What are the indications, dosing, contraindications, and side effects of guanfacine (Intuniv) for hypertension and attention‑deficit/hyperactivity disorder?

Guanfacine (Intuniv): Indications, Dosing, Contraindications, and Side Effects

Guanfacine extended-release is FDA-approved for ADHD in children and adolescents aged 6–17 years, with off-label use for hypertension in adults, and should be started at 1 mg once daily in the evening, titrated weekly by 1 mg to a target of 0.05–0.12 mg/kg/day (maximum 7 mg/day), with mandatory tapering by 1 mg every 3–7 days upon discontinuation to prevent rebound hypertension. 1

FDA-Approved Indications

ADHD (Primary Indication)

• Approved for children and adolescents aged 6–17 years with ADHD, either as monotherapy or adjunctive therapy to stimulants 1, 2
• Guanfacine extended-release and clonidine extended-release are the only two medications with FDA approval and sufficient evidence for adjunctive use with stimulants 1
• Not approved for children younger than 6 years; behavioral therapy is first-line for ages 4–5 years 1

Hypertension (Off-Label in Pediatrics)

• FDA-approved for hypertension in adolescents and adults, but reserved as last-line therapy due to significant CNS adverse effects (sedation, dry mouth, orthostatic hypotension), especially in older adults 1, 3

Mechanism of Action

• Alpha-2A adrenergic receptor agonist that enhances noradrenergic neurotransmission in the prefrontal cortex, strengthening top-down guidance of attention, thought, and working memory 1, 2
• Ten times higher specificity for alpha-2A receptors compared to clonidine, explaining its less sedative profile 1, 2
• Works by directly targeting alpha-2A receptors rather than affecting dopamine or norepinephrine reuptake 1

Dosing Guidelines

ADHD Dosing

• Starting dose: 1 mg once daily 1, 4
• Titration: Increase by 1 mg per week based on response and tolerability 1
• Target range: 0.05–0.12 mg/kg/day or 1–7 mg/day 1, 4
• Maximum dose: 7 mg/day (some jurisdictions specify 6 mg/day) 1
• Evening administration is strongly preferred to minimize daytime somnolence and fatigue, which are the most common adverse effects 1

Weight-Based Dosing Considerations

• Doses adjusted to body weight at 0.1 mg/kg once daily as a rule of thumb 1, 2
• Data suggest weight-adjusted doses >0.08 mg/kg but ≤0.12 mg/kg may provide additional clinical benefits if tolerated 5
• For adolescents weighing >70 kg, higher doses may be needed, though doses >4 mg/day require careful monitoring due to limited study data 5, 6

Timing and Administration

• Once-daily dosing provides "around-the-clock" symptom control lasting approximately 24 hours 1
• Evening dosing helps minimize daytime sedation that could interfere with school performance 1
• Therapeutic effects require 2–4 weeks before clinical benefits become apparent, unlike stimulants which work immediately 1, 2
• Tablets should ideally be given whole; if necessary, discuss with pharmacy about appropriate liquid formulations 1

Hypertension Dosing (Off-Label in Pediatrics)

• Typical adult range: 0.1–0.8 mg daily, though this is not the primary indication in pediatric populations 1

Contraindications and Precautions

Absolute Contraindications

• Baseline bradycardia (heart rate <60 bpm) 1
• Baseline hypotension (systolic BP <90 mmHg) 1
• Known hypersensitivity to guanfacine 1

Relative Contraindications and Special Populations

• Cardiac conditions: Patients with Wolf-Parkinson-White syndrome, unexplained fainting, family history of sudden cardiac death, hypertrophic cardiomyopathy, or long QT syndrome require careful evaluation before initiation 1
• Pregnancy: Use with caution due to limited safety data; one small study showed no congenital malformations but 20% of infants had low birth weight 1
• Elderly patients: More susceptible to hypotensive effects and CNS adverse effects 1
• Autonomic dysfunction or orthostatic hypotension: Requires closer monitoring 1

Drug Interactions

• CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): May increase guanfacine levels, requiring dose reduction 1
• CYP3A4 inducers (e.g., rifampin, phenytoin): May decrease guanfacine levels, requiring dose increase 1
• CYP1A2 inhibitors (e.g., oral contraceptives): Require dose reduction and monitoring 1
• CNS depressants (phenothiazines, barbiturates, benzodiazepines, alcohol, trazodone): Additive sedative effects expected; monitor for excessive somnolence, hypotension, and bradycardia 1

Cardiovascular Monitoring Requirements

Baseline Assessment

• Obtain baseline blood pressure and heart rate before initiating guanfacine 1
• Screen for personal and family cardiac history, including specific cardiac symptoms, sudden death, Wolf-Parkinson-White syndrome, hypertrophic cardiomyopathy, and long QT syndrome 1

Expected Cardiovascular Effects

• Decreases systolic and diastolic BP by approximately 1–4 mm Hg 1, 4
• Decreases heart rate by approximately 1–2 bpm on average 1, 4
• These effects are opposite to stimulants, which increase both parameters 1

Ongoing Monitoring

• Monitor BP and heart rate at each dose adjustment and periodically during maintenance therapy 1
• 5–15% of individuals may experience more substantial decreases requiring closer monitoring 1
• When combining with stimulants, monitor for opposing cardiovascular effects 1

Side Effects and Adverse Events

Most Common Adverse Effects (>5%)

• Somnolence/sedation (most frequent, typically mild-to-moderate, tends to lessen with continued treatment) 1, 4, 6
• Fatigue (15.2% of patients) 1
• Headache (20.5% of patients) 1, 4
• Dry mouth 1, 2
• Dizziness 1, 4
• Irritability 1, 4
• Upper abdominal pain 1, 4
• Nausea 4
• Constipation (5–16% of patients, dose-dependent) 1

Cardiovascular Adverse Effects

• Hypotension and bradycardia (common though typically not clinically significant in most patients) 1, 4
• Sinus bradycardia 5
• Cardiac conduction abnormalities (rare) 1
• Blunted physiologic BP response upon standing in a dose-related manner 5

Serious but Uncommon Adverse Effects

• Hallucinations and psychotic symptoms (uncommon) 1
• Hepatitis (rare cases observed, though association is stronger with atomoxetine) 1
• Increased suicidal thoughts (reported infrequently, more closely linked to atomoxetine) 1

Discontinuation-Related Effects

• Rebound hypertension can occur with abrupt cessation 1, 7
• Guanfacine must never be abruptly discontinued—taper by 1 mg every 3–7 days 1, 2
• Abrupt cessation can precipitate rebound hypertension even in normotensive or hypotensive individuals 1

Timing of Adverse Events

• Somnolence, sedation, and fatigue adverse events emerge within the first 2 weeks of dosing and generally resolve by study end 4
• Most adverse events are mild to moderate, transient, and dose-related 1

Clinical Efficacy

ADHD Symptom Reduction

• Effect size of approximately 0.7 compared to placebo (medium range) 1, 4
• Stimulant medications demonstrate larger effect sizes (approximately 1.0) and remain first-line therapy 1
• Improvements in functional impairment and quality of life sustained over 24 months in open-label extension trials 1

Position in Treatment Algorithm

• Second-line treatment after stimulants due to relatively smaller effect sizes 1
• May be preferred as first-line in specific scenarios:
  • Comorbid sleep disorders 1
  • Comorbid tic disorders or Tourette syndrome 1
  • Substance use disorders (non-controlled medication status) 1
  • Disruptive behavior disorders or oppositional symptoms 1
  • Stimulant intolerance or contraindications 1

Combination Therapy with Stimulants

• FDA-approved for adjunctive use with stimulants 1
• Allows for lower stimulant dosages, potentially reducing stimulant-related adverse effects (insomnia, appetite suppression, rebound symptoms) 1
• Particularly appropriate for adolescents with substance abuse risk, as adding guanfacine may minimize stimulant exposure while maintaining efficacy 1

Special Clinical Scenarios

ADHD with Sleep Disturbances

• Evening administration addresses sleep problems while providing around-the-clock ADHD symptom control 1
• Unlike stimulants, which can worsen insomnia, guanfacine's sedating properties improve sleep onset when administered at bedtime 1

ADHD with Tics

• Treats both ADHD and tics without worsening tic severity, unlike stimulants which may exacerbate tics 1
• Higher specificity for alpha-2A receptors results in less sedation compared to clonidine while maintaining therapeutic efficacy for both symptoms 1

ADHD with Irritability or Explosive Behavior

• Can be considered when stimulants cause behavioral activation (irritability, disinhibition, aggression, emotional lability) 1
• Full therapeutic benefit for mood lability requires 2–4 weeks of steady dosing 1
• If explosive behavior persists after 4–6 weeks of optimized guanfacine, refer to child psychiatry for mood-disorder evaluation 1

Intellectual Disability with ADHD

• Guanfacine can be considered when stimulants fail or are not tolerated, though evidence is limited to small trials 1
• Methylphenidate remains first-line despite lower effect sizes (0.39–0.52) in this population 1

Critical Safety Warnings

Discontinuation Protocol

• Never stop guanfacine abruptly—taper by 1 mg every 3–7 days to avoid rebound hypertension 1, 2, 7
• If multiple doses are accidentally missed, do not restart at full dose without medical guidance 1

Monitoring During Treatment

• Systematic monitoring of ADHD symptoms at each dose adjustment using parent and teacher reports 1
• Cardiovascular parameters should be monitored during dose adjustments 1
• Contact healthcare provider immediately if experiencing chest pain, very slow heart rate, irregular heartbeat, or severe hypotension 1

Multimodal Treatment Approach

• Pharmacotherapy should be combined with behavioral interventions and psychoeducation to optimize outcomes 1
• For elementary-school-aged children (6–11 years), prescribe together with evidence-based parent- and/or teacher-administered behavior therapy 1

Common Pitfalls to Avoid

• Do not expect immediate results—counsel families that 2–4 weeks are required for therapeutic effects, unlike stimulants 1, 2
• Do not administer in the morning if sedation is a concern—evening dosing is strongly preferred 1
• Do not abruptly discontinue—always taper to prevent rebound hypertension 1, 2
• Do not overlook cardiovascular monitoring—baseline and ongoing BP/HR checks are essential 1
• Do not use in children younger than 6 years—behavioral therapy is first-line for preschoolers 1
• Do not assume interchangeability with clonidine—guanfacine has higher alpha-2A specificity and different adverse effect profile 1, 2
• Do not add a second alpha-2 agonist (clonidine + guanfacine together)—this increases sedation risk and cardiovascular effects without clear evidence of superior efficacy 1