Guanfacine Extended Release

Guanfacine extended release is a non-stimulant treatment for attention deficit hyperactivity disorder in children and adolescents aged 6 to 17 years, and in adults in some regions. It is used when stimulants are not tolerated, are ineffective, or are unsuitable, and it can be added to a stimulant. It reduces impulsivity, hyperactivity and emotional dysregulation, but it takes 2 to 4 weeks to work and can cause sedation and low blood pressure.

Classification. Selective alpha-2A adrenergic agonist, non-stimulant.

Mechanism. Stimulates postsynaptic alpha-2A adrenoceptors in the prefrontal cortex, which strengthens network signalling for attention and impulse control.

Pharmacokinetics. Peak in about 5 to 6 hours for extended release; a high-fat meal increases exposure by about 75%. Metabolised by CYP3A4. Half-life about 18 hours. Mainly cleared in urine as metabolites.

All regimens are oral with no loading dose.

ADHD, children aged 6 to 17 years.

• Start 1 mg once daily.
• Titration: increase by 1 mg at weekly intervals, based on response and tolerability.
• Target 0.05 to 0.12 mg/kg daily. Maximum 4 mg daily in children aged 6 to 12 years and 7 mg daily in adolescents aged 13 to 17 years (some labels allow up to 7 mg in children by weight).
• Give in the morning or evening, consistently.

ADHD, adults (licensed in some regions, specialist use). Start 1 mg once daily, increase weekly to the target of 0.05 to 0.12 mg/kg daily; maximum 7 mg daily.

Dose limits. Strong CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin): halve the dose. Strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin, St John’s wort): the dose may need to be doubled over 1 to 2 weeks. Valproate: levels of valproate may rise, so reduce the guanfacine dose. Severe kidney impairment: reduce the dose by about 25%. Liver impairment: use cautiously.

Contraindications. Hypersensitivity. Use with great caution in bradycardia, heart block, hypotension and known QT prolongation.

Serious adverse effects. Hypotension, bradycardia, syncope (particularly if dehydrated), QT prolongation, rebound hypertension on abrupt stopping, sedation that impairs driving or daily activity, weight gain, rare psychotic symptoms.

Common adverse effects. Somnolence, fatigue, headache, abdominal pain, dizziness, dry mouth, nausea, irritability.

Interactions. Strong CYP3A4 inhibitors raise levels; inducers lower them. Antihypertensives, beta-blockers and diuretics add hypotension and bradycardia. Alcohol and sedatives add drowsiness. Valproate levels rise. High-fat meals increase exposure, so give consistently with or without meals.

Common prescribing errors. Crushing or chewing the tablet; abrupt stopping causing rebound hypertension; not adjusting for CYP3A4 inhibitors or inducers; not warning about dizziness on standing; dosing with grapefruit juice.

Special groups.

• Pregnancy: limited data; avoid unless the benefit clearly outweighs the risk.
• Breastfeeding: excreted in milk; avoid or monitor the infant.
• Children: licensed from 6 years; weight-based targets.
• Older adults: limited data; lower the starting dose.
• Kidney impairment: reduce the dose in severe impairment.
• Liver impairment: use cautiously.

Formulations. Extended-release tablets 1 mg, 2 mg, 3 mg and 4 mg. Swallow whole with water or milk; do not crush, chew or break. Do not take with a high-fat meal or grapefruit juice.

Baseline. Blood pressure, pulse, ECG if there is a cardiac history or QT-prolonging medicines, weight, hydration, medicines list for CYP3A4 inhibitors and inducers.

Monitoring. Check blood pressure and pulse at baseline, after each dose change, and every 3 months. Review sedation, weight and mood. Review the need yearly.

Stopping. Reduce by 1 mg every 3 to 7 days to avoid rebound hypertension; never stop abruptly.

Referral and escalation. Refer to a specialist for syncope, persistent bradycardia, QT prolongation or lack of response. Fainting or a pulse under 50 beats a minute needs urgent assessment.