Fluvoxamine

Medical uses

In many countries (e.g., Australia, the United Kingdom,) it is commonly used for major depressive disorder. Fluvoxamine is also approved in the United States for obsessive–compulsive disorder (OCD), 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.Seibell PJ, Hamblin RJ, Hollander E.

Obsessive-compulsive disorder: Overview and standard treatment strategies. Psychiatric Annals. 2015 Jun 1;45(6):297-302. The (off-label) 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:

• Abdominal pain
• Agitation
• Anxiety
• Asthenia (weakness)
• Constipation
• Diarrhea
• Dizziness
• Dyspepsia (indigestion)
• Headache
• Hyperhidrosis (excess sweating)
• Insomnia
• Loss of appetite
• Malaise
• Nausea
• Nervousness
• Palpitations
• Restlessness
• Sexual dysfunction (including delayed ejaculation, erectile dysfunction, decreased libido, etc.)
• Somnolence (drowsiness)
• Tachycardia (high heart rate)
• Tremor
• Vomiting
• Weight loss
• Xerostomia (dry mouth)
• Yawning

Uncommon

Uncommon side effects occurring with 0.1–1% incidence:

• Arthralgia
• Confusional state
• Cutaneous hypersensitivity reactions (e.g. oedema [buildup of fluid in the tissues], rash, pruritus)
• Extrapyramidal side effects (e.g. dystonia, parkinsonism, tremor, etc.)
• Hallucination
• Orthostatic hypotension

Rare

Rare side effects occurring with 0.01–0.1% incidence:

• Abnormal hepatic (liver) function
• Galactorrhoea (expulsion of breast milk unrelated to pregnancy or breastfeeding)
• Mania
• Photosensitivity (being abnormally sensitive to light)
• Seizures

Unknown frequency

• Akathisia a sense of inner restlessness that presents itself with the inability to stay still
• Bed-wetting
• Bone fractures
• Dysgeusia
• Ecchymoses
• Glaucoma
• Haemorrhage
• Hyperprolactinaemia (elevated plasma prolactin levels leading to galactorrhoea, amenorrhoea [cessation of menstrual cycles], etc.)
• Hyponatraemia
• Mydriasis
• Neuroleptic malignant syndrome – practically identical presentation to serotonin syndrome except with a more prolonged onset
• Paraesthesia
• Serotonin syndrome – a potentially fatal condition characterised by abrupt onset muscle rigidity, hyperthermia (elevated body temperature), rhabdomyolysis, mental status changes (e.g. coma, hallucinations, agitation), etc.
• Suicidal ideation and behaviour
• Syndrome of inappropriate antidiuretic hormone secretion
• Urinary incontinence
• Urinary retention
• Violence toward others
• Weight changes
• Withdrawal symptoms

Interactions

Fluvoxamine inhibits the following cytochrome P450 enzymes:

• CYP1A2 (strongly) which metabolizes agomelatine, amitriptyline, caffeine, clomipramine, clozapine, duloxetine, haloperidol, imipramine, phenacetin, tacrine, tamoxifen, theophylline, olanzapine, etc.
• CYP3A4 (moderately) which metabolizes alprazolam, aripiprazole, clozapine, haloperidol, quetiapine, pimozide, ziprasidone, etc.
• CYP2D6 (weakly) which metabolizes aripiprazole, chlorpromazine, clozapine, codeine, fluoxetine, haloperidol, olanzapine, oxycodone, paroxetine, perphenazine, pethidine, risperidone, sertraline, thioridazine, zuclopenthixol, etc.
• CYP2C9 (moderately) which metabolizes nonsteroidal anti-inflammatory drugs, phenytoin, sulfonylureas, etc.
• CYP2C19 (strongly) which metabolizes clonazepam, diazepam, phenytoin, etc.
• CYP2B6 (weakly) which metabolizes bupropion, cyclophosphamide, sertraline, tamoxifen, valproate, etc.

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 (e.g., triazolam, midazolam, alprazolam, and diazepam) are likely to be increased when co-administered with fluvoxamine. However, the clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam; oxazepam, which is coincidentally a metabolite of diazepam; temazepam) 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 (clonazepam, nitrazepam) 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 (Dextromethorphan, ondansetron, amphetamine, sumatriptan, Tramadol, Hypericum perforatum, etc.). 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 (thereby its serotonergic potential) and inhibits its metabolism to its strongly-noradrenergic metabolite, norclomipramine.

Pharmacology

Pharmacodynamics

Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter. It behaves as a potent agonist at this receptor and has the highest affinity (36 nM) of any SSRI for doing so. 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

Literature reviews 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 (particularly CYP1A2, and less potently CYP3A4 and CYP2D6) 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.

History

Fluvoxamine was developed by Kali-Duphar, part of Solvay Pharmaceuticals, Belgium, now Abbott Laboratories, and introduced as Floxyfral in Switzerland in 1983. It was approved by the U.S. Food and Drug Administration (FDA) in 1994, and introduced as Luvox in the US. In India, it is available, among several other brands, as Uvox by Abbott. It was one of the first SSRI antidepressants to be launched, and is prescribed in many countries to patients with major depression. It was the first SSRI, a non-TCA drug, approved by the U.S. FDA specifically for the treatment of OCD. At the end of 1995, more than ten million patients worldwide had been treated with fluvoxamine. Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997. In Japan, fluvoxamine was the first SSRI to be approved for the treatment of depression in 1999 and was later in 2005 the first drug to be approved for the treatment of social anxiety disorder. Fluvoxamine was the first SSRI approved for clinical use in the United Kingdom. Manufacturers include BayPharma, Synthon, and Teva, among others.

Research directions

A 2022 review concluded that according to low-certainty evidence, fluvoxamine may slightly decrease all-cause mortality by day 28 and potentially reduce the risk of hospitalization or death in outpatients with mild COVID-19. While early studies have suggested potential benefits for fluvoxamine as an anti-inflammatory agent and a possible impact on reducing cytokine storms, further studies did not confirm this expected benefit on COVID-19 patients. A cytokine storm refers to an excessive immune response characterized by a release of large amounts of pro-inflammatory cytokines.

In May 2022, based on a review of available scientific evidence, the U.S. Food and Drug Administration (FDA) did not issue an emergency use authorization covering the use of fluvoxamine to treat COVID-19, saying that, at the time, the data was not sufficient to conclude that fluvoxamine may be effective in treating non-hospitalized people with COVID-19 to prevent serious illness or hospitalization. The agency stated that study results suggest that further clinical trials may be warranted.

Reviews published in 2024 indicate that clinical trials have shown fluvoxamine to be more effective than a placebo in reducing clinical deterioration and hospitalization in COVID-19 patients, particularly those taking 200 mg or more daily.

Environment

Fluvoxamine is a common finding in waters near human settlement. Christensen et al. 2007 finds it is "very toxic to aquatic organisms" by European Union standards.

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