Fluvoxamine

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Abstract
Fluvoxamine is a potent and selective serotonin reuptake inhibitor (SSRI) that has little or no effect on other monoamine reuptake mechanisms. Relative to other SSRIs, fluvoxamine is a weak inhibitor of cytochrome P450 (CYP) 2D6, a moderate inhibitor of CYP2C19 and CYP3A4 and a potent inhibitor of CYP1A2. In randomised, double-blind trials, fluvoxamine 100 to 300 mg/day for 6 to 10 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) compared with placebo. Response rates of 38 to 52% have been reported with fluvoxamine, compared with response rates of 0 to 18% with placebo. In patients with OCD, fluvoxamine had similar efficacy to that of clomipramine and, in smaller trials, the SSRIs paroxetine and citalopram and was significantly more effective than desipramine. Maintenance therapy with fluvoxamine may reduce the likelihood of relapses in up to 67% of patients with OCD. Fluvoxamine ≤300 mg/day for 6 to 8 weeks was as effective as imipramine in patients with panic disorder, and significantly more effective than placebo. In addition, treatment with fluvoxamine ≤300 mg/day for ≥8 weeks improved symptoms of social phobia (social anxiety disorder), post-traumatic stress disorder (PTSD), pathological gambling, compulsive buying, trichotillomania, kleptomania, body dysmorphic disorder, eating disorders and autistic disorder. Large trials comparing the efficacy of fluvoxamine and other SSRIs in patients with anxiety disorders are warranted. Fluvoxamine is generally well tolerated; in postmarketing studies, nausea was the only adverse event occurring in >10% of patients with less commonly reported events including somnolence, asthenia, headache, dry mouth and insomnia. Fluvoxamine is associated with a low risk of suicidal behaviour, sexual dys-function and withdrawal syndrome. Fewer anticholinergic or cardiovascular events are associated with fluvoxamine than tricyclic antidepressants. Although comparative data are lacking, the tolerability profile of fluvoxamine appears to be broadly similar to those of other SSRIs. Conclusion: Fluvoxamine has demonstrated short term efficacy in the treatment of OCD, panic disorder, social phobia, PTSD and in a range of obsessive-compulsive spectrum disorders. The drug is as effective as clomipramine in patients with OCD but appears to have a better tolerability profile. On the basis of current treatment guidelines, fluvoxamine, like other SSRIs, is recommended as first-line treatment for a number of anxiety disorders. It appears to offer some pharmacokinetic advantages and a different drug interaction profile to the other SSRIs with a broadly similar spectrum of adverse events. However, direct comparisons are required to assess the relative efficacy and tolerability of the different agents of this drug class. Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI). It has little or no effect on other monoamine reuptake mechanisms or monoamine neuronal function and has low affinity for other neurotransmitter receptors. The drug has relatively few cardiovascular or anticholinergic effects, unlike tricyclic antidepressants (TCAs). Furthermore, fluvoxamine appears to have negligible proconvulsant or sedative effects, and has shown minimal effects on psychomotor and cognitive function in humans/animals. Fluvoxamine is almost completely absorbed from the gastrointestinal tract after oral administration: maximum plasma drug concentrations are reached within 2 to 8 hours and are not affected by the concomitant intake of food. Nonlinear pharmacokinetics are reported in volunteers after repeated administration of therapeutic dosages of fluvoxamine. The drug is widely distributed throughout the body (25 L/kg) but has a relatively low level of protein binding (77%) compared with fluoxetine (94%), paroxetine (95%) and sertraline (98 to 99%). It has an absolute oral bioavailability of ≈50% because of extensive first-pass metabolism; the specific hepatic cytochrome P450 (CYP) isozymes involved remain to be identified. Most of an oral fluvoxamine dose is excreted in the urine, but only 3% as unchanged drug. 11 pharmacologically inactive metabolites have been identified in urine after a radiolabelled dose. Excretion of fluvoxamine via breast milk is minimal. Clearance of fluvoxamine may be slowed in the elderly and in patients with hepatic impairment, but the pharmacokinetic profile of the drug is not affected in patients with impaired renal function. Evidence suggests that fluvoxamine is a weak inhibitor of CYP2D6 relative to other SSRIs, a moderate inhibitor of CYP2C19 and CYP3A4 and a potent inhibitor of CYP1A2 in hepatic microsomes. The drug is therefore likely to inhibit the metabolism and prolong the elimination of CYP1A2 substrates such as caffeine, clozapine, propranolol, tacrine, tertiary amine TCAs, theophylline and warfarin. Other drugs that potentially have their metabolic elimination impaired by fluvoxamine include those benzodiazepines which undergo oxidative metabolism by CYP3A4 (e.g. alprazolam and diazepam), methadone and thioridazine. There are no appreciable pharmacokinetic interactions between fluvoxamine and lithium, digoxin or ethanol (alcohol). Obsessive-compulsive disorder: Oral administration of fluvoxamine at dosages of 100 to 300 mg/day for 6 to 10 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) compared with placebo in randomised, double-blind trials. Significant reductions in the Yale-Brown Obsessive-Compulsive Scale and the National Institute of Mental Health Obsessive-Compulsive global rating scale occurred after 3 to 4 weeks, a delay similar to that seen with fluvoxamine in the treatment of depression. Most placebo-controlled studies reported a response rate (percentage of patients who were rated as ‘much improved’ or ‘very much improved’ on the Clinical Global Impression scale between 38 and 52% for fluvoxamine compared with 0 and...

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