treatment at 18 years of age, creating challenges for prescribers and patients.⁴

The PBAC noted that initiation of atomoxetine was restricted to patients under the age of 18, but that continuing restrictions permitted patients to remain on treatment without age restrictions. The PBAC therefore recommended similar continuing restrictions for guanfacine.⁴

The recommended starting dose for guanfacine is 1 mg, taken orally once daily.⁵

The dose can then be adjusted (depending on clinical response and tolerability) in increments of no more than 1 mg per week, to a maximum dose of 4 mg per day in children aged 6–12 years and 7 mg per day in people aged 13–17 years. Doses above these maximums have not been evaluated and are not recommended.⁵

The target dose range is 0.05–0.12 mg/kg/day.⁵

For adjunctive treatment with stimulants the maximum recommended dose of guanfacine is 4 mg per day.⁵

Discontinuation of guanfacine requires dose tapering to avoid rebound hypertension.⁴ The dose should be tapered by no more than 1 mg every 3–7 days, with careful monitoring of pulse and blood pressure.⁵

Advise patients and carers:

• tablets should be swallowed whole with water, and not broken, crushed or chewed
• guanfacine should not be taken with fatty foods and/or grapefruit juice-containing products as these may interact with guanfacine and alter its effects
• if drowsiness is a problem, teenagers should avoid driving or operating machinery
• not to stop taking guanfacine without talking to their doctor, as stopping treatment suddenly can lead to serious side effects such as high blood pressure
• if they forget a dose, they should wait until the next day and take the usual (not double) dose. If two or more doses are missed they should talk to their doctor or pharmacist as re-titration may be required.

Discuss the Intuniv Consumer Medicine Information (CMI) leaflet with the patient.