Chemical formula: C₁₅H₂₁F₃N₂O₂ Molecular mass: 318.34 g/mol PubChem compound: 3404
The mechanism of action of fluvoxamine is thought to be related to selective serotonin re-uptake inhibition in brain neurones. There is minimum interference with noradrenergic processes. Receptor binding studies have demonstrated that fluvoxamine has negligible binding capacity to alpha adrenergic, beta adrenergic, histaminergic, muscarine cholinergic, dopaminergic or serotonergic receptors.
In a placebo-controlled trial in 120 patients with OCD, aged between 8 and 17 years, a statistically significant improvement was seen in the total population in favour of fluvoxamine at 10 weeks. A further subgroup analysis showed improvement on the C-YBOCS rating scale in children whereas no effect was seen in adolescents. The mean dose was respectively 158 mg and 168 mg/day.
No formal clinical trials were conducted investigating the dose response of fluvoxamine. However, it is clinical experience that up-titrating the dose might be beneficial for some patients.
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.
In vitro plasma protein binding of fluvoxamine is 80%. Volume of distribution in humans is 25 1/kg.
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 inhibition was found for CYP2C9, CYP2D6 and CYP3A4.
Fluvoxamine displays linear single-dose pharmacokinetics. Steady-state concentrations are higher than calculated from single-dose data, and this disproportional increase is more pronounced with higher daily doses.
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 in adults.
There is no evidence of carcinogenicity or mutagenicity with fluvoxamine.
Animal studies on male and female fertility revealed reduction of mating performance, decreased sperm count, and fertility index and increased ovary weights at levels higher than human exposure. The effects were observed at exposures >two-fold higher than exposures at the maximum therapeutic dose. As there is no safety margin between exposure at the NOAEL in the reproductive studies and the exposure at the maximum therapeutic dose a risk to patients cannot be ruled out.
Reproductive toxicity studies in rats have shown that fluvoxamine is embryotoxic (increased embryofetal death [resorptions], increased fetal eye abnormalities [folded retina], reduced fetal weights and delayed ossification). The effects on fetal weights and ossification are likely to be secondary to maternal toxicity (reduced maternal bodyweight and bodyweight gain).
In addition an increased incidence of perinatal pup mortality in pre-and postnatal studies was seen.
The safety margin for reproductive toxicity is unknown.
The potential for abuse, tolerance and physical dependence has been studied in a non-human primate model. No evidence of dependency phenomena was found.
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