What is the use and dosage of Guanfacine (Guanfacine) XR?

Guanfacine Extended Release (XR) for ADHD

Guanfacine XR is initiated at 1 mg once daily (preferably in the evening) and titrated weekly by 1 mg increments based on response to a target dose range of 0.05-0.12 mg/kg/day or 1-7 mg/day, with a maximum of 7 mg daily. 1, 2

Mechanism of Action

Guanfacine is a selective alpha-2A adrenergic receptor agonist that enhances noradrenergic neurotransmission in the prefrontal cortex, strengthening top-down guidance of attention, thought, and working memory. 3, 1 Unlike stimulants that affect dopamine/norepinephrine reuptake, guanfacine directly targets alpha-2A receptors with approximately 10 times higher specificity than clonidine, resulting in less sedation. 3, 1

Dosing Protocol

Starting Dose

• Begin with 1 mg once daily, preferably administered in the evening to minimize daytime somnolence and fatigue. 3, 1, 2

Titration Schedule

• Increase by 1 mg weekly based on clinical response and tolerability. 3, 1, 2
• Target dose range: 0.05-0.12 mg/kg/day or 1-7 mg/day absolute. 1, 2
• Maximum dose: 7 mg daily (doses above 4 mg/day have limited study data). 2, 4

Critical Timing Consideration

• Evening administration is strongly preferred because somnolence/fatigue are the most common adverse effects, and evening dosing minimizes daytime sedation that interferes with school performance. 1
• The medication provides 24-hour symptom control with once-daily dosing. 1

Expected Timeline for Response

Expect 2-4 weeks before observing clinical benefits, which is substantially longer than stimulants that work immediately. 1 This delayed onset is a critical counseling point for families to prevent premature discontinuation. 1

Clinical Positioning

FDA Approval and Indications

• Approved for children and adolescents aged 6-17 years with ADHD. 3, 2
• Can be used as monotherapy or adjunctive therapy with stimulants. 1, 5

Treatment Algorithm Position

• Second-line treatment after stimulants due to smaller effect sizes (approximately 0.7 compared to placebo versus larger effects with stimulants). 1, 5
• Consider as first-line when:
  • Stimulants are contraindicated or not tolerated 5
  • Substance use disorder is present (non-controlled medication status) 1
  • ADHD co-occurs with oppositional symptoms or disruptive behavior 1, 6

Combination Therapy

• Both guanfacine XR and clonidine XR are FDA-approved specifically for adjunctive therapy with stimulants, demonstrating safety in combination. 1
• Never combine guanfacine with clonidine as this increases sedation and cardiovascular effects without evidence of superior efficacy. 1

Safety Profile and Monitoring

Baseline Assessment Required

• Obtain blood pressure and heart rate before initiation. 1
• Screen for cardiac history including Wolf-Parkinson-White syndrome, unexplained syncope, or family history of sudden cardiac death. 1

Most Common Adverse Effects

• Somnolence/sedation (most frequent, typically mild-moderate and diminishing with continued treatment) 3, 4, 6
• Headache (20.5% of patients) 1
• Fatigue (15.2% of patients) 1
• Constipation (5-16%, dose-dependent) 1
• Upper abdominal pain 6

Cardiovascular Effects

• Modest decreases in blood pressure and heart rate are common but typically not clinically significant. 1, 4
• Monitor cardiovascular parameters during dose adjustments. 1
• Bradycardia and hypotension can occur, requiring vigilance. 1

Serious Warnings

• Hypotension/bradycardia 1
• Cardiac conduction abnormalities (rare) 1
• Hallucinations/psychotic symptoms (uncommon but possible) 1
• One long-term study found 6.2% experienced serious treatment-emergent adverse events, and 26% discontinued due to adverse effects. 4

Critical Discontinuation Protocol

NEVER abruptly stop guanfacine—it MUST be tapered to avoid rebound hypertension. 1, 7

Tapering Schedule

• Decrease by 1 mg every 3-7 days when discontinuing. 1
• Rebound hypertension, when it occurs, typically appears after 2-4 days (delayed compared to clonidine due to longer half-life). 7
• In most cases, blood pressure returns to pretreatment levels slowly within 2-4 days without ill effects after proper tapering. 7

Special Populations

Pregnancy and Breastfeeding

• Use with extreme caution in pregnancy—very limited safety data available. 3
• One small study (30 patients with preeclampsia, all beyond first trimester) showed no congenital malformations but 20% of infants had low birth weight. 3, 1
• Not recommended during breastfeeding—no published studies available, and alternative agents are preferred. 3

Adolescents

• Evidence is stronger for elementary school-aged children (6-11 years) than adolescents (12-18 years), though guanfacine can be prescribed for adolescents. 2

Administration Details

• Tablets should be swallowed whole for extended-release formulation. 1
• If unable to swallow whole, discuss with pharmacy about appropriate liquid formulations or switching to immediate-release with adjusted dosing schedules. 1
• The extended-release formulation is NOT interchangeable with immediate-release guanfacine on a milligram-for-milligram basis due to different pharmacokinetics. 4

Drug Interactions

• Primarily metabolized via CYP3A4 and excreted predominantly renally. 3
• When combined with other sedating medications (e.g., trazodone), monitor carefully for excessive somnolence, hypotension, and bradycardia. 1

Efficacy Data

• Effect sizes compared to placebo are in the medium range (approximately 0.7), smaller than stimulants but clinically meaningful. 1, 5
• Improvements in ADHD symptoms and functional impairment were sustained over 24 months in open-label extension trials. 1
• Demonstrated efficacy for oppositional symptoms in children with ADHD (effect size 0.59 for oppositional subscale, 0.92 for ADHD symptoms). 6

When to Contact Provider Immediately

Patients should contact their healthcare provider immediately if they experience: 1

• Chest pain
• Very slow heart rate or irregular heartbeat
• Accidental missed multiple doses (do NOT restart at full dose without medical guidance)