Guanfacine

Indications

• Intuniv extended-release is FDA-approved for ADHD in patients age 6 to 17 years, as monotherapy or as adjunct to stimulant therapy.
• Immediate-release guanfacine is FDA-approved only for hypertension in adults and carries no pediatric ADHD indication.
• Extended-release guanfacine is particularly useful for ADHD with prominent hyperactivity, impulsivity, oppositionality, or emotional dysregulation.
• Used off-label for tic disorders and Tourette syndrome, where alpha-2 agonists reduce tic severity and treat comorbid ADHD at once.
• Used off-label for adult ADHD, aggression and irritability in autism spectrum disorder, and hyperarousal symptoms of PTSD.
• Frequently added off-label to a morning stimulant to cover evening rebound, homework hours, and sleep-onset difficulty.

Mechanism of action

• Selective postsynaptic alpha-2A adrenergic receptor agonist, roughly 15 to 20 times more selective for alpha-2A than clonidine.
• Stimulating alpha-2A receptors on prefrontal cortical dendritic spines closes HCN channels and strengthens network connectivity.
• Improved prefrontal signal transmission enhances working memory, impulse control, and regulation of attention and emotion.
• Alpha-2A selectivity means less alpha-2B and alpha-2C activity, which translates into less sedation and hypotension than clonidine.
• The therapeutic effect is postsynaptic rather than presynaptic, so it does not depend on reducing central noradrenergic firing.

Pharmacokinetics

• Extended-release tablets reach Tmax at about 5 hours, roughly 3 hours later than immediate-release, with lower peak concentrations.
• Half-life is approximately 17-18 hours, supporting once-daily dosing in either the morning or the evening.
• Metabolized mainly by CYP3A4 to inactive metabolites, with about half of a dose excreted unchanged by the kidneys.
• High-fat meals raise extended-release exposure substantially, so the tablet should be taken consistently apart from such meals.
• Immediate-release and extended-release products are not interchangeable on a milligram basis and require independent titration.

Dosing

• Intuniv: start 1 mg PO once daily and adjust by no more than 1 mg per week, targeting 0.05-0.12 mg/kg/day as tolerated.
• Maximum studied dose is 4 mg/day in children 6-12 years and 7 mg/day in adolescents 13-17 years, including adjunctive use above 4 mg only rarely.
• Tablets must be swallowed whole, since crushing or chewing accelerates release and converts the product to an immediate-release exposure.
• Immediate-release guanfacine for hypertension in adults: 1 mg PO at bedtime, increasing to 2 mg after 3-4 weeks, with a maximum of 3 mg/day.
• When discontinuing, taper by no more than 1 mg every 3 to 7 days to avoid rebound hypertension, tachycardia, and agitation.
• Reduce the dose in significant renal or hepatic impairment, since clearance falls through both renal excretion and CYP3A4 metabolism.

Adverse effects

• Somnolence in about 38 percent, fatigue, sedation, headache, abdominal pain, and dry mouth are the leading adverse effects.
• Hypotension, bradycardia, dizziness, and syncope are dose related and are the usual limits on titration in slim younger children.
• Sedation typically peaks in the first 2-3 weeks and often improves with continued treatment or by moving the dose to bedtime.
• Abrupt discontinuation can cause rebound hypertension, tachycardia, headache, and nervousness, which is why a taper is required.
• Weight gain, irritability, and mild depressive symptoms are reported less commonly but occasionally lead to discontinuation.
• Overdose causes profound bradycardia, hypotension, and central nervous system depression and warrants cardiac monitoring.

Monitoring

• Baseline heart rate, blood pressure, and orthostatic vitals, repeated after each titration step and periodically during maintenance.
• Ask about daytime sedation, school performance, and sleepiness at each visit, since these determine dose timing more than dose size.
• Track ADHD symptoms with a validated scale at baseline and after 4-6 weeks at a stable dose before declaring nonresponse.
• Recheck cardiovascular status when other antihypertensives, sedatives, or CYP3A4 inhibitors are added to the regimen.
• Assess for missed doses, since interruptions of several days can produce rebound blood pressure elevation and irritability.

Interactions

• Strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, and ritonavir raise guanfacine exposure and generally warrant halving the dose.
• Strong CYP3A4 inducers such as carbamazepine, phenytoin, and rifampin lower exposure and may require doubling the dose.
• Additive sedation occurs with alcohol, benzodiazepines, opioids, antihistamines, and other central nervous system depressants.
• Additive hypotension and bradycardia occur with beta-blockers, calcium channel blockers, clonidine, and other antihypertensives.
• Valproate levels may rise when guanfacine is added, so check concentrations if the two are used together.

Special populations

• Pregnancy: human data are limited and animal studies show no clear teratogenicity; use only when the benefit justifies the risk.
• Lactation: excretion into human milk is not characterized, so watch the breastfed infant for sedation and poor feeding.
• Pediatric: extended-release is approved from age 6; safety and effectiveness below age 6 have not been established.
• Geriatric: efficacy and safety of the extended-release product have not been established in older adults, who are prone to hypotension and falls.
• Renal or hepatic impairment: reduce the dose, since about half of guanfacine is cleared unchanged renally and the rest through CYP3A4.

Clinical pearls

• Never substitute immediate-release for extended-release milligram for milligram; retitrate from 1 mg.
• Sedation almost always fades by week 3; bedtime dosing usually rescues an otherwise useful trial.
• Stopping abruptly can cause rebound hypertension; taper by 1 mg every 3 to 7 days.