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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.
Overview of Pharmacodynamic Properties
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.
Overview of Pharmacokinetic Properties
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 18% for placebo.
Evidence suggests that fluvoxamine has efficacy similar to that of the TCA clomipramine and the SSRIs paroxetine and citalopram in patients with OCD, and is significantly more effective than the noradrenaline uptake inhibitor desipramine.
Limited data suggest that maintenance therapy with fluvoxamine may reduce the likelihood of relapses in up to 67% of patients with OCD. Furthermore, treatment with fluvoxamine (up to 300 mg/day) may enhance the efficacy of behavioural therapy in this patient group.
Panic disorder: Placebo-controlled trials in patients with panic disorder found that 6 or 8 weeks’ treatment with fluvoxamine (≤300 mg/day) reduced the weekly number of full panic attacks by 54 to 100%; in comparison, the weekly number of full panic attacks in patients receiving placebo ranged from an increase of 10% to a reduction of 75%. Comparisons with placebo for this end-point were significant (p < 0.05) in most studies. Where evaluated, a higher proportion of fluvoxamine (47 to 81%) than placebo (22 to 61%) recipients were free from panic attacks in the final week of treatment, although not all studies showed a significant between-group difference.
Fluvoxamine also significantly reduced anxiety (assessed by the Hamilton Anxiety Scale or the Clinical Anxiety Scale) in these patients compared with placebo.
Limited comparative data in patients with panic disorder show that fluvoxamine ≤300 mg/day is as effective as the same dosage of the TCA imipramine (8-week study), but that a 150 mg/day dosage may be slightly less effective than the monoamine oxidase inhibitor (MAOI) brofaromine 150 mg/day (12-week study).
Limited evidence suggests that fluvoxamine ≤300 mg/day reduces anxiety levels significantly more effectively than cognitive therapy alone in patients with panic disorder; when coadministered with exposure or cognitive therapy the effects of fluvoxamine may be additive.
Other disorders: Results from small, generally noncomparative trials suggest that fluvoxamine (≤300 mg/day for 8 to 12 weeks) is effective in patients with post-traumatic stress disorder. Fluvoxamine was significantly more effective than placebo in 2 double-blind comparative studies in patients with eating disorders. In addition, limited data suggest that fluvoxamine has efficacy in the treatment of various other obsessive-compulsive spectrum disorders, including pathological gambling, body dysmorphic disorder, autistic disorder, trichotillomania, compulsive buying and kleptomania. Furthermore, the drug reduced symptoms of social phobia (social anxiety disorder) significantly more effectively than placebo in 2 double-blind studies.
Fluvoxamine is generally well tolerated in patients with non-depressive disorders. Approximately 42% of patients with or without depression who received fluvoxamine ≤300 mg/day for between 4 and 52 weeks in postmarketing studies reported ≥1 adverse event. Adverse events were generally transient, and mild to moderately severe. Nausea was the most frequently reported event (15.7%), with other less common events including somnolence (6.4%), asthenia (5.1%), headache (4.8%), dry mouth (4.8%) and insomnia (4.0%).
The risk of suicidal behaviour in fluvoxamine recipients is low, as is the likelihood of sexual dysfunction. A small portion of patients (≈0.4%) may experience a withdrawal syndrome 1 to 4 days after discontinuing fluvoxamine therapy; these symptoms are generally mild and resolve within 25 days.
The drug causes fewer anticholinergic or cardiovascular effects than TCAs, and its use is not associated with the increase in bodyweight, impairment of psychomotor performance or sexual function sometimes seen with these agents. The tolerability profile of fluvoxamine appears to be broadly similar to those of other SSRIs, although few directly comparative data are available.
Fluvoxamine is well tolerated in the elderly and in patients with mild cardiovascular disease. Because of limited isolated reports of fluvoxamine-induced seizures, the drug should be used with caution in patients at risk of seizures.
Dosage and Administration
Dosage recommendations for oral fluvoxamine in adults with anxiety disorders are currently only available for the treatment of OCD. In this patient group, the recommended fluvoxamine starting dosage is 50mg administered as a single daily dose at bedtime. In clinical trials in patients with OCD, fluvoxamine was generally titrated within a dosage range of 100 to 300 mg/day. As a result, it is recommended that the dosage of fluvoxamine should be titrated in 50mg increments every 4 to 7 days (depending on tolerability) until maximum therapeutic benefit is achieved. The daily dosage of fluvoxamine should not exceed 300mg; dosages >100 mg/day should be administered in 2 divided doses and, if the doses are not equal, the larger dose should be administered at bedtime. Similar dosage regimens have been used in clinical trials of fluvoxamine for the treatment of other anxiety disorders. It may be appropriate to modify the initial dose and subsequent dosage titrations in elderly patients and in patients with hepatic dysfunction.
Fluvoxamine is contraindicated in combination with MAOIs. According to US recommendations, administration of fluvoxamine is also contraindicated within 2 weeks of withdrawing an MAOI and vice versa. According to European recommendations, fluvoxamine treatment can be initiated 2 weeks after discontinuation of an irreversible MAOI or the following day after discontinuation of a reversible MAOI; at least 1 week should elapse between discontinuation of fluvoxamine and initiation of therapy with any MAOI.
It is recommended that fluvoxamine be used with caution and/or appropriate monitoring in patients taking other drugs with which it is known to interact, such as alprazolam, diazepam, theophylline and warfarin.
KeywordsAnxiety Disorder Fluvoxamine Social Phobia Bulimia Nervosa Pathological Gambling
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