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Pharmacotherapeutic group: Antidepressants, Selective serotonin reuptake inhibitors. ATC code: N06AB08.
Pharmacology: Pharmacodynamics: Receptor binding studies have demonstrated that fluvoxamine is a potent serotonin reuptake inhibitor in vitro as well as in vivo and has a minimal affinity for serotonin receptors subtypes. Its capacity of binding to alpha adrenergic, beta adrenergic, histaminergic, muscarinic, cholinergic or dopaminergic receptors is negligible.
Fluvoxamine has a high affinity for sigma-1 receptors, where it acts as an agonist at therapeutic doses.
Pharmacokinetics: Absorption: Fluvoxamine is completely absorbed following oral administration. Maximum plasma concentrations occur within 3-8 hours of dosing. The mean absolute bioavailability is 53%, due to first-pass metabolism.
The pharmacokinetics of fluvoxamine is not influenced by concomitant food intake.
Distribution: In vitro plasma protein binding of fluvoxamine is 80%. Volume of distribution in humans is 25 l/kg.
Metabolism: Fluvoxamine undergoes extensive metabolism in the liver. Although CYP2D6 is in vitro the main isoenzyme involved in fluvoxamine's metabolism, plasma concentrations in poor metabolisers for CYP2D6 are not much higher than those in extensive metabolisers.
The mean plasma half-life is approximately 13-15 hours after a single dose, and slightly longer (17-22 hours) during repeated dosing, when steady-state plasma levels are usually achieved within 10-14 days.
Fluvoxamine undergoes extensive hepatic transformation, mainly via oxidative demethylation, into at least nine metabolites, which are excreted by the kidneys. The two major metabolites showed negligible pharmacological activity. The other metabolites are not expected to be pharmacologically active. Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19. A moderate inhibitor was found for CYP2C9, SYP2D6 and CYP3A4.
Fluvoxamine displays linear single-dose pharmacokinetics. Steady-state concentrations are higher than calculated from single-dose data, and are disproportionally higher at higher daily doses.
Special patients groups: The pharmacokinetics of fluvoxamine is similar in healthy adults, elderly patients, and patients with renal insufficiency. The metabolism of fluvoxamine is impaired in patients with liver disease.
Steady-state plasma concentrations of fluvoxamine were twice as high in children (aged 6-11) as in adolescents (aged 12-17). Plasma concentrations in adolescents are similar to those of adults.
Toxicology: Preclinical safety data: Carcinogenesis and mutagenesis: There is no evidence of carcinogenicity or mutagenicity with fluvoxamine.
Fertility and reproductive toxicity: Reproduction studies in animals revealed impaired fertility, increased embryofoetal death and decreased foetal body weight. The effects were observed at an exposure that exceeds the exposure under therapeutic doses in humans two-fold. In addition an increased incidence of perinatal pup mortality in pre-and postnatal studies were seen.
Physical and psychological dependence: The potential for abuse, tolerance and physical dependence has been studied in a nonhuman primate model. No evidence of dependency phenomena was found.
