INTUNIV- guanfacine hydrochloride tablet, extended release
Shire US Manufacturing Inc.
INTUNIV® is indicated for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) as monotherapy and as adjunctive therapy to stimulant medications. The efficacy of INTUNIV® was studied for the treatment of ADHD in three controlled monotherapy clinical trials (up to 8 weeks in duration) and one controlled adjunctive trial with psychostimulants (8 weeks in duration) in children and adolescents ages 6-17 who met DSM-IV® criteria for ADHD [see Clinical Studies (14)]. The effectiveness of INTUNIV® for longer-term use (more than 8 weeks) has not been systematically evaluated in controlled trials.
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.
INTUNIV should be taken once daily, either in the morning or evening, at approximately same time each day. Begin at a dose of 1 mg/day, and adjust in increments of no more than 1 mg/week. Maintain the dose within the range of 1 mg to 4 mg once daily, depending on clinical response and tolerability, for both monotherapy and adjunctive therapy to a psychostimulant. Doses above 4 mg/day have not been systematically studied in controlled clinical studies [see Clinical Studies (14.1)].
Clinically relevant improvements were observed beginning at doses in the range 0.05-0.08 mg/kg once daily in both mono- and adjunctive therapy. Efficacy increased with increasing weight-adjusted dose (mg/kg). If well tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit.
In clinical trials, there were dose-related and exposure-related risks for several clinically significant adverse reactions (hypotension, bradycardia, sedative events). Thus, consideration should be given to dosing INTUNIV® on a mg/kg basis, in order to balance the exposure-related potential benefits and risks of treatment.
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 a delayed Tmax , reduced Cmax and lower bioavailability compared to those of the same dose of immediate-release guanfacine [see Clinical Pharmacology (12.3)].
It is generally agreed that pharmacological treatment of ADHD may be needed for an extended period. The effectiveness of INTUNIV® for longer-term use (more than 9 weeks) has not been systematically evaluated in controlled trials. Therefore the physician electing to use INTUNIV® for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
Infrequent, transient elevations in blood pressure above original baseline (i.e., rebound) have been reported to occur upon abrupt discontinuation of guanfacine. To minimize these effects, the dose should generally be tapered in decrements of no more than 1 mg every 3 to 7 days.
When reinitiating patients to the previous maintenance dose after two or more missed consecutive doses, physicians should consider titration based on patient tolerability.
Dosage adjustments for INTUNIV® are recommended with concomitant use of strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole), or CYP3A4 inducers (e.g., avasimibe, carbamazepine, phenytoin, rifampin, and St.John’s wort) (Table 1) [ see Drug Interactions (7)].
Table 1: Dose Adjustments in Patients Taking Concomitant CYP3A4 Inhibitors or Inducers
Initiate INTUNIV® when taking comedications
|Continue INTUNIV® when adding a comedication||Stop a comedication when continuing INTUNIV®|
|Strong CYP3A4 Inhibitors||INTUNIV® dose should be limited to 2 mg/day||INTUNIV® dose should be decreased by half.||INTUNIV® dose should be doubled based on patient tolerability. The maximum dose should not exceed 4 mg/day|
|Strong CYP3A4 Inducers||INTUNIV® dose may be titrated up to 8 mg/day. Consider faster titration (e.g. in increments of 2 mg/week)||Consider increase INTUNIV® dose gradually in 1-2 weeks to 2 fold of the original dose based on patienttolerability.||INTUNIV® dose should be decreased by half in 1-2 weeks based on patient tolerability. The maximum dose should not exceed 4 mg/day|
1 mg, 2 mg, 3 mg and 4 mg extended-release tablets
Patients with a history of hypersensitivity to INTUNIV® , its inactive ingredients [see Description (11)] or other products containing guanfacine should not take INTUNIV®.
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. Use INTUNIV® with caution in patients with a history of hypotension, heart block, bradycardia, cardiovascular disease, or who have a history of syncope or may have a condition that predisposes them to syncope, such as hypotension, orthostatic hypotension, bradycardia, or dehydration. Use INTUNIV® with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Advise patients to avoid becoming dehydrated or overheated.
Somnolence and sedation were commonly reported adverse reactions in clinical studies [see Adverse Reactions (6.1)]. Before using INTUNIV® with other centrally active depressants (such as phenothiazines, barbiturates, or benzodiazepines), 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.