iation of therapy (see DOSAGE AND ADMINISTRATION [2.3]).
Pediatric Subjects: The pharmacokinetics of LUVOX CR Capsules have not been eva luated in pediatric patients. However, the multiple-dose pharmacokinetics of fluvoxamine were determined in male and female children (ages 6-11) and adolescents (ages 12-17). Steady-state plasma fluvoxamine concentrations were 2- to 3-fold higher in children than in adolescents. AUC and Cmax in children were 1.5- to 2.7-fold higher than that in adolescents (see Table 4). As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC (0-12) and Cmax compared to male children and, therefore, lower doses of immediate-release fluvoxamine maleate tablets may produce therapeutic benefit (see Table 5). No gender differences were observed in adolescents. Steady-state plasma fluvoxamine concentrations were similar in adults and adolescents at a dose of 300 mg/day, indicating that fluvoxamine exposure was similar in these two populations (see Table 4). Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.
TABLE 4 COMPARISON OF MEAN (SD) IMMEDIATE-RELEASE TABLET FLUVOXAMINE MALEATE PHARMACOKINETIC PARAMETERS BETWEEN CHILDREN, ADOLESCENTS, AND ADULTS Pharmacokinetic Parameter
(body weight corrected)
Dose = 200 mg/day
(100 mg Twice Daily)
Dose = 300 mg/day
(150 mg Twice Daily)
Children
(n = 10)
Adolescent
(n = 17)
Adolescent
(n= 13)
Adult
(n = 16)
AUC 0-12 (ng•h/mL/kg)
155.1 (160.9)
43.9 (27.9)
69.6 (46.6)
59.4 (40.9)
Cmax (ng/mL/kg)
14.8 (14.9)
4.2 (2.6)
6.7 (4.2)
5.7 (3.9)
Cmin (ng/mL/kg)
11.0 (11.9)
2.9 (2.0)
4.8 (3.8)
4.6 (3.2)
TABLE 5 COMPARISON OF MEAN (SD) IMMEDIATE-RELEASE TABLET FLUVOXAMINE MALEATE PHARMACOKINETIC PARAMETERS BETWEEN MALE AND FEMALE CHILDREN (6-11 YEARS) Pharmacokinetic Parameter
(body weight corrected)
Dose = 200 mg/day (100 mg Twice Daily)
Male Children
(n = 7)
Female Children
(n = 3)
AUC 0-12 (ng•h/mL/kg)
95.8 (83.9)
293.5 (233.0)
Cmax (ng/mL/kg)
9.1 (7.6)
28.1 (21.1)
Cmin (ng/mL/kg)
6.6 (6.1)
21.2 (17.6)
Hepatic and Renal Disease: A cross-study comparison (healthy subjects versus patients with hepatic dysfunction) using immediate-release fluvoxamine maleate tablets suggested a 30% decrease in fluvoxamine clearance in association with hepatic dysfunction. The mean minimum plasma concentrations in renally impaired patients (creatinine clearance of 5 mL/min to 45 mL/min) after 4 weeks and 6 weeks of treatment (50 mg given twice daily, N = 13) were comparable to each other, suggesting no accumulation of fluvoxamine in these patients (see WARNINGS AND PRECAUTIONS-Use in Patients with Concomitant Illness [5.15]).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: There was no evidence of carcinogenicity in rats treated orally with fluvoxamine maleate for 30 months or hamsters treated orally with fluvoxamine maleate for 20 months (females) or 26 months (males). The daily doses in the high-dose groups in these studies |
