What are the differences in formulation and dosing for guanfacine (Extended-Release (ER) and Immediate-Release (IR)) in patients with Attention-Deficit/Hyperactivity Disorder (ADHD) and hypertension?

Formulation and Dosing Differences Between Guanfacine Extended-Release (ER) and Immediate-Release (IR) for ADHD and Hypertension

Guanfacine extended-release (ER) offers once-daily dosing with more consistent blood levels compared to immediate-release (IR) formulations, making it the preferred formulation for ADHD treatment, while guanfacine IR is primarily indicated for hypertension with multiple daily dosing. 1, 2

Formulation Differences

Guanfacine Extended-Release (ER)

• Available in tablet form with doses of 1,2,3, and 4 mg 3, 1
• Designed for once-daily administration, typically in the morning 1
• Dosing is adjusted to body weight (approximately 0.1 mg/kg as a general guideline) 3, 1
• In Japan, available in 1 mg and 3 mg formulations with a maximum recommended daily dose of 6 mg 1
• Specifically developed and approved for ADHD treatment 4, 5

Guanfacine Immediate-Release (IR)

• Available in tablet form with doses of 0.1 and 0.2 mg 3
• Typically administered multiple times daily or at bedtime for hypertension 2
• Recommended starting dose for hypertension is 1 mg daily given at bedtime to minimize somnolence 2
• Maximum recommended dose is 3 mg/day for hypertension, with adverse effects increasing significantly at higher doses 2
• Has been used "off-label" for ADHD treatment before ER formulation was available 5

Pharmacokinetic Differences

• Guanfacine ER provides more consistent blood levels over 24 hours compared to IR formulation 6, 7
• Studies have shown that 4 mg/day of guanfacine ER has similar plasma levels to 3 mg/day of guanfacine IR after 24 hours (3.46 ng/mL vs. 3.40 ng/mL) 7
• Direct dose substitution between IR and ER formulations on a milligram-for-milligram basis is inappropriate due to different pharmacokinetic profiles 8
• Guanfacine ER has a longer half-life, which reduces the risk of rebound hypertension upon discontinuation compared to IR formulations 2, 6

Dosing for ADHD

• Guanfacine ER is the preferred formulation for ADHD treatment 1, 4
• Therapeutic effects of guanfacine ER for ADHD may take 2-4 weeks to fully manifest, unlike stimulants which work more rapidly 3, 1
• In clinical practice, guanfacine ER is often positioned as a second-line treatment after stimulants have proven ineffective or not tolerated 1
• Guanfacine ER can be used as monotherapy or as adjunctive therapy with stimulants for ADHD 4, 8

Dosing for Hypertension

• Guanfacine IR is primarily indicated for hypertension treatment 2
• Starting dose is 1 mg daily at bedtime, with potential increase to 2 mg if needed after 3-4 weeks 2
• Most of the antihypertensive effect is seen at 1 mg, though doses up to 3 mg/day may be used 2
• When used for hypertension, guanfacine IR reduces peripheral vascular resistance and heart rate by stimulating central α2-adrenergic receptors 2

Discontinuation Considerations

• Abrupt discontinuation of guanfacine IR may cause rebound hypertension after 2-4 days 2
• Guanfacine ER shows less risk of rebound hypertension upon discontinuation compared to IR formulations 1, 6
• The American Academy of Pediatrics recommends tapering guanfacine ER rather than abrupt discontinuation to minimize potential withdrawal effects 1
• In a study comparing abrupt cessation versus tapering of guanfacine ER, no clinically significant elevations in blood pressure were observed with abrupt cessation, though tapering is still recommended 6

Side Effect Profiles

• Both formulations share similar adverse effect profiles, with somnolence being the most common 3, 4, 8
• Common adverse effects for both formulations include fatigue, sedation, dry mouth, irritability, insomnia, and nightmares 3
• Cardiovascular effects include modest reductions in blood pressure and heart rate 3, 2, 8
• Somnolence is the most frequently cited reason for discontinuation of guanfacine ER 4, 8

Regional Availability

• In Japan, guanfacine ER (GXR) is available for ADHD treatment with a maximum daily dose of 6 mg 3, 1
• In India, guanfacine ER is not available; clonidine is used as an alternative alpha-2 agonist 3
• In Europe, guanfacine ER is approved only when stimulants are not suitable, not tolerated, or ineffective 3
• In the Republic of Korea, extended-release clonidine is available but not guanfacine ER 3