Fluvoxamine

Indications

• FDA-approved for obsessive-compulsive disorder in adults and in pediatric patients aged 8 to 17, the only US indication for the tablets.
• The extended-release capsule is additionally FDA-approved for social anxiety disorder in adults at 100-300 mg once daily.
• Not approved for major depressive disorder in the United States, although it is licensed and widely used for depression elsewhere.
• Off-label for panic disorder, post-traumatic stress disorder, and binge-eating disorder when other serotonergic agents have failed.
• Off-label at low doses for insomnia or for augmenting clozapine exposure, a strategy that demands close clozapine level monitoring.
• Its potent sigma-1 agonism has driven off-label interest in catatonia and delirium, but the supporting evidence remains preliminary.

Mechanism of action

• Potent serotonin transporter inhibitor with no meaningful affinity for norepinephrine or dopamine transporters at therapeutic concentrations.
• Has the highest sigma-1 receptor agonist potency of any SSRI, which may modulate glutamate signaling and endoplasmic reticulum stress responses.
• Sustained transporter blockade desensitizes 5-HT1A autoreceptors and downregulates postsynaptic 5-HT2 receptors over the weeks of OCD response.
• Free of muscarinic, histaminic, and alpha-1 blockade, so its tolerability problems are gastrointestinal and sedative rather than anticholinergic.
• Potent inhibition of CYP1A2 and CYP2C19 is a molecular property unrelated to serotonin reuptake and defines its clinical interaction risk.

Pharmacokinetics

• Well absorbed with about 53 percent bioavailability due to first-pass metabolism; food does not meaningfully change the extent of absorption.
• Half-life is roughly 15 to 16 hours, short enough that doses above 100 mg/day of the tablet are conventionally split twice daily.
• Metabolized primarily by CYP2D6 through oxidative demethylation, with no clinically active metabolites contributing to effect.
• Kinetics are nonlinear, so a doubling of dose can more than double plasma concentration, especially across the 100 to 300 mg range.
• Cigarette smoking induces CYP1A2 and lowers fluvoxamine levels by roughly 25 percent, so levels rise when a patient quits smoking.

Dosing

• Start the tablet at 50 mg PO at bedtime and increase by 50 mg every four to seven days as tolerated toward the target dose.
• Adult maximum is 300 mg/day; total daily doses above 100 mg are divided twice daily with the larger portion given at bedtime.
• Pediatric OCD starts at 25 mg at bedtime with 25 mg increments; the maximum is 200 mg/day in ages 8 to 11 and 300 mg/day in adolescents.
• The extended-release capsule starts at 100 mg at bedtime, increases by 50 mg weekly, and is given once daily up to 300 mg/day.
• In hepatic impairment reduce the starting dose and titrate more slowly, since clearance falls by about 30 percent in cirrhosis.
• Taper over several weeks when stopping, since the short half-life makes discontinuation symptoms common after abrupt cessation.

Adverse effects

• Nausea affects up to 40 percent of patients and is the most common reason for early discontinuation, though it usually abates within two weeks.
• Somnolence and sedation are more prominent than with other SSRIs, which is why the dose is anchored at bedtime from the outset.
• Sexual dysfunction, insomnia, headache, asthenia, and dry mouth are common and roughly comparable to rates seen with other SSRIs.
• Hyponatremia from SIADH, increased bleeding risk with NSAIDs or anticoagulants, and treatment-emergent mania are the serious concerns.
• Serotonin syndrome risk is amplified because CYP inhibition raises levels of many co-prescribed serotonergic and sedating drugs.
• Anorexia and weight loss occur early, though weight typically normalizes with longer-term treatment at a stable dose.

Monitoring

• Review every co-prescribed medication for CYP1A2 and CYP2C19 dependence before starting, and again at each dose increase.
• Check clozapine and olanzapine levels within one week of starting or changing fluvoxamine, since exposure can rise several-fold.
• Assess suicidality, activation, and agitation weekly for the first four weeks and after each dose change, especially under age 25.
• Track OCD response with the Y-BOCS every four weeks, allowing 10 to 12 weeks at an adequate dose before declaring nonresponse.
• Check serum sodium at baseline and within two to four weeks in older adults or patients on diuretics.

Interactions

• Contraindicated with MAOIs, linezolid, tizanidine, thioridazine, pimozide, alosetron, and ramelteon because of markedly raised exposure.
• Potent CYP1A2 inhibition raises clozapine, olanzapine, theophylline, caffeine, duloxetine, and melatonin levels, sometimes dangerously.
• Potent CYP2C19 inhibition raises diazepam, omeprazole, phenytoin, and citalopram exposure, and moderate 3A4 and 2C9 inhibition raises warfarin INR.
• Additive serotonin syndrome risk with triptans, tramadol, fentanyl, lithium, and St. John's wort, compounded by its CYP effects.
• Smoking status changes exposure by about 25 percent through CYP1A2 induction, so reassess dose when a patient starts or stops smoking.

Special populations

• Limited pregnancy data show no clear teratogenic signal, but the small dataset means better-studied SSRIs are usually preferred.
• Relative infant dose in breast milk is low, under 2 percent, so fluvoxamine is generally considered acceptable during lactation.
• Approved from age 8 for OCD; female pediatric patients often need lower doses than males, and adolescents tolerate adult ceilings.
• In older adults clearance is about 50 percent lower, so start at 25 mg and titrate slowly with attention to sedation and falls.
• Reduce the starting dose in hepatic impairment; no adjustment is required for renal impairment since elimination is hepatic.

Clinical pearls

• The 1A2 problem: fluvoxamine can triple clozapine levels and cause seizures or severe sedation.
• Only SSRI approved in the US solely for OCD, with the ER capsule adding social anxiety disorder.
• Doses above 100 mg/day of the tablet are split twice daily, larger dose at bedtime.