Fluvoxamine


Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor class. It is primarily used to treat major depressive disorder and, perhaps more-especially, obsessive–compulsive disorder, but is also used to treat anxiety disorders such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.
Fluvoxamine's side-effect profile is similar to that of other SSRIs. Common adverse effects include constipation, gastrointestinal problems, headache, anxiety, irritation, sexual problems, dry mouth, sleep problems, and an increased risk of suicide at the start of treatment. These effects appear to be significantly weaker than with other SSRIs, with the exception of gastrointestinal side-effects.
Fluvoxamine appears to be more tolerable than other SSRIs, particularly with respect to cardiovascular complications. Compared to escitalopram and sertraline, fluvoxamine's gastrointestinal profile may be less intense, often being limited to nausea. Mosapride has demonstrated efficacy in treating fluvoxamine-induced nausea. It is also advised practice to divide total daily doses of fluvoxamine greater than 100 mg, with the higher fraction being taken in the evening. In any case, high starting daily doses of fluvoxamine rather than the recommended gradual titration may increase the likelihood of nausea.
It is on the World Health Organization's List of Essential Medicines.

Medical uses

In many countries it is commonly used for major depressive disorder. Fluvoxamine is also approved in the United States for obsessive–compulsive disorder, and social anxiety disorder. In Japan, it is also approved to treat OCD, social anxiety disorder, and major depressive disorder. Fluvoxamine is indicated for children and adolescents with OCD. The NICE guidelines in the United Kingdom have, as of 2005, authorized its use for obsessive-compulsive disorder in adults and adolescents of any age and children over the age of 7.
There is evidence that fluvoxamine is effective for generalised social anxiety in adults, although, as with other SSRIs, some of the results may be compromised by having been funded by pharmaceutical companies. Of the SSRIs, however, fluvoxamine, paroxetine, and sertraline do appear consistent as viable treatments for generalised social anxiety.
Fluvoxamine is also effective for treating a range of anxiety disorders in children and adolescents, including generalized anxiety disorder, social anxiety disorder, panic disorder, and separation anxiety disorder.
The drug works long-term, and retains its therapeutic efficacy for at least one year.
The average therapeutic dose for fluvoxamine is 100 to 300 mg/day, with 300 mg being the upper daily limit normally recommended. Obsessive-compulsive disorder, however, often requires higher doses; doses of up to 450 mg/day may be prescribed in this case. The upper daily limits for other serotonin-reuptake inhibitors used in the treatment of obsessive-compulsive disorder, by analogy, are 400 mg for sertraline, 100 mg for paroxetine, 120 mg for both fluoxetine and citalopram, 60 mg for escitalopram and 300 mg for clomipramine.
In any case with fluvoxamine, treatment is generally begun at 50 mg and increased in 50 mg increments every 4 to 7 days until a therapeutic optimum is reached.

Adverse effects

Fluvoxamine's side-effect profile is very similar to other SSRIs. Gastrointestinal side effects are characteristic of those receiving treatment with fluvoxamine.
In comparison to other SSRIs, fluvoxamine has the second highest rate of causing Discontinuation syndrome, as a result of the low half life of fluvoxamine

Common

Common side effects occurring with 1–10% incidence:
Uncommon side effects occurring with 0.1–1% incidence:
Rare side effects occurring with 0.01–0.1% incidence:
Fluvoxamine inhibits the following cytochrome P450 enzymes:
By so doing, fluvoxamine can increase serum concentration of the substrates of these enzymes.
Fluvoxamine may also elevate plasma levels of olanzapine by approximately two times. Combined olanzapine and fluvoxamine, which may cause increased sedation, should be used cautiously and controlled clinically and by therapeutic drug monitoring to avoid olanzapine induced adverse effects and/or intoxication.
The plasma levels of oxidatively metabolized benzodiazepines are likely to be increased when co-administered with fluvoxamine. However, the clearance of benzodiazepines metabolized by glucuronidation are not affected by fluvoxamine and may be safely taken alongside fluvoxamine should concurrent treatment with a benzodiazepine be necessary. Additionally, it appears that benzodiazepines metabolized by nitro-reduction may also, in a somewhat similar vein, be unlikely to be affected by fluvoxamine.
Using fluvoxamine and alprazolam together can increase alprazolam plasma concentrations. If alprazolam is coadministered with fluvoxamine, the initial alprazolam dose should be reduced to the lowest effective dose.
As with all SSRI medications, using fluvoxamine with NSAIDs like ibuprofen may increase the risk of bleeding, particularly in the GI tract.
Fluvoxamine is contraindicated with other medications that increase serotonin. Combining these medications may rarely lead to a life-threatening complication known as serotonin syndrome.
Fluvoxamine and ramelteon coadministration is not indicated.
Fluvoxamine has been observed to increase serum concentrations of mirtazapine, which is mainly metabolized by CYP1A2, CYP2D6, and CYP3A4, by three- to four-fold in humans. Caution and adjustment of dosage as necessary are warranted when combining fluvoxamine and mirtazapine.
Fluvoxamine seriously affects the pharmacokinetics of tizanidine and increases the intensity and duration of its effects. Because of the potentially hazardous consequences, the concomitant use of tizanidine with fluvoxamine, or other potent inhibitors of CYP1A2, should be avoided.
When a beta-blocker is required, atenolol, pindolol and, possibly, metoprolol may be safer choices than propranolol, as the latter's metabolism is seriously, potentially dangerously, inhibited by fluvoxamine. Indeed, fluvoxamine may increase propranolol blood-levels by five-fold.
Clomipramine increases fluvoxamine levels and, conversely-likewise, fluvoxamine increases clomipramine levels and inhibits its metabolism to its strongly-noradrenergic metabolite, norclomipramine.

Pharmacology

Pharmacodynamics

SiteKi
2.5
1427
5-HT2C5786
α1-adrenergic1288
σ136

Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter. It has negligible affinity for the dopamine transporter or any other site, with the sole exception of the σ1 receptor. It behaves as a potent agonist at this receptor and has the highest affinity of any SSRI for doing so. This may contribute to its antidepressant and anxiolytic effects and may also afford it some efficacy in treating the cognitive symptoms of depression. It increases concentrations of the neurosteroid allopregnanolone, which may also contribute to its anxiolytic effects. Unlike some other SSRIs, fluvoxamine's metabolites are pharmacologically neutral.

Pharmacokinetics

s have stated that fluvoxamine is metabolized primarily by CYP2D6 and to a minor extent by CYP1A2. However, CYP2D6 poor metabolizers do not have considerably higher fluvoxamine levels than extensive metabolizers. Fluvoxamine inhibits oxidative drug metabolising enzymes The mean plasma half-life of fluvoxamine after multiple oral doses of 100 mg/day in healthy, young volunteers was 13.6-15.6 hours. In the elderly, however the half life ranged from 17.4 to 25.9. Steady-state plasma fluvoxamine concentrations were 2-3 fold higher in children than in adolescents.