Luvox CR (Fluvoxamine Maleate) - Description and Clinical Pharmacology

DESCRIPTION

     LUVOX CR is an extended-release capsule for oral administration that contains fluvoxamine maleate, a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the chemical series, the 2-aminoethyl oxime ethers of aralkylketones.

     Fluvoxamine maleate is chemically designated as 5-methoxy-4'-(trifluoromethyl) valerophenone-(E)-O-(2-aminoethyl)oxime maleate (1:1) and has the empirical formula C₁₅H₂₁O₂N₂F₃•C₄H₄O₄. Its molecular weight is 434.41.

     The structural formula is:

     Fluvoxamine maleate is a white to off-white, odorless, crystalline powder that is sparingly soluble in water, freely soluble in ethanol and chloroform, and practically insoluble in diethyl ether.

     LUVOX CR Capsules are available in 100 mg and 150 mg strengths for oral administration. In addition to the active ingredient, fluvoxamine maleate, each capsule contains the following inactive ingredients: talc, sugar spheres, ammonio methacrylate copolymer type B, dibutyl sebacate, red iron oxide, FD&C Blue No. 2, titanium dioxide, gelatin (porcine- or bovine-derived), and Opacode Grey. LUVOX CR Capsules are gluten-free.

CLINICAL PHARMACOLOGY

Mechanism of Action

     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. 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 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

      Bioavailability: A single-dose crossover study in 28 healthy subjects was conducted to compare the pharmacokinetics of fluvoxamine after administration of LUVOX CR Capsules and immediate-release fluvoxamine maleate tablets.

     In the single-dose crossover study, mean C_max was 38% lower and relative bioavailability was 84% for LUVOX CR Capsules versus immediate-release fluvoxamine maleate tablets.

     In a multiple-dose proportionality study, LUVOX CR Capsules were administered over a dose range of 100 mg/day to 300 mg/day to 20 healthy volunteers. Steady-state plasma concentrations were achieved within a week of dosing. Mean maximum plasma concentrations were 47 ng/mL, 161 ng/mL, and 319 ng/mL, respectively, at the 100 mg, 200 mg, and 300 mg administered dose levels. Fluvoxamine exhibited nonlinear pharmacokinetics producing disproportionately higher concentrations over the dose range. The AUC and C_max values increased 5.7-fold following the 3-fold increase in dose from 100 mg to 300 mg.

     Food caused the mean AUC and C_max of fluvoxamine to increase only slightly; therefore, administration of LUVOX CR Capsules with food does not significantly affect the absorption of fluvoxamine.

      Distribution/Protein Binding: 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 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 [ 7 ]).

      Elimination: Following a ¹⁴C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours.

     After administration of a 100 mg, single oral dose of LUVOX CR Capsules, the mean plasma half-life of fluvoxamine in healthy male and female volunteers was 16.3 hours.

      Gender: In a study with 15 male and 13 female healthy volunteers who were administered LUVOX CR Capsules 100 mg, AUC and C_max of fluvoxamine were increased by approximately 60% in females compared to males. There were no differences in the elimination half-life between males and females.

      Elderly Subjects: In a study using immediate-release fluvoxamine maleate tablets at 50 mg and 100 mg and comparing elderly (ages 66-73 years) and young subjects (ages 19-35 years), mean maximum plasma concentrations in the elderly were 40% higher. The multiple-dose elimination half-life of fluvoxamine was 17.4 hours and 25.9 hours in the elderly compared to 13.6 hours and 15.6 hours in the young subjects at steady state for 50 mg and 100 mg doses, respectively.

     In elderly patients administered immediate-release fluvoxamine maleate tablets, the clearance of fluvoxamine was reduced by about 50%; therefore, LUVOX CR Capsules should be slowly titrated during initiation of therapy (see DOSAGE AND ADMINISTRATION [ 2.3 ]).

      Pediatric Subjects: The pharmacokinetics of LUVOX CR Capsules have not been evaluated 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 C_max 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 C_max 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 ]).

NONCLINICAL TOXICOLOGY

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 were increased over the course of the study from a minimum of 160 mg/kg to a maximum of 240 mg/kg in rats, and from a minimum of 135 mg/kg to a maximum of 240 mg/kg in hamsters. The maximum dose of 240 mg/kg is approximately 6 times the maximum recommended human dose (MRHD) on a mg/m² basis.

      Mutagenesis: No evidence of genotoxic potential was observed in a mouse micronucleus test, an in vitro chromosome aberration test, or the Ames microbial mutagen test with or without metabolic activation.

      Impairment of Fertility: In a study in which male and female rats were administered fluvoxamine (60, 120, or 240 mg/kg) orally prior to and during mating and gestation, fertility was impaired at doses of 120 mg/kg or greater, as evidenced by increased latency to mating, decreased sperm count, decreased epididymal weight, and decreased pregnancy rate. In addition, the numbers of implantations and embryos were decreased at the highest dose. The no effect dose for fertility impairment was 60 mg/kg (approximately 2 times the MRHD on a mg/m² basis).

CLINICAL STUDIES

Obsessive Compulsive Disorder (OCD)

     The effectiveness of LUVOX CR Capsules for the treatment of OCD was demonstrated in a 12-week, multicenter, placebo-controlled study of adult outpatients. Patients in this trial were titrated in 50 mg increments over the first six weeks of the study on the basis of response and tolerance from a dose of 100 mg/day to a fluvoxamine maleate dose within a range of 100 mg to 300 mg once-a-day. Patients in this study had moderate to severe OCD (DSM-IV), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), total scores of 26.6 and 26.3 for fluvoxamine and placebo-treatment groups, respectively.

     Patients receiving LUVOX CR Capsules demonstrated statistically significant improvement over placebo patients at the primary endpoint (Week 12) compared to baseline on the Y-BOCS. The mean daily dose of LUVOX CR Capsules administered to patients was 261 mg at end of study.

     Exploratory analyses for age and gender effects on outcomes did not show any significant differential responsiveness on the basis of age or sex.

     The effectiveness of immediate-release fluvoxamine maleate tablets for the treatment of 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, after which the dose was adjusted within a range of 100-300 mg/day (given in two doses per day), 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.

Adult OCD Maintenance Study with Immediate-Release Fluvoxamine Maleate Tablets

     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 immediate-release fluvoxamine 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 immediate-release fluvoxamine 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 immediate-release fluvoxamine 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

     LUVOX CR Capsules have not been evaluated in pediatric patients. However, the effectiveness of immediate-release fluvoxamine maleate tablets for the treatment of OCD was demonstrated in a 10-week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages 8-17 years). 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 (given in two doses per day) 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.

     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 year to 11 year age group and essentially no effect in the 12 year to 17 year 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 [ 12.3 ]) 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/day) may be indicated to achieve therapeutic benefit.