Fluvoxamine Maleate

FLUVOXAMINE MALEATE- fluvoxamine maleate tablet, film coated
Synthon Pharmaceuticals, Inc.

25 mg, 50 mg and 100 mg

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Fluvoxamine Maleate or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Fluvoxamine is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See Warnings and Precautions: Pediatric Use.) (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)

DESCRIPTION

Fluvoxamine maleate is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to a new chemical series, the 2-aminoethyl oxime ethers of aralkylketones. It is chemically unrelated to other SSRIs and clomipramine. It is chemically designated as 5-methoxy-4′-(trifluoromethyl)valerophenone-(E)-O-(2-aminoethyl)oxime maleate (1:1) and has the empirical formula C15 H21 O2 N2 F3 • C4 H4 O4 . Its molecular weight is 434.4.

The structural formula is:

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

Fluvoxamine Maleate Tablets are available in 25 mg, 50 mg and 100 mg strengths for oral administration. In addition to the active ingredient, fluvoxamine maleate, each tablet contains the following inactive ingredients: hypromellose, mannitol, polyethylene glycol, pregelatinized starch (corn), colloidal silicon dioxide, sodium stearyl fumarate, starch (corn), titanium dioxide and talc.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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. 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 psychotic drugs.

Pharmacokinetics

Bioavailability

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 3-8 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.

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 PRECAUTIONS-Drug Interactions)

Elimination

Following a 14 C-labelled 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.

Elderly Subjects

In a study of 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 Tablets should be slowly titrated during initiation of therapy.

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 adolescents. AUC and Cmax in children were 1.5- to 2.7-fold higher than that in adolescents (see table below). 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 Tablets may produce therapeutic benefit (see table below). 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 below). Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.

Comparison of Mean (SD) fluvoxamine pharmacokinetic parameters between children, adolescents and adults
Pharmacokinetic Parameter(Body weight corrected) Dose=200 mg/day (100 mg/day bid) Dose=300 mg/day (150 mg bid)
Children(n=10) Adolescent(n=17) Adolescents(n=13) Adults(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)
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 bid)
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)

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