RECENT MAJOR CHANGES

Indications and Usage (1), 02/2011

Dosage and Administration, Dose Selection (2.2), 02/2011

Warnings and Precautions, Hypotension, Bradycardia, and Syncope (5.1), 02/2011

Warnings and Precautions, Sedation and Somnolence (5.2), 02/2011

INDICATIONS AND USAGE

INTUNIV® is a selective alpha2A-adrenergic receptor agonist indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications. The efficacy of INTUNIV® is based on results of two 8 to 9 week monotherapy studies and one 9 week adjunctive study in combination with psychostimulants in children and adolescents (14.1). Maintenance treatment has not been systematically eva luated, and patients who are continued on longer-term treatment require periodic reassessment (1).

DOSAGE AND ADMINISTRATION

For all patients (2.1):

• Dose once daily.
• Tablets should not be crushed, chewed or broken before swallowing.
• Do not administer with high-fat meals, because of increased exposure.
• Do not substitute for immediate-release guanfacine tablets on a mg-per-mg basis, because of differing pharmacokinetic profiles.

Dose selection (2.2):

• If switching from immediate-release guanfacine, discontinue that treatment and titrate with INTUNIV® as directed.
• Begin at a dose of 1 mg once daily and adjust in increments of no more than 1 mg/week.
• Maintain the dose within the range of 1 mg to 4 mg per day, depending on clinical response and tolerability.
• Consider dosing on a mg/kg basis. Improvements observed starting at doses of 0.05-0.08 mg/kg once daily. Doses up to 0.12 mg/kg once daily may provide additional benefit.
• Doses above 4 mg/day have not been studied.

Discontinuation (2.4):

• When discontinuing, taper the dose in decrements of no more than 1 mg every 3 to 7 days.

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 (e.g. TENEX®) (4).

WARNINGS AND PRECAUTIONS

• Hypotension, bradycardia, and syncope: Use INTUNIV® with caution in patients at risk for hypotension, bradycardia, heart block, or syncope (e.g., those taking antihypertensives). Measure heart rate and blood pressure prior to initiation of therapy, following dose increases, and periodically while on therapy. Advise patients to avoid becoming dehydrated or overheated (5.1).
• 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).
• Other guanfacine-containing products: Do not use INTUNIV® concomitantly with other products containing guanfacine (e.g., Tenex) (5.3).

ADVERSE REACTIONS

Most common adverse reactions (≥5% and at least twice placebo rate) in the monotherapy trials: somnolence, fatigue, nausea, lethargy, and hypertension (6). Most common adverse reactions (≥5% and at least twice placebo rate) in the adjunctive trial: somnolence, fatigue, insomnia, dizziness, and abdominal pain (6).

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.

DRUG INTERACTIONS

• CYP3A4/5 inhibitors (e.g., ketoconazole): Coadministration may increase rate and extent of guanfacine exposure. Use concomitantly with caution. (7.1).
• CYP3A4 inducers (e.g., rifampin): Coadministration may decrease rate and extent of guanfacine exposure. Consider dose increase of INTUNIV® (7.2).
• Valproic acid: Coadministration may increase serum valproic acid concentrations (7.3).
• Antihypertensive drugs: Use caution when coadministered with INTUNIV® (5.1, 7.4).
• CNS depressants: Use caution when coadministered with INTUNIV® (5.2, 7.5).

USE IN SPECIFIC POPULATIONS

Hepatic or Renal Impairment: dose reduction may be required in patients with clinically significant impairment of hepatic or renal function (8.6).