Guanfacine

FDA Drug Information • Also known as: Guanfacine, Guanfacine Extended-Release, Guanfacine Hydrochloride, Intuniv

Brand Names: Guanfacine, Guanfacine Extended-Release, Guanfacine Hydrochloride, Intuniv
Drug Class: Central alpha-2 Adrenergic Agonist [EPC]
Route: ORAL
Dosage Form: TABLET, EXTENDED RELEASE
Product Type: HUMAN PRESCRIPTION DRUG

Description

11 DESCRIPTION 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 C 9 H 9 Cl 2 N 3 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. Meets USP dissolution test 3

What Is Guanfacine Used For?

1 INDICATIONS AND USAGE Guanfacine extended-release tablets are indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies (14)] . Guanfacine extended-release tablets are a central alpha 2A -adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications (1, 14).

Dosage and Administration

2 DOSAGE AND ADMINISTRATION Recommended dose: 1 mg to 7 mg (0.05 to 0.12 mg/kg target weight based dose range) once daily in the morning or evening based on clinical response and tolerability (2.2). Begin at a dose of 1 mg once daily and adjust in increments of no more than 1 mg/week (2.2). Do not crush, chew or break tablets before swallowing (2.1). Do not administer with high-fat meals, because of increased exposure (2.1). Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles (2.3). If switching from immediate-release guanfacine, discontinue that treatment and titrate with guanfacine extended-release tablets as directed (2.3). When discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension (2.5). 2.1 General Instruction for Use Swallow tablets whole. Do not crush, chew, or break tablets because this will increase the rate of guanfacine release. Do not administer with high fat meals, due to increased exposure. 2.2 Dose Selection Take guanfacine extended-release tablets orally once daily, either in the morning or evening, at approximately the same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. In monotherapy clinical trials, there was dose- and exposure-related clinical improvement as well as risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). To balance the exposure-related potential benefits and risks, the recommended target dose range depending on clinical response and tolerability for guanfacine extended-release tablets is 0.05 to 0.12 mg/kg/day (total daily dose between 1 to 7 mg) (See Table 1). Table 1: Recommended Target Dose Range for Therapy with guanfacine extended-release tablets Weight Target dose range (0.05 to 0.12 mg/kg/day) 25 to 33.9 kg 2 to 3 mg/day 34 to 41.4 kg 2 to 4 mg/day 41.5 to 49.4 kg 3 to 5 mg/day 49.5 to 58.4 kg 3 to 6 mg/day 58.5 to 91 kg 4 to 7 mg/day >91 kg 5 to 7 mg/day Doses above 4 mg/day have not been evaluated in children (ages 6 to 12 years) and doses above 7 mg/day have not been evaluated in adolescents (ages 13 to 17 years) In the adjunctive trial which evaluated guanfacine extended-release tablets treatment with psychostimulants, the majority of patients reached optimal doses in the 0.05 to 0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in adjunctive trials. 2.3 Switching from Immediate-Release Guanfacine to Guanfacine Extended-Release Tablets If switching from immediate-release guanfacine, discontinue that treatment, and titrate with guanfacine extended-release tablets following above recommended schedule. Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. Guanfacine extended-release tablets has significantly reduced C max (60% lower), bioavailability (43% lower), and a...

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Hypotension, bradycardia, and syncope [see Warnings and Precautions (5.1)] Sedation and somnolence [see Warnings and Precautions (5.2)] Cardiac conduction abnormalities [see Warnings and Precautions (5.3)] Rebound Hypertension [see Warnings and Precautions (5.4)] Most common adverse reactions (≥ 5% and at least twice placebo rate) in fixed-dose monotherapy ADHD trials in children and adolescents (6 to 17 years): hypotension, somnolence, fatigue, nausea, and lethargy (6.1). Flexible dose-optimization ADHD trials in children (6 to 12 years) and adolescents (13 to 17 years): somnolence, hypotension, abdominal pain, insomnia, fatigue, dizziness, dry mouth, irritability, nausea, vomiting, and bradycardia (6.1). Adjunctive treatment to psychostimulant ADHD trial in children and adolescents (6 to 17 years): somnolence, fatigue, insomnia, dizziness, and abdominal pain (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect clinical trial exposure to guanfacine in 2,825 patients. This includes 2,330 patients from completed studies in children and adolescents, ages 6 to 17 years and 495 patients in completed studies in adult healthy volunteers. The mean duration of exposure of 446 patients that previously participated in two 2-year, open-label long-term studies was approximately 10 months. Fixed Dose Trials Table 3: Percentage of Patients Experiencing Most Common (≥ 5% and at least twice the rate for placebo) Adverse Reactions in Fixed Dose Studies 1 and 2 GUANFACINE (mg) Adverse Reaction Term Placebo (N = 149) 1 mg* (N = 61) 2 mg (N = 150) 3 mg (N = 151) 4 mg (N = 151) All Doses of Guanfacine (N = 513) Somnolence a 11% 28% 30% 38% 51% 38% Fatigue 3% 10% 13% 17% 15% 14% Hypotension b 3% 8% 5% 7% 8% 7% Dizziness 4% 5% 3% 7% 10% 6% Lethargy 3% 2% 3% 8% 7% 6% Nausea 2% 7% 5% 5% 6% 6% Dry mouth 1% 0% 1% 6% 7% 4% *The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased). Table 4: Adverse Reactions Leading to Discontinuation (≥ 2% for all doses of Guanfacine and > rate than in placebo) in Fixed Dose Studies 1 and 2 GUANFACINE (mg) Adverse Reaction Term Placebo (N = 149) 1 mg* (N = 61) 2 mg (N = 150) 3 mg (N = 151) 4 mg (N = 151) All Doses of Guanfacine (N = 513) n (%) n (%) n (%) n (%) n (%) n (%) Total patients 4 (3%) 2 (3%) 10 (7%) 15 (10%) 27 (18%) 54 (11%) Somnolence a 1 (1%) 2 (3%) 5 (3%) 6 (4%) 17 (11%) 30 (6%) Fatigue 0 (0%) 0 (0%) 2 (1%) 2 (1%) 4 (3%) 8 (2%) Adverse reactions leading to discontinuation in ≥ 2% in any dose group but did not meet this criteria in all doses combined: hypotension (hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased), headache, and dizziness. * The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The somnolence term includes somnolence, sedation, and hypersomnia. Table 5: Other Common Adverse Reactions (≥ 2% for all doses of Guanfacine and > rate than in placebo) in Fixed Dose Studies 1 and 2 GUANFACINE(mg) Adverse Reaction Term Placebo (N = 149) 1 mg* (N = 61) 2 mg (N = 150) 3 mg (N = 151) 4 mg (N = 151) All Doses of Guanfacine (N = 513)...

Drug Interactions

7 DRUG INTERACTIONS Table 14 contains clinically important drug interactions with guanfacine [see Clinical Pharmacology (12.3)] . Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and administration (2.7)] Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure Consider dose increase [see Dosage and administration (2.7)] Strong and moderate CYP3A4 inhibitors increase guanfacine exposure. Decrease guanfacine to 50% of target dosage when coadministered with strong and moderate CYP3A4 inhibitors (2.7). Strong and moderate CYP3A4 inducers decrease guanfacine exposure. Based on patient response, consider titrating guanfacine dosage up to double the target dosage over 1 to 2 weeks (2.7). See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Contraindications

4 CONTRAINDICATIONS Guanfacine is contraindicated in patients with a history of a hypersensitivity reaction to guanfacine extended-release tablets or its inactive ingredients, or other products containing guanfacine. Rash and pruritus have been reported. History of hypersensitivity to guanfacine, its inactive ingredients, or other products containing guanfacine (4).

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ADHD medications, including guanfacine extended-release tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for ADHD Medications at 1-866-961-2388. Risk Summary Available data with guanfacine over decades of use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. However, use of guanfacine in pregnant women over this time has been infrequent. In animal reproduction studies, rabbits and rats exposed to 3 and 4 times the maximum recommended human dose (MRHD), respectively, showed no adverse outcomes. However, higher doses were associated with reduced fetal survival and maternal toxicity ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Reproduction studies conducted in rats have shown that guanfacine crosses the placenta. However, administration of guanfacine to rabbits and rats during organogenesis at 3 (rabbit) and 4 (rat) times the MRHD of 0.12 mg/kg/day on a mg/m 2 basis resulted in no evidence of harm to the fetus. Higher doses (13.5 times the MRHD in both rabbits and rats) were associated with reduced fetal survival and maternal toxicity.

Overdosage

10 OVERDOSAGE Symptoms 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. Treatment 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Guanfacine extended-release tablets 1 mg are white to off-white, round shaped tablets with “RJ70” debossed on one side and plain on the other side. NDC 63629-1102-1 Bottles of 100 Storage - Store at 20° - 25° C (68° - 77° F) [See USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.