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 , 1 4 ).
Contraindications
Guanfacine extended-release tablets are 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 extended-release tablets, its inactive ingredients, or other products containing guanfacine ( 4 ).
Warnings and precautions
Hypotension, bradycardia, syncope: Titrate slowly and monitor vital signs frequently in patients at risk for hypotension, heart block, bradycardia, syncope, cardiovascular disease, vascular disease, cerebrovascular disease or chronic renal failure. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Avoid concomitant use of drugs with additive effects unless clinically indicated.
Advise patients to avoid becoming dehydrated or overheated ( 5.1 ). Sedation and somnolence: Occur commonly with guanfacine extended-release tablets. Consider the potential for additive sedative effects with CNS depressant drugs. Caution patients against operating heavy equipment or driving until they know how they respond to guanfacine extended-release tablets ( 5.2 ). Cardiac Conduction Abnormalities: May worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs.
Titrate slowly and monitor vital signs frequently ( 5.3 ). Rebound Hypertension: Abrupt discontinuation of guanfacine extended-release tablets can lead to clinically significant and persistent rebound hypertension. Subsequent hypertensive encephalopathy was also reported. To minimize the risk of rebound hypertension upon discontinuation, the total daily dose of guanfacine-extended released tablets should be tapered in decrements of no more than 1 mg every 3 to 7 days ( 5.4 ).
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5.1Hypotension, Bradycardia, and Syncope Treatment
with guanfacine extended-release tablets can cause dose-dependent decreases in blood pressure and heart rate. Decreases were less pronounced over time of treatment. Orthostatic hypotension and syncope have been reported [see Adverse Reactions (6.1) ]. Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Titrate guanfacine extended-release tablets slowly in patients with a history of hypotension, and those with underlying conditions that may be worsened by hypotension and bradycardia; e.g., heart block, bradycardia, cardiovascular disease, vascular disease, cerebrovascular disease, or chronic renal failure.
In patients who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration, advise patients to avoid becoming dehydrated or overheated. Monitor blood pressure and heart rate, and adjust dosages accordingly in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope.
5.2Sedation and Somnolence Somnolence
and sedation were commonly reported adverse reactions in clinical studies [see Adverse Reactions (6.1) ]. Before using guanfacine extended-release tablets with other centrally active depressants, consider the potential for additive sedative effects. Caution patients against operating heavy equipment or driving until they know how they respond to treatment with guanfacine extended-release tablets. Advise patients to avoid use with alcohol.
5.3Cardiac Conduction Abnormalities
The sympatholytic action of guanfacine extended-release tablets may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate guanfacine extended-release tablets slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs.
5.4Rebound Hypertension
In post marketing experience, abrupt discontinuation of guanfacine extended-release tablets has resulted in clinically significant and persistent rebound hypertension above baseline levels and increases in heart rate. Hypertensive encephalopathy has also been reported in association with rebound hypertension with both guanfacine extended-release tablets and immediate release guanfacine [see Adverse Reactions ( 6.2 )] .
In these cases, high-dosage guanfacine was discontinued; concomitant stimulant use was also reported, which may potentially increase hypertensive response upon abrupt discontinuation of guanfacine. Children commonly have gastrointestinal illnesses that lead to vomiting, and a resulting inability to take medications, so they may be especially at risk for rebound hypertension. To minimize the risk of rebound hypertension upon discontinuation, the total daily dose of guanfacine extended-release tablets should be tapered in decrements of no more than 1 mg every 3 to 7 days [see Dosage and Administration ( 2.5 )] .
Blood pressure and heart rate should be monitored when reducing the dose or discontinuing guanfacine extended-release tablets. If abrupt discontinuation occurs (especially with concomitant stimulant use), patients should be closely followed for rebound hypertension.
Interactions
Table 14 contains clinically important drug interactions with guanfacine extended-release tablets [see Clinical Pharmacology (12.3) ]. Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Extended-Release Tablets 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 extended-release tablets 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 extended-release tablets dosage up to double the target dosage over 1 to 2 weeks ( 2.7 ).
Pregnancy and breastfeeding
8.1Pregnancy 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.
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 Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 extended-release tablets 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 Extended-Release Tablets (mg) Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of Guanfacine Extended-Release Tablets (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 Extended-Release Tablets and >rate than in placebo) in Fixed Dose Studies 1 and 2 Guanfacine Extended-Release Tablets (mg) Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of Guanfacine Extended-Release Tablets (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 Extended-Release Tablets and >rate than in placebo) in Fixed Dose Studies 1 and 2 Guanfacine Extended-Release Tablets (mg) Adverse Reaction Term Placebo (N=149) 1mg* (N=61) 2mg (N=150) 3mg (N=151) 4mg (N=151) All Doses of Guanfacine Extended-Release Tablets (N=513) Headache 19% 26% 25% 16% 28% 23% Abdominal Pain a 9% 10% 7% 11% 15% 11% Decreased Appetite 4% 5% 4% 9% 6% 6% Irritability 4% 5% 8% 3% 7% 6% Constipation 1% 2% 2% 3% 4% 3% Nightmare b 0% 0% 0% 3% 4% 2% Enuresis c 1% 0% 1% 3% 2% 2% Affect Lability d 1% 2% 1% 3% 1% 2% Adverse reactions ≥2% for all doses of guanfacine extended-release tablets and >rate in placebo in any dose group but did not meet this criteria in all doses combined: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia, sleep disorder), vomiting, diarrhea, abdominal/stomach discomfort (abdominal discomfort, epigastric discomfort, stomach discomfort), rash (rash, rash generalized, rash papular), dyspepsia, increased weight, bradycardia (bradycardia, sinus bradycardia), asthma (asthma, bronchospasm, wheezing), agitation, anxiety (anxiety, nervousness), sinus arrhythmia, blood pressure increased (blood pressure increased, blood pressure diastolic increased), and first degree atrioventricular block. * The lowest dose of 1 mg used in Study 2 was not randomized to patients weighing more than 50 kg. a: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness. b: The nightmare term includes abnormal dreams, nightmare, and sleep terror. c: The enuresis term includes enuresis, nocturia, and urinary incontinence. d: The affect lability term includes affect lability and mood swings.
Monotherapy Flexible Dose Trials Table 6: Percentage of Patients Experiencing Most Common (≥5% and at least twice the rate for placebo) Adverse Reactions in the Monotherapy Flexible Dose Study 4 Guanfacine Extended-Release Tablets Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of Guanfacine Extended-Release Tablets (N=221) Somnolence a 15% 57% 54% 56% Abdominal Pain b 7% 8% 19% 14% Fatigue 3% 10% 11% 11% Irritability 3% 7% 7% 7% Nausea 1% 6% 5% 5% Dizziness 3% 6% 4% 5% Vomiting 2% 7% 4% 5% Hypotension c 0% 6% 4% 5% Decreased Appetite 3% 6% 3% 4% Enuresis d 1% 2% 5% 4% a: The somnolence term includes somnolence, sedation, and hypersomnia. b: The abdominal pain term includes abdominal pain, abdominal pain lower, abdominal pain upper, and abdominal tenderness c: The hypotension term includes hypotension, diastolic hypotension, orthostatic hypotension, blood pressure decreased, blood pressure diastolic decreased, blood pressure systolic decreased. d: The enuresis term includes enuresis, nocturia, and urinary incontinence.
Table 7: Adverse Reactions Leading to Discontinuation (≥2% for all doses of Guanfacine Extended-Release Tablets and >rate than in placebo) in Monotherapy Flexible Dose Study 4 Guanfacine Extended-Release Tablets Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of Guanfacine Extended-Release Tablets (N=221) n (%) n (%) n (%) n (%) Total patients 0 (0%) 8 (7%) 7 (6%) 15 (7%) Somnolence a 0 (0%) 4 (4%) 3 (3%) 7 (3%) Adverse reactions leading to discontinuation in ≥2% in any dose group but did not meet this criteria in all doses combined: fatigue a: The somnolence term includes somnolence, sedation, and hypersomnia.
Table 8: Other Common Adverse Reactions (≥2% for all doses of Guanfacine Extended-Release Tablets and >rate than in placebo) in the Monotherapy Flexible Dose Study 4 Guanfacine Extended-Release Tablets Adverse Reaction Term Placebo (N=112) AM (N=107) PM (N=114) All Doses of Guanfacine Extended-Release Tablets (N=221) Headache 11% 18% 16% 17% Insomnia a 6% 8% 6% 7% Diarrhea 4% 4% 6% 5% Lethargy 0% 4% 3% 3% Constipation 2% 2% 4% 3% Dry Mouth 1% 3% 3% 3% Adverse reactions ≥2% for all doses of guanfacine extended-release tablets and >rate in placebo in any dose group but did not meet this criteria in all doses combined: affect lability (affect lability, mood swings), increased weight, syncope/loss of co
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Composition
Active ingredients
GUANFACINE HYDROCHLORIDE EQ 4MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
