HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use INTUNIV ® safely and effectively. See full prescribing information for INTUNIV ®.
INTUNIV ® (guanfacine) extended-release tablets, for oral use
Initial U.S. Approval: 1986
RECENT MAJOR CHANGES
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Dosage and Administration (2.5) |
03/2016 |
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Warnings and Precautions (5.4) |
03/2016 |
INDICATIONS AND USAGE
INTUNIV® is a central alpha2A-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
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Recommended dose: 1 mg to 7 mg (0.05-0.12 mg/kg target weight based dose range) once daily in the morning or evening based on clinical response and tolerability (2.2).
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Begin at a dose of 1 mg once daily and adjust in increments of no more than 1 mg/week (2.2).
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Do not crush, chew or break tablets before swallowing (2.1).
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Do not administer with high-fat meals, because of increased exposure (2.1).
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Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles (2.3).
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If switching from immediate-release guanfacine, discontinue that treatment and titrate with INTUNIV® as directed (2.3).
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When discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension (2.5).
DOSAGE FORMS AND STRENGTHS
Extended-release tablets: 1 mg, 2 mg, 3 mg and 4 mg ( 3)
CONTRAINDICATIONS
History of hypersensitivity to INTUNIV ®, its inactive ingredients, or other products containing guanfacine ( 4).
WARNINGS AND PRECAUTIONS
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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).
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Sedation and somnolence: Occur commonly with INTUNIV®. 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 INTUNIV® (5.2).
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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).
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Blood Pressure and Heart Rate Increase upon Discontinuation: Hypertensive encephalopathy has been very rarely reported upon abrupt discontinuation. To minimize the risk of an increase in blood pressure upon discontinuation, the total daily dose of INTUNIV® should be tapered in decrements of no more than 1 mg every 3 to 7 days (5.4).
ADVERSE REACTIONS
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 Shire US Inc. at 1-800-828-2088 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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Strong CYP3A4 inhibitors increase guanfacine exposure. Decrease INTUNIV® to 50% of target dosage when coadministered with strong CYP3A4 inhibitors (2.7).
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Strong CYP3A4 inducers decrease guanfacine exposure. Based on patient response, consider titrating INTUNIV 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.
Revised: 3/2016
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
INTUNIV® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
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 INTUNIV 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 INTUNIV® is 0.05-0.12 mg/kg/day (total daily dose between 1-7 mg) (See Table 1).
In the adjunctive trial which eva luated INTUNIV® treatment with psychostimulants, the majority of patients reached optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been studied in adjunctive trials.
2.3 Switching from Immediate-Release Guanfacine to INTUNIV®
If switching from immediate-release guanfacine, discontinue that treatment, and titrate with INTUNIV® following above recommended schedule.
Do not substitute for immediate-release guanfacine tablets on a milligram-per-milligram basis, because of differing pharmacokinetic profiles. INTUNIV® has significantly reduced Cmax (60% lower), bioavailability (43% lower), and a delayed Tmax (3 hours later) compared to those of the same dose of immediate-release guanfacine [see Clinical Pharmacology (12.3)].
2.4 Maintenance Treatment
Pharmacological treatment of ADHD may be needed for extended periods. Healthcare providers should periodically re-eva luate the long-term use of INTUNIV®, and adjust weight-based dosage as needed. The majority of children and adolescents reach optimal doses in the 0.05-0.12 mg/kg/day range. Doses above 4 mg/day have not been eva luated in children (ages 6-12 years) and above 7 mg/day have not been eva luated in adolescents (ages 13-17 years) [see Clinical Studies (14)].
2.5 Discontinuation of Treatment
Following discontinuation of INTUNIV®, patients may experience increases in blood pressure and heart rate [see Warnings and Precautions (5.4) and Adverse Reactions (6)]. Patients/caregivers should be instructed not to discontinue INTUNIV® without consulting their health care provider. Monitor blood pressure and pulse when reducing the dose or discontinuing the drug. Taper the daily dose in decrements of no more than 1 mg every 3 to 7 days to avoid rebound hypertension.
2.6 Missed Doses
When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, consider titration based on patient tolerability.
2.7 Dosage Adjustment with Concomitant Use of Strong CYP3A4 Inhibitors or Inducers
Dosage adjustments for INTUNIV® are recommended with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole), or CYP3A4 inducers (e.g., carbamazepine) (Table 2) [see Drug Interactions (7)].
3 DOSAGE FORMS AND STRENGTHS
1 mg, 2 mg, 3 mg and 4 mg extended-release tablets
4 CONTRAINDICATIONS
INTUNIV is contraindicated in patients with a history of a hypersensitivity reaction to INTUNIV or its inactive ingredients, or other products containing guanfacine. Rash and pruritus have been reported.
5 WARNINGS AND PRECAUTIONS
5.1 Hypotension, Bradycardia, and Syncope
Treatment with INTUNIV® 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 INTUNIV 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.
5.2 Sedation and Somnolence
Somnolence and sedation were commonly reported adverse reactions in clinical studies [see Adverse Reactions (6.1)]. Before using INTUNIV® 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 INTUNIV®. Advise patients to avoid use with alcohol.
5.3 Cardiac Conduction Abnormalities
The sympatholytic action of INTUNIV® may worsen sinus node dysfunction and atrioventricular (AV) block, especially in patients taking other sympatholytic drugs. Titrate INTUNIV slowly and monitor vital signs frequently in patients with cardiac conduction abnormalities or patients concomitantly treated with other sympatholytic drugs.
5.4 Blood Pressure and Heart Rate Increase upon Discontinuation
Blood pressure and pulse may increase following discontinuation of INTUNIV®. In postmarketing experience, hypertensive encephalopathy has been very rarely reported upon abrupt discontinuation of INTUNIV® [see Adverse Reactions (6.2)]. To minimize the risk of an increase in blood pressure upon discontinuation, the total daily dose of INTUNIV® 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 pulse should be monitored when reducing the dose or discontinuing INTUNIV®.
6 ADVERSE REACTIONS
The following serious adverse reactions are described elsewhere in the labeling:
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 INTUNIV® 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.
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