Guanfacine: Uses and Dosing
Guanfacine is FDA-approved for hypertension in adults and adolescents, and the extended-release formulation is approved for ADHD in children and adolescents aged 6-17 years, though it should be considered a second-line agent for ADHD with limited efficacy data in adults. 1, 2
Primary Indications
ADHD Treatment (Extended-Release Formulation)
- Starting dose: 1 mg once daily 1
- Titration: Increase by 1 mg per week based on response and tolerability 1
- Target dose range: 0.05 to 0.12 mg/kg/day or 1 to 7 mg/day 1
- Maximum dose: 4 mg/day (doses above this lack adequate study data) 3
- Approval status: Approved in Canada for children and adolescents aged 6-17 years only; limited efficacy data exists for adult ADHD treatment 1
Hypertension (Immediate-Release Formulation)
- Starting dose: 1 mg daily at bedtime to minimize somnolence 2
- Titration: After 3-4 weeks, may increase to 2 mg if needed 2
- Maximum dose: 3 mg/day (adverse reactions increase significantly above this dose) 2
- Administration: Given at bedtime as monotherapy or combined with other antihypertensives 2
Mechanism and Pharmacology
- Mechanism: Alpha-2A adrenoreceptor agonist that enhances noradrenaline functioning in the prefrontal cortex for ADHD; reduces sympathetic outflow for hypertension 1, 4, 5
- Metabolism: Primarily via CYP3A4, with predominantly renal excretion 1
- Onset of action: ADHD effects typically observed after 2-4 weeks of treatment 1
- Half-life: Prolonged elimination half-life allows once-daily dosing 6
Efficacy Considerations
Guanfacine demonstrates medium effect sizes for ADHD that are smaller than stimulants, making it appropriate as second-line therapy. 1
- Effective as monotherapy and adjunctive therapy to stimulants in short-term trials 3, 5
- Improves functional impairment and quality of life beyond core ADHD symptoms 1
- Longer-term maintenance of treatment effects is documented 1
- Critical limitation: Limited data on efficacy, safety, and tolerability in adults with ADHD 1
Adverse Effects and Monitoring
Common Adverse Effects
- Most frequent: Somnolence, sedation, fatigue, irritability, insomnia, nightmares 1
- Cardiovascular: Modest reductions in blood pressure and heart rate, hypotension, bradycardia 1, 3
- Other: Dry mouth, constipation 6
- Severity: Typically mild to moderate, dose-related, and transient 3, 5
Serious Considerations
- Discontinuation rates: 26% discontinued due to adverse events in one long-term study 3
- Serious adverse events: 6.2% experienced serious treatment-emergent adverse events in long-term trials 3
- QTc prolongation: Reported in overdose cases (QTc up to 593 ms) 7
- Orthostatic hypotension: Can be delayed and persistent, particularly in overdose 7
Withdrawal Effects
- Rebound hypertension: Low frequency but can occur 2-4 days after abrupt discontinuation 2
- Blood pressure typically returns to pretreatment levels slowly (within 2-4 days) without ill effects in most cases 2
Special Populations
Pregnancy
- Recommendation: Alternative agents preferred; use only after risk-benefit discussion 1
- Safety data: One study in 30 preeclampsia patients (outside first trimester) showed no congenital malformations, but 20% had low birth weight infants who later developed normally 1
- First trimester data: No published studies available 1
Breastfeeding
- Recommendation: Caution advised; no published studies exist 1
- Monitoring: If used, monitor infants for drowsiness and hypotonia (similar to clonidine concerns) 1
Critical Clinical Pitfalls
- Do not substitute immediate-release for extended-release on a milligram-for-milligram basis due to different pharmacokinetics 3
- Weight-adjusted dosing is essential for optimal efficacy in ADHD treatment 3, 5
- Delayed symptom onset in overdose: Symptoms may not appear until 30+ hours post-ingestion, requiring extended monitoring 7
- Avoid doses above 4 mg/day due to lack of safety data and increased adverse effects 2, 3
- Not first-line for ADHD: Stimulants remain the preferred initial treatment 1