Fluvoxamine

Like other SSRIs, fluvoxamine increases serotonin activity by blocking its reuptake into nerve cells [2]. In laboratory studies it had no significant affinity for histamine, adrenergic, muscarinic or dopamine receptors, the receptors linked to the sedative, heart and anticholinergic side effects of some other psychiatric drugs [1].

Adults start at 50 mg at bedtime and go up by 50 mg every 4 to 7 days as tolerated, to no more than 300 mg a day; doses above 100 mg are split in two. Children and adolescents start at 25 mg, with a maximum of 200 mg a day up to age 11 [1].

Fluvoxamine is extensively metabolized in the liver, and its main metabolites are inactive or far weaker than the parent drug. About half of an oral dose reaches the bloodstream (bioavailability 53%), and the half-life at steady state is about 15.6 hours. Its kinetics are not proportional to dose: average peak levels at steady state were 88, 283 and 546 ng/mL at 100, 200 and 300 mg a day. Clearance is about 50% lower in older adults, and levels in children aged 6 to 11 were 2 to 3 times those in adolescents [1].

A CYP2D6 result is an activity score: each copy of the gene gets a value (1 for normal function, 0.5 or 0.25 for decreased function, 0 for no function) and the two are added. A score of 0 means poor metabolizer, 0.25 to 1 intermediate, 1.25 to 2.25 normal and above 2.25 ultrarapid [2][3].

The label describes a single-dose study comparing 13 CYP2D6 poor metabolizers with 16 people with normal activity. In the poor metabolizers, peak levels were 52% higher, total exposure (AUC) 200% higher and the half-life 62% longer, which suggests fluvoxamine is metabolized at least partly by CYP2D6. The label advises caution in people known to have reduced CYP2D6 activity and in those taking CYP2D6 inhibitors such as quinidine [1]. CPIC adds that poor metabolizers had significantly greater exposure across studies and that there are too few data to judge the effect of ultrarapid metabolism [2].

In CPIC's frequency tables, about 6.5% of people of European ancestry are CYP2D6 poor metabolizers, compared with 2% to 3% in most other groups and under 1% of people of East Asian ancestry [4].

The Clinical Pharmacogenetics Implementation Consortium (CPIC) covers fluvoxamine in its 2023 guideline on serotonin reuptake inhibitors [2]. Fluvoxamine and CYP2D6 are CPIC level B: genetic information could be used to change prescribing, because alternative therapy or dosing is extremely likely to be as effective and safe as non-genetic dosing [5]. CPIC calculated that poor metabolizers would need about a 30% lower dose, but because that is hard to achieve with the tablet strengths available, it settled on a 25% to 50% reduction [2].

The FDA label gives no genotype-based dose. FDA's Table of Pharmacogenetic Associations lists fluvoxamine with CYP2D6 poor metabolizers in its section for effects on drug levels only: higher systemic concentrations, use with caution [6].

Bring the report to your prescriber or pharmacist with a list of everything you take. CPIC notes that people who are stable on an effective dose without troublesome side effects may not benefit from genotype-based changes [2]. Do not start, stop or change fluvoxamine because of a genetic result without talking to your prescriber.

Fluvoxamine affects other medicines

Fluvoxamine is a potent inhibitor of CYP1A2 and also inhibits CYP2C19, CYP3A4 and CYP2C9; in laboratory studies it is a relatively weak CYP2D6 inhibitor [1]. FDA lists it as a strong inhibitor of CYP1A2 and CYP2C19 [7]. The label contraindicates it with four drugs: tizanidine, whose exposure rose 33-fold in a study; thioridazine, whose levels tripled; pimozide; and alosetron [1]. It also flags drugs with a narrow margin between effective and toxic doses, including warfarin, theophylline, phenytoin and omeprazole [1].

Because fluvoxamine strongly blocks CYP2C19, the CYP2C19 results in your report may not reflect how that enzyme works while you take it. This mismatch between genes and actual metabolism is called phenoconversion, and CPIC notes there is no agreed method for adjusting a predicted phenotype for it [2].

Quinidine, a CYP2D6 inhibitor, is the example the label gives of a drug that warrants caution with fluvoxamine [1]; FDA's list of strong CYP2D6 inhibitors also includes bupropion, fluoxetine, paroxetine and terbinafine [7].

Consumer arrays from 23andMe, AncestryDNA and MyHeritage are not clinical-grade tests, and their raw data is labeled as not for medical use. They read fixed positions and can miss rare variants. Array processing uses imputation to infer some variants that were not measured directly, but a variant at a position the data does not cover cannot be seen, so a normal result means none of the assessed variants was found among the positions your data covers. "Indeterminate" means the alleles found could not be assigned a function.

Age and liver function change fluvoxamine clearance on their own [1], and a genotype does not account for the other medicines you take.

Does CYP2C19 affect fluvoxamine?

CPIC makes CYP2C19-based recommendations for citalopram, escitalopram and sertraline, not for fluvoxamine [2]. The CYP2C19 issue with fluvoxamine runs the other way: it blocks the enzyme; see Using your result.

My result is intermediate. Should my dose be lower?

CPIC advises the usual starting dose for intermediate metabolizers [2].

1. Fluvoxamine maleate tablets (Apotex): prescribing information. DailyMed, US National Library of Medicine. Indication, dosing, the CYP2D6 poor metabolizer study and contraindicated combinations.
2. Bousman CA et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes and serotonin reuptake inhibitor antidepressants. Clin Pharmacol Ther (2023). CPIC recommendations and the evidence behind them.
3. CPIC. CYP2D6 allele functionality table (spreadsheet). Function and activity value of each CYP2D6 allele, including the duplications.
4. CPIC. CYP2D6 frequency table (spreadsheet). Allele and phenotype frequencies by biogeographic group, with methods and caveats.
5. CPIC. Assignment of CPIC levels for genes/drugs (ClinPGx). What the CPIC levels mean.
6. US Food and Drug Administration. Table of Pharmacogenetic Associations. FDA's summary of gene-drug interactions in labeling.
7. US Food and Drug Administration. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong and moderate CYP2D6 and CYP2C19 inhibitors and inducers.