The mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. Receptor binding studies have demonstrated that fluvoxamine is a potent serotonin reuptake inhibitor in vitro as well as in vivo. In preclinical studies, it was found that fluvoxamine inhibited neuronal uptake of serotonin.
In in vitro studies fluvoxamine maleate had no significant affinity for histaminergic, alpha or beta adrenergic, muscarinic, or dopaminergic receptors. Antagonism of some of these receptors is thought to be associated with various sedative, cardiovascular, anticholinergic, and extrapyramidal effects of some psychotropic drugs.
The absolute bioavailability of fluvoxamine maleate is 53%. Oral bioavailability is not significantly affected by food.
In a dose proportionality study involving fluvoxamine maleate at 100, 200 and 300 mg/day for 10 consecutive days in 30 normal volunteers, steady state was achieved after about a week of dosing. Maximum plasma concentrations at steady state occurred within 3 to 8 hours of dosing and reached concentrations averaging 88, 283 and 546 ng/mL, respectively. Thus, fluvoxamine had nonlinear pharmacokinetics over this dose range, i.e., higher doses of fluvoxamine maleate produced disproportionately higher concentrations than predicted from the lower dose.
The mean apparent volume of distribution for fluvoxamine is approximately 25 L/kg, suggesting extensive tissue distribution.
Approximately 80% of fluvoxamine is bound to plasma protein, mostly albumin, over a concentration range of 20 to 2000 ng/mL.
Fluvoxamine maleate is extensively metabolized by the liver; the main metabolic routes are oxidative demethylation and deamination. Nine metabolites were identified following a 5 mg radiolabeled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. A third metabolite, fluvoxethanol, formed by oxidative deamination, accounted for about 10%. Fluvoxamine acid and fluvoxethanol were tested in an in vitro assay of serotonin and norepinephrine reuptake inhibition in rats; they were inactive except for a weak effect of the former metabolite on inhibition of serotonin uptake (1 to 2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged (see PRECAUTIONS, Drug Interactions).
Following a 14C-labeled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours.
The mean plasma half-life of fluvoxamine at steady state after multiple oral doses of 100 mg/day in healthy, young volunteers was 15.6 hours.
In a study of fluvoxamine maleate tablets at 50 and 100 mg comparing elderly (ages 66 to 73) and young subjects (ages 19 to 35), mean maximum plasma concentrations in the elderly were 40% higher. The multiple dose elimination half-life of fluvoxamine was 17.4 and 25.9 hours in the elderly compared to 13.6 and 15.6 hours in the young subjects at steady state for 50 and 100 mg doses, respectively.
In elderly patients, the clearance of fluvoxamine was reduced by about 50% and, therefore, fluvoxamine maleate tablets should be slowly titrated during initiation of therapy.
The multiple-dose pharmacokinetics of fluvoxamine were determined in male and female children (ages 6 to 11) and adolescents (ages 12 to 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 T able 1). As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC (0 to 12) and Cmax compared to male children and, therefore, lower doses of fluvoxamine maleate tablets may produce therapeutic benefit (see T able 2). 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 T able 1). Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.
Table 1 Comparison of Mean (SD) fluvoxamine pharmacokinetic parameters between children, adolescents, and adults
| Pharmacokinetic Parameter (body weight corrected) || Dose = 200 mg/day (100 mg b.i.d.) || Dose = 300 mg/day (150 mg b.i.d.) |
| Children (n = 10) || Adolescents (n = 17) || Adolescents (n = 13) || Adults (n = 16) |
| AUC 0 to 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 (11.9) || 2.9 (2.0) || 4.8 (3.8) || 4.6 (3.2) |
Table 2 Comparison of Mean (SD) fluvoxamine pharmacokinetic parameters between male and female children (6 to 11 years)
| Pharmacokinetic Parameter (body weight corrected) || Dose = 200 mg/day (100 mg b.i.d.) |
| Male Children (n = 7) || Female Children (n = 3) |
| AUC 0 to 12 (ng•h/mL/kg) || 95.8 (83.9) || 293.5 (233) |
| 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 vs. patients with hepatic dysfunction) 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 to 45 mL/min) after 4 and 6 weeks of treatment (50 mg b.i.d., N = 13) were comparable to each other, suggesting no accumulation of fluvoxamine in these patients (see PRECAUTIONS, Use in Patients with Concomitant Illness).
Adult OCD Studies
The effectiveness of fluvoxamine maleate tablets for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 10 week multicenter, parallel group studies of adult outpatients. Patients in these trials were titrated to a total daily fluvoxamine maleate dose of 150 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 100 to 300 mg/day (on a b.i.d. schedule), on the basis of response and tolerance. Patients in these studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), total score of 23. Patients receiving fluvoxamine maleate experienced mean reductions of approximately 4 to 5 units on the Y-BOCS total score, compared to a 2 unit reduction for placebo patients.
Table 3 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impressions (CGI) scale for both studies combined.
| OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN POOL OF TWO ADULT OCD STUDIES |
| Outcome Classification || Fluvoxamine (N = 120) || Placebo (N = 134) |
| Very Much Improved || 13% || 2% |
| Much Improved || 30% || 10% |
| Minimally Improved || 22% || 32% |
| No Change || 31% || 51% |
| Worse || 4% || 6% |
Exploratory analyses for age and gender effects on outcomes did not suggest any differential responsiveness on the basis of age or sex.
Pediatric OCD Study
The effectiveness of fluvoxamine maleate tablets for the treatment of OCD was also demonstrated in a 10 week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages 8 to 17). Patients in this study were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 50 to 200 mg/day (on a b.i.d. schedule) on the basis of response and tolerance. All patients had moderate-to-severe OCD (DSM-III-R) with mean baseline ratings on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score of 24. Patients receiving fluvoxamine maleate experienced mean reductions of approximately six units on the CY-BOCS total score, compared to a three-unit reduction for placebo patients.
Table 4 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study.
| OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN PEDIATRIC STUDY |
| Outcome Classification || Fluvoxamine (N = 38) || Placebo (N = 36) |
| Very Much Improved || 21% || 11% |
| Much Improved || 18% || 17% |
| Minimally Improved || 37% || 22% |
| No Change || 16% || 44% |
| Worse || 8% || 6% |
Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender. Further exploratory analyses revealed a prominent treatment effect in the 8 to 11 age group and essentially no effect in the 12 to 17 age group. While the significance of these results is not clear, the 2 to 3 fold higher steady state plasma fluvoxamine concentrations in children compared to adolescents (see Pharmacokinetics) is suggestive that decreased exposure in adolescents may have been a factor, and dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.