Fluvoxamine

Source: Wikipedia, the free encyclopedia.
Not to be confused with Fluoxetine.

Fluvoxamine
Clinical data
Trade namesLuvox, others
AHFS/Drugs.comMonograph
MedlinePlusa695004
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classSelective serotonin reuptake inhibitor (SSRI)
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability53% (90% confidence interval: 44–62%)[3]
Protein binding77–80%[3][4]
MetabolismLiver (primarily O-demethylation)
Major: CYP1A2
Minor: CYP3A4
Minor: CYP2C19[3]
Elimination half-life12–13 hours (single dose), 22 hours (repeated dosing)[3]
ExcretionKidney (98%; 94% as metabolites, 4% as unchanged drug)[3]
Identifiers
  • 2-{[(E)-{5-Methoxy-1-[4-(trifluoromethyl)phenyl] pentylidene}amino]oxy}ethanamine[5]
JSmol)
  • FC(F)(F)c1ccc(\C(=N\OCCN)CCCCOC)cc1
  • InChI=1S/C15H21F3N2O2/c1-21-10-3-2-4-14(20-22-11-9-19)12-5-7-13(8-6-12)15(16,17)18/h5-8H,2-4,9-11,19H2,1H3/b20-14+ checkY
  • Key:CJOFXWAVKWHTFT-XSFVSMFZSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Fluvoxamine, sold under the brand name Luvox among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class.[6] It is primarily used to treat major depressive disorder and obsessive–compulsive disorder (OCD),[7] but is also used to treat anxiety disorders[8] such as panic disorder, social anxiety disorder, and post-traumatic stress disorder.[9][10][11]

Fluvoxamine's side-effect profile is very similar to other SSRIs:

sleep problems and a risk of suicide at the start of treatment by lifting the psychomotor inhibition, but these effects appear to be significantly weaker than with other SSRIs (except gastrointestinal side-effects).[12]

Although the many drug-drug interactions of fluvoxamine can be problematic (and may temper enthusiasm for its prescribing, advocation and usage to some), its tolerance-profile itself is actually superior in some respects to other SSRIs (particularly with respect to cardiovascular complications), despite its age.[13] Compared to escitalopram and sertraline, indeed, fluvoxamine's gastrointestinal profile may be less intense,[14] often being limited to nausea.[15] Mosapride has demonstrated efficacy in treating fluvoxamine-induced nausea.[16] It is also advised practice to divide total daily doses of fluvoxamine greater than 100 milligrams, with the higher fraction being taken at bedtime (e.g., 50 mg at the beginning of the waking day and 200 mg at bedtime). In any case, high starting daily doses of fluvoxamine rather than the recommended gradual titration (starting at 50 milligrams and gradually titrating, up to 300 if necessary) may predispose to nauseous discomfort.[17]

It is on the World Health Organization's List of Essential Medicines.[18]

Medical uses

In many countries (e.g., Australia,

obsessive-compulsive disorder in adults and adolescents of any age and children over the age of 7.[medical citation needed
]

There is evidence that fluvoxamine is effective for

SSRIs, however, fluvoxamine, paroxetine and sertraline do appear consistent as viable treatments for generalised social anxiety.[30][31] Phenelzine,[32][33] brofaromine, venlafaxine, gabapentin, pregabalin and clonazepam represent other viable options for the pharmacological treatment of generalised social anxiety.[medical citation needed
]

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.[34][35][36]

The drug works long-term, and retains its therapeutic efficacy for at least one year.[37] It has also been found to possess some analgesic properties in line with other SSRIs and tricyclic antidepressants.[38][39][40]

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.[41][42][43] 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.[44]

Adverse effects

Fluvoxamine's side-effect profile is very similar to other SSRIs, with

gastrointestinal side effects more characteristic of those receiving treatment with fluvoxamine.[3][23][19][21][45][46]

Common

Common side effects occurring with 1–10% incidence:

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 effecs 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

Interactions

Luvox (fluvoxamine) 100 mg film-coated scored tablets

Fluvoxamine inhibits the following cytochrome P450 enzymes:[48][49][50][51][52][53][54][55][56][excessive citations]

By so doing, fluvoxamine can increase serum concentration of the substrates of these enzymes.[48]

Fluvoxamine may also elevate plasma levels of olanzapine by approximately two times.[59] Combined olanzapine and fluvoxamine, which may cause increased sedation,[60] should be used cautiously and controlled clinically and by therapeutic drug monitoring to avoid olanzapine induced adverse effects and/or intoxication.[61][62]

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;[63] temazepam)[64][65] are not affected by fluvoxamine and may be safely taken alongside fluvoxamine should concurrent treatment with a benzodiazepine be necessary.[66] 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.[67][68]

Using fluvoxamine and alprazolam together can increase alprazolam plasma concentrations.[69] If alprazolam is coadministered with fluvoxamine, the initial alprazolam dose should be reduced to the lowest effective dose.[70][71]

Fluvoxamine and ramelteon coadministration is not indicated.[72][73]

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.[74] Caution and adjustment of dosage as necessary are warranted when combining fluvoxamine and mirtazapine.[74]

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.[75]

When a beta-blocker is required, atenolol,[76] pindolol[77][78][79] and, possibly, metoprolol[80][81][57][82] may be safer choices than propranolol, as the latter's metabolism is seriously, potentially dangerously, inhibited by fluvoxamine.[83] Indeed, fluvoxamine may increase propranolol blood-levels by five-fold.[84]

Clomipramine increases fluvoxamine levels and, conversely-likewise, fluvoxamine increases clomipramine levels (thereby its serotoninergic potential) and inhibits its metabolism to its strongly-noradrenergic metabolite, norclomipramine.[85][86]

Pharmacology

Receptor affinity profile[87][88][89]
Site Ki (nM)
SERTTooltip Serotonin transporter 2.5
NETTooltip Norepinephrine transporter 1,427
5-HT2C 5,786
α1-adrenergic 1,288
σ1 36

Fluvoxamine is a potent selective serotonin reuptake inhibitor with around 100-fold affinity for the serotonin transporter over the norepinephrine transporter.[49] It has negligible affinity for the dopamine transporter or any other site, with the sole exception of the σ1 receptor.[90][13] It behaves as a potent agonist at this receptor and has the highest affinity (36 nM) of any SSRI for doing so.[90] This may contribute to its antidepressant and anxiolytic effects and may also afford it some efficacy in treating the cognitive symptoms of depression.[91] Unlike some other SSRIs, fluvoxamine's metabolites are pharmacologically neutral.[92]

History

Fluvoxamine was developed by Kali-Duphar,

Solvay Pharmaceuticals, Belgium, now Abbott Laboratories, and introduced as Floxyfral in Switzerland in 1983.[93] It was approved by the U.S. Food and Drug Administration (FDA) in 1994, and introduced as Luvox in the US.[94] In India, it is available, among several other brands, as Uvox by Abbott.[95] It was one of the first SSRI antidepressants to be launched, and is prescribed in many countries to patients with major depression.[96] It was the first SSRI, a non-TCA drug, approved by the U.S. FDA specifically for the treatment of OCD.[97] At the end of 1995, more than ten million patients worldwide had been treated with fluvoxamine.[98][failed verification] Fluvoxamine was the first SSRI to be registered for the treatment of obsessive compulsive disorder in children by the FDA in 1997.[99] In Japan, fluvoxamine was the first SSRI to be approved for the treatment of depression in 1999[100][101] and was later in 2005 the first drug to be approved for the treatment of social anxiety disorder.[102] Fluvoxamine was the first SSRI approved for clinical use in the United Kingdom.[103] Manufacturers include BayPharma, Synthon, and Teva, among others.[104]

Research directions

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.[105][106] A cytokine storm refers to an excessive immune response characterized by a release of large amounts of pro-inflammatory cytokines.[107]

In May 2022, based on a review of available scientific evidence, the U.S.

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.[108][109]

A large double-blind randomized controlled trial called ACTIV-6, published in 2023 in JAMA, revealed that taking 200 mg of fluvoxamine every day for about two weeks was not significantly better than placebo at shortening the duration of mild or moderate COVID-19 symptoms.[110][medical citation needed]

There is tentative evidence that fluvoxamine may reduce the overall morbidity of COVID-19 and complications thereof.[111][112]

Environment

Fluvoxamine is a common finding in waters near human settlement.[113] Christensen et al. 2007 finds it is "very toxic to aquatic organisms" by European Union standards.[113]

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