y metabolized by CYP3A4. In pooled human hepatic microsomes, guanfacine did not inhibit the activities of the major cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5). Guanfacine is a substrate of CYP3A4/5 and exposure is affected by CYP3A4/5 inducers/inhibitors.
Renal and Hepatic Impairment
The impact of renal impairment on PK of guanfacine in children was not assessed . [] SEE USE IN SPECIFIC POPULATIONS (8.6)
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis No carcinogenic effect of guanfacine was observed in studies of 78 weeks in mice or 102 weeks in rats at doses up to 6-7 times the maximum recommended human dose of 4 mg/day on a mg/ m basis.
2
Mutagenesis Guanfacine was not genotoxic in a variety of test models, including the Ames test and an chromosomal aberration test; however, a marginal increase in numerical aberrations (polyploidy) was observed in the latter study.
in vitro
Impairment of Fertility No adverse effects were observed in fertility studies in male and female rats at doses up to 30 times the maximum recommended human dose on a mg/ m basis.
2
14 CLINICAL STUDIES
14.1 Safety and Efficacy Studies
The efficacy of INTUNIV in the treatment of ADHD was established in 3 placebo-controlled monotherapy trials (Studies 1, 2, and 4) and in 1 placebo-controlled adjunctive trial with psychostimulants (Study 3) in pediatric population. Studies 1, 2, and 3 were conducted in children and adolescents ages 6-17 and Study 4 was conducted in children ages 6-12 years. ®
Studies 1 and 2: Fixed-dose INTUNIV Monotherapy ®
Study 1 was a double-blind, placebo-controlled, parallel-group, fixed dose study, in which efficacy of once daily dosing with INTUNIV (2 mg, 3 mg and 4 mg) was eva luated for 5 weeks (n=345). Study 2 was a double-blind, placebo-controlled, parallel-group, fixed-dose study, in which efficacy of once daily dosing with INTUNIV (1 mg, 2 mg, 3 mg and 4 mg) was eva luated for 6 weeks (n=324). In both studies, randomized subjects in 2 mg, 3 mg and 4 mg dose groups were titrated to their target fixed dose, and continued on the same dose until a dose tapering phase started The lowest dose of 1 mg used in Study 2 was assigned only to patients less than 50 kg (110 lbs). Patients who weighed less than 25 kg (55 lbs) were not included in either study. ®®
Signs and symptoms of ADHD were eva luated on a once weekly basis using the clinician administered and scored ADHD Rating Scale (ADHD-RS-IV), which includes both hyperactive/impulsive and inattentive subscales. The primary efficacy outcome was the change from baseline to endpoint in ADHD-RS-IV total scores. Endpoint was defined as the last post-randomization treatment week for which a valid score was obtained prior to dose tapering (up to Week 5 in Study 1 and up to Week 6 in Study 2).
The mean reductions in ADHD-RS-IV total scores at endpoint were statistically significantly greater for INTUNIV compared to placebo for Studies 1 and 2. Placebo-adjusted changes from baseline were statistically significant for each of the 2 mg, 3 mg, and 4 mg INTUNIV randomized treatment groups in both studies, as well as the 1 mg INTUNIV treatment group (for patients 55-110 lbs) that was included only in Study 2 (see Table 6).
Dose-responsive efficacy was evident, particularly when data were examined on a weight-adjusted (mg/kg) basis. When eva luated over the dose range of 0.01-0.17 mg/kg/day, clinically rel |
