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Luvox

CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism of action of fluvoxamine maleate (fluvoxamine maleate) in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitro and in vivo.

Pharmacodynamics

In in vitro studies, fluvoxamine maleate (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.

Pharmacokinetics

Absorption: The absolute bioavailability of fluvoxamine maleate (fluvoxamine maleate) is 53%. Oral bioavailability is not significantly affected by food.

In a dose proportionality study involving fluvoxamine maleate (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 3-8 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 (fluvoxamine maleate) produced disproportionately higher concentrations than predicted from the lower dose.

Distribution: 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.

Metabolism: Fluvoxamine maleate (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 radiolabelled 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 (1-2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged. (See DRUG INTERACTIONS)

Elimination: Following a 14C-labelled oral dose of fluvoxamine maleate (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.

Elderly Subjects: In a study of Fluvoxamine Maleate (fluvoxamine maleate) Tablets at 50 and 100 mg comparing elderly (ages 66-73) and young subjects (ages 19-35), 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 (fluvoxamine maleate) Tablets should be slowly titrated during initiation of therapy. (See DOSAGE AND ADMINISTRATION)

Pediatric Subjects: 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 2-3 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 Fluvoxamine Maleate (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. (See DOSAGE AND ADMINISTRATION)

TABLE 4: 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)
Adolescent
(N=17)
Adolescent
(N=13)
Adult
(N=16)
AUC0-12 (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) FLUVOXAMINE PHARMACOKINETIC PARAMETERS BETWEEN MALE AND FEMALE CHILDREN (6-11 YEARS)

Pharmacokinetic Parameter
(body weight corrected)
Dose = 200 mg/day
(100 mg b.i.d.)
Male Children
(N=7)
Female Children
(N=3)
AUC0-12 (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) 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 WARNINGS AND PRECAUTIONS - Use in Patients with Concomitant Illness)

Clinical Studies

Adult OCD Studies

The effectiveness of Fluvoxamine Maleate (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 (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 100-300 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 (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 6 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impressions (CGI) scale for both studies combined.

TABLE 6: 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.

Adult OCD Maintenance Study

In a maintenance trial of adult outpatients with OCD, 114 patients meeting DSM-IV criteria for OCD and with a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score ≥ 18 were titrated to an effective dose of Fiuvoxamine Maleate Tablets 100 to 300 mg/day as part of an initial 10-week single-blind treatment phase. Treatment response during this single-blind phase was defined as Y-BOCS scores at least 30% lower than baseline at the end of weeks 8 and 10. Of the patients who responded, their average duration of response was 4 weeks. Patients who responded during this initial phase were randomized either to continuation of Fiuvoxamine Maleate Tablets (N=56) or to placebo (N=58) in a double-blind phase for observation of relapse. Relapse during the double-blind phase was defined as an increase in the Y-BOCS score of at least 30% over the baseline for that phase or patient refusal to continue treatment due to a substantial increase in OCD symptoms. In the double-blind phase, patients receiving continued Fiuvoxamine Maleate Tablets treatment experienced, on average, a significantly lower relapse rate than those receiving placebo.

An examination of population subgroups from this trial did not reveal any clear evidence of a differential maintenance effect on the basis of age or gender.

Pediatric OCD Study

The effectiveness of Fiuvoxamine 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 8-17). 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 50-200 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 (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 7 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study.

TABLE 7: 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 8-11 age group and essentially no effect in the 12-17 age group. While the significance of these results is not clear, the 2-3 fold higher steady-state plasma fluvoxamine concentrations in children compared to adolescents (see CLINICAL PHARMACOLOGY - Pediatric Subjects) 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.

Last reviewed on RxList: 5/9/2011
This monograph has been modified to include the generic and brand name in many instances.

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