Obsessive-compulsive disorder (OCD), ages 8 and older (fluvoxamine and fluvoxamine CR)
Social anxiety disorder (fluvoxamine CR)
Mechanism of Action
Fluvoxamine presumably increases serotonergic neurotransmission by blocking the serotonin reuptake pump (transporter), which results in desensitization of serotonin receptors, especially serotonin 1A receptors
Fluvoxamine also binds at sigma 1 receptors
Formulation
Tablets 25 mg, 50 mg scored, 100 mg scored
Controlled-release capsules 100 mg, 150 mg
How to Dose
In children (immediate release): initial dose 25 mg at bedtime; can increase by 25 mg every 4–7 days; maximum dose 200 mg/day; daily doses over 50 mg should be divided
In adolescents (immediate release): initial dose 25 mg at bedtime; can increase by 25 mg every 4–7 days; maximum dose 300 mg/day; daily doses over 50 mg should be divided
In adults (immediate-release): initial dose 50 mg/day; increase by 50 mg/day in 4–7 days; usually wait a few weeks to assess drug effects before increasing dose further, but can increase by 50 mg/day every 4–7 days until desired efficacy is reached; maximum 300 mg/day; daily doses over 100 mg can be divided or given as a single dose at night
In adults (controlled-release): initial dose 100 mg/day; increase by 50 mg/day each week until desired efficacy is reached; maximum generally 300 mg/day
Dosing Tips
To improve tolerability of immediate-release formulation, dosing can either be given once a day, usually all at night, or split either symmetrically or asymmetrically, usually with more of the dose given at night
Some patients take more than 300 mg/day
Controlled-release capsules should not be chewed or crushed
The more anxious and agitated the patient, the lower the starting dose, the slower the titration, and the more likely the need for a concomitant agent such as trazodone or even a benzodiazepine if warranted
If intolerable anxiety, insomnia, agitation, akathisia, or activation occur either upon dosing initiation or discontinuation, consider the possibility of activated bipolar disorder and switch to an atypical antipsychotic or a mood stabilizer
These symptoms may also indicate the need to evaluate for a mixed features episode and thus discontinuing fluvoxamine and considering an atypical antipsychotic or a mood stabilizer or lithium
Notable or Dangerous Side Effects
Mostly central nervous system side effects (insomnia but more so sedation, especially if not sleeping at night; agitation, tremors, headache, dizziness)
Treatment-emergent activation syndrome (TEAS) includes hypomania, agitation, anxiety, panic attacks, irritability, hostility/aggression, impulsivity, insomnia, and suicidality
Sexual dysfunction (men: delayed ejaculation, erectile dysfunction; men and women: decreased sexual desire, anorgasmia)
Autonomic (sweating)
Bruising and rare bleeding, especially if combined with NSAIDS, aspirin, antiplatelet or anticoagulant drugs
SIADH (syndrome of inappropriate antidiuretic hormone secretion) (risk is higher in the elderly)
Rare: seizures, hyponatremia, induction of mania, activation of suicidal ideation and behavior (suicidality) (short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo beyond age 24)
Warnings
Add or initiate other antidepressants with caution for up to 2 weeks after discontinuing fluvoxamine
As with any antidepressant, use with caution in patients with history of seizure
As with any antidepressant, use with caution in patients with bipolar disorder unless treated with concomitant mood-stabilizing agent
May cause photosensitivity
Carefully weigh the risks and benefits of pharmacological treatment against the risks and benefits of nontreatment with antidepressants and it is a good idea to document this in the patient’s chart
Warn patients and their caregivers about the possibility of activating side effects and advise them to report such symptoms immediately
Monitor patients for activation of suicidal ideation, especially children and adolescents
Contraindications
If the patient is taking an MAO inhibitor
If the patient is taking thioridazine, pimozide, tizanidine, alosetron, or ramelteon
Many patients tolerate 50% dose reduction for 3 days, then another 50% reduction for 3 days, then discontinuation
If withdrawal symptoms emerge during discontinuation, raise dose to stop symptoms and then restart withdrawal much more slowly
Pharmacokinetics
Parent drug has 9–28-hour half-life in adults
Steady-state plasma concentrations are higher in children than in adolescents or adults
Substrate for CYP450 2D6
Inhibits CYP450 3A4, 1A2, and 2C9/2C19
Drug Interactions
Tramadol increases the risk of seizures in patients taking an antidepressant
Can increase tricyclic antidepressant levels; use with caution with tricyclic antidepressants
Can cause a fatal “serotonin syndrome” when combined with MAO inhibitors, so do not use with MAO inhibitors or for at least 14 days after MAOIs are stopped
Do not start an MAO inhibitor for at least 5 half-lives (5 to 7 days for most drugs) after discontinuing fluvoxamine
May displace highly protein-bound drugs (e.g., warfarin)
Can rarely cause weakness, hyperreflexia, and incoordination when combined with sumatriptan or possibly with other triptans, requiring careful monitoring of patient
Possible increased risk of bleeding, especially when combined with anticoagulants (e.g., warfarin, NSAIDs)
NSAIDs may impair the effectiveness of SSRIs
Via CYP450 1A2 inhibition, fluvoxamine may reduce the clearance of theophylline and clozapine, thus raising their levels and requiring their dosing to be lowered
Fluvoxamine administered with either caffeine or theophylline can thus cause jitteriness, excessive stimulation, or rarely seizures, so concomitant use should proceed cautiously
Metabolism of fluvoxamine may be enhanced in smokers and thus its levels lowered, requiring higher dosing
Via CYP450 3A4 inhibition, fluvoxamine may reduce the clearance of carbamazepine and benzodiazepines such as alprazolam and triazolam, and thus require dosage reduction
Via CYP450 3A4 inhibition, fluvoxamine could theoretically increase concentrations of certain cholesterol-lowering HMG CoA reductase inhibitors, especially simvastatin, atorvastatin, and lovastatin, but not pravastatin or fluvastatin, which would increase the risk of rhabdomyolysis; thus, coadministration of fluvoxamine with certain HMG CoA reductase inhibitors should proceed with caution
Via CYP450 3A4 inhibition, fluvoxamine could theoretically increase the concentrations of pimozide, and cause QTc prolongation and dangerous cardiac arrhythmias
Pregnancy
Controlled studies have not been conducted in pregnant women
Not generally recommended for use during pregnancy, especially during the first trimester
Nonetheless, continuous treatment during pregnancy may be necessary and has not been proven to be harmful to the fetus
Must weigh the risk of treatment (first-trimester fetal development, third-trimester newborn delivery) to the child against the risk of no treatment (recurrence of depression, maternal health, infant bonding) to the mother and child
For many patients, this may mean continuing treatment during pregnancy
Exposure to SSRIs early in pregnancy may be associated with an increased risk of septal heart defects (absolute risk is small)
SSRI use beyond the 20th week of pregnancy may be associated with increased risk of pulmonary hypertension in newborns, although this is not proven
Exposure to SSRIs late in pregnancy may be associated with increased risk of gestational hypertension and preeclampsia
Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding; reported symptoms are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome, and include respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying
At delivery, there may be more bleeding in the mother and transient irritability or sedation in the newborn
Renal Impairment
Consider lower initial dose
Hepatic Impairment
Lower dose or give less frequently, perhaps by half; use slower titration
Cardiac Impairment
Preliminary research suggests that fluvoxamine is safe in these patients
Treating depression with SSRIs in patients with acute angina or following myocardial infarction may reduce cardiac events and improve survival as well as mood
Pearls
Often a preferred treatment of anxious depression as well as major depressive disorder comorbid with anxiety disorders
Some withdrawal effects, especially gastrointestinal effects
May have lower incidence of sexual dysfunction than other SSRIs
Not FDA approved for depression, but used widely for depression in many countries
CR formulation may be better tolerated than immediate-release formulation, particularly with less sedation
SSRIs may be less effective in women over 50, especially if they are not taking estrogen
SSRIs may be useful for hot flushes in perimenopausal women
Actions at sigma 1 receptors may explain in part fluvoxamine’s sometimes rapid onset effects in anxiety disorders and insomnia
Actions at sigma 1 receptors may explain potential advantages of fluvoxamine for psychotic depression and delusional depression
For treatment-resistant OCD, consider cautious combination of fluvoxamine and clomipramine by an expert
Normally, clomipramine (CMI), a potent serotonin reuptake blocker, at steady state is metabolized extensively to its active metabolite desmethyl-clomipramine (de-CMI), a potent noradrenergic reuptake blocker
Thus, at a steady state, plasma drug activity is generally more noradrenergic (with higher de-CMI levels) than serotonergic (with lower parent CMI levels)
The addition of a CYP450 1A2 inhibitor, fluvoxamine, blocks this conversion and results in higher CMI levels than de-CMI levels
Thus, the addition of the SSRI fluvoxamine to CMI in treatment-resistant OCD can powerfully enhance serotonergic activity, not only due to the inherent serotonergic activity of fluvoxamine but also due to a favorable pharmacokinetic interaction inhibiting CYP450 1A2 and thus converting CMI’s metabolism to a more powerful serotonergic portfolio of parent drug