Guanfacine (Page 4 of 7)
9.1 Controlled Substance
Guanfacine is not a controlled substance and has no known potential for abuse or dependence.
Postmarketing reports of guanfacine extended-release tablets overdosage indicate that hypotension, drowsiness, lethargy, and bradycardia have been observed following overdose. Initial hypertension may develop early and may be followed by hypotension. Similar symptoms have been described in voluntary reports to the American Association of Poison Control Center’s National Poison Data System. Miosis of the pupils may be noted on examination. No fatal overdoses of guanfacine extended-release tablets have been reported in published literature.
Consult a Certified Poison Control Center by calling 1-800-222-1222 for up-to-date guidance and advice.
Management of guanfacine overdose should include monitoring for and the treatment of initial hypertension, if that occurs, as well as hypotension, bradycardia, lethargy and respiratory depression. Children and adolescents who develop lethargy should be observed for the development of more serious toxicity including coma, bradycardia and hypotension for up to 24 hours, due to the possibility of delayed onset hypotension.
Guanfacine is a once-daily, extended-release formulation of guanfacine hydrochloride (HCl), USP in a matrix tablet formulation for oral administration only. The chemical designation is N-amidino-2-(2,6-dichlorophenyl) acetamide monohydrochloride. The molecular formula is C9 H9 Cl2 N3 O•HCl corresponding to a molecular weight of 282.55. The chemical structure is:
Guanfacine hydrochloride, USP is a white or almost white crystalline powder, sparingly soluble in water, methanol and ethanol. Each tablet contains guanfacine HCl equivalent to 1 mg, 2 mg, 3 mg, or 4 mg of guanfacine base. The tablets also contain colloidal silicon dioxide, fumaric acid, glyceryl dibehenate, hypromellose, lactose monohydrate, methacrylic acid copolymer, microcrystalline cellulose, and povidone. In addition, the 3 mg and 4 mg tablets also contain FD&C blue #2/indigo carmine aluminum lake and ferric oxide yellow.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Guanfacine is a central alpha2A -adrenergic receptor agonist. Guanfacine is not a central nervous system (CNS) stimulant. The mechanism of action of guanfacine in ADHD is not known.
Guanfacine is a selective central alpha2A -adrenergic receptor agonist in that it has a 15 to 20 times higher affinity for this receptor subtype than for the alpha2B or alpha2C subtypes.
Guanfacine is a known antihypertensive agent. By stimulating central alpha2A -adrenergic receptors, guanfacine reduces sympathetic nerve impulses from the vasomotor center to the heart and blood vessels. This results in a decrease in peripheral vascular resistance and a reduction in heart rate.
In a thorough QT study, the administration of two dose levels of immediate-release guanfacine (4 mg and 8 mg) produced concentrations approximately 2 to 4 times the concentrations observed with the maximum recommended dose of guanfacine of 0.12 mg/kg. Guanfacine was not shown to prolong the QTc interval to any clinically relevant extent.
Absorption and Distribution
Guanfacine is readily absorbed and approximately 70% bound to plasma proteins independent of drug concentration. After oral administration of guanfacine extended-release tablets the time to peak plasma concentration is approximately 5 hours in children and adolescents with ADHD.
Immediate-release guanfacine and extended-release guanfacine have different pharmacokinetic characteristics; dose substitution on a milligram per milligram basis will result in differences in exposure.
A comparison across studies suggests that the Cmax is 60% lower and AUC0-∞ 43% lower, respectively, for extended-release guanfacine compared to immediate-release guanfacine. Therefore, the relative bioavailability of extended-release guanfacine to immediate-release guanfacine is 58%. The mean pharmacokinetic parameters in adults following the administration of extended-release guanfacine 1 mg once daily and immediate-release guanfacine 1 mg once daily are summarized in Table 15.
Table 15: Comparison of Pharmacokinetics: Extended-release Guanfacine vs. Immediate release Guanfacine in Adults
Extended-release guanfacine 1 mg once daily
(n = 52)
1 mg once daily
(n = 12)
1 ± 0.3
2.5 ± 0.6
32 ± 9
56 ± 15
6 (4 to 8)
3 (1.5 to 4)
18 ± 4
16 ± 3
Note: Values are mean +/- SD, except for tmax which is median (range)
Figure 1: Comparison of Pharmacokinetics: Extended-release Guanfacine vs. Immediate-release guanfacine in Adults
Exposure to guanfacine was higher in children (ages 6 to 12) compared to adolescents (ages 13 to 17) and adults. After oral administration of multiple doses of guanfacine extended-release tablets 4 mg, the Cmax was 10 ng/mL compared to 7 ng/mL and the AUC was 162 ng.h/mL compared to 116 ng.h/mL in children (ages 6 to 12) and adolescents (ages 13 to 17), respectively. These differences are probably attributable to the lower body weight of children compared to adolescents and adults.
The pharmacokinetics were affected by intake of food when a single dose of guanfacine extended-release tablets 4 mg was administered with a high-fat breakfast. The mean exposure increased (Cmax ~75% and AUC ~40%) compared to dosing in a fasted state.
Following administration of guanfacine extended-release tablets in single doses of 1 mg, 2 mg, 3 mg, and 4 mg to adults, Cmax and AUC0-∞ of guanfacine were proportional to dose.
Metabolism and Elimination
In vitro studies with human liver microsomes and recombinant CYP’s demonstrated that guanfacine was primarily metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5); guanfacine is also not an inducer of CYP3A, CYP1A2 and CYP2B6. Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors.
Guanfacine inhibits MATE1 and OCT1, but does not inhibit BSEP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, or MATE2K. Guanfacine is a substrate of OCT1 and OCT2, but not BCRP, OATP1B1, OATP1B3, OAT1, OAT3, MATE1, or MATE2. Concomitant administration of guanfacine with OCT1 substrates might potentially increase the exposure of these OCT1 substrates.
Studies in Specific Populations
The impact of renal impairment on the pharmacokinetics of guanfacine in children was not assessed. In adult patients with impaired renal function, the cumulative urinary excretion of guanfacine and the renal clearance diminished as renal function decreased. In patients on hemodialysis, the dialysis clearance was about 15% of the total clearance. The low dialysis clearance suggests that the hepatic elimination (metabolism) increases as renal function decreases.
The impact of hepatic impairment on PK of guanfacine in children was not assessed. Guanfacine in adults is cleared both by the liver and the kidney, and approximately 50% of the clearance of guanfacine is hepatic [see Hepatic Impairment (8.7)].
Drug Interaction Studies
Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be affected significantly by CYP3A4 inhibitors or inducers (Figure 2).
Figure 2: Effect of Other Drugs on the Pharmacokinetics (PK) of Guanfacine
Guanfacine does not significantly affect exposures of methylphenidate and lisdexamfetamine when coadministered (Figure 3).
Figure 3: Effect of Guanfacine on the Pharmacokinetics (PK) of Other Drugs
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