What are the potential drug interactions with fluvoxamine (Luvox)?

From the Guidelines

Fluvoxamine has numerous significant drug interactions that require careful monitoring, particularly with medications metabolized by CYP1A2, CYP2C19, CYP2C9, CYP3A4, and CYP2D6, and should be avoided or used with caution in combination with MAOIs, certain antipsychotics, benzodiazepines, warfarin, and other serotonergic drugs due to increased risk of serotonin syndrome, cardiac arrhythmias, or excessive sedation 1.

Key Interactions

• Fluvoxamine strongly inhibits CYP1A2 and CYP2C19 enzymes, potentially increasing blood levels of medications metabolized through these pathways, such as alprazolam, triazolam, and certain antipsychotics 1.
• Combining fluvoxamine with other serotonergic drugs like SSRIs, SNRIs, triptans, tramadol, or St. John's Wort increases serotonin syndrome risk 1.
• Fluvoxamine can also enhance the effects of caffeine, potentially causing jitteriness or anxiety, and increases levels of warfarin, methadone, theophylline, requiring dose adjustments 1.

Recommendations

• When prescribing fluvoxamine, it is essential to carefully review the patient's medication list and medical history to identify potential drug interactions, and to start with a low dose and gradually increase as needed and tolerated, while monitoring for symptoms of serotonin syndrome or other adverse effects 1.
• Alternative SSRIs, such as sertraline or citalopram/escitalopram, may be considered if a lower risk of drug interactions is desired, particularly in patients taking medications that are substrates of CYP2C9 or CYP3A4, such as warfarin 1.
• Patients should be closely monitored for signs of serotonin syndrome, cardiac arrhythmias, or excessive sedation, and educated on the risks and symptoms of these potential interactions 1.

From the FDA Drug Label

Patients should be cautioned about the concomitant use of fluvoxamine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when fluvoxamine and tizanidine are used together, fluvoxamine should not be used with tizanidine Because of the potential for the increased risk of serious adverse reactions when fluvoxamine and alosetron are used together, fluvoxamine should not be used with Lotronex™ (alosetron). Potential Interactions with Drugs that Inhibit or are Metabolized by Cytochrome P450 Isozymes Multiple hepatic cytochrome P450 (CYP450) enzymes are involved in the oxidative biotransformation of a large number of structurally different drugs and endogenous compounds The available knowledge concerning the relationship of fluvoxamine and the CYP450-enzyme system has been obtained mostly from pharmacokinetic interaction studies conducted in healthy volunteers, but some preliminary in vitro data are also available Based on a finding of substantial interactions of fluvoxamine with certain of these drugs (see later parts of this section and also WARNINGS for details) and limited in vitro data for the 3A4 isozyme, it appears that fluvoxamine inhibits the following isozymes that are known to be involved in the metabolism of the listed drugs: 1A2, 2C9, 3A4, 2C19 Warfarin, Alprazolam, Omeprazole, Theophylline, Propranolol, Tizanidine In vitro data suggest that fluvoxamine is a relatively weak inhibitor of the 2D6 isozyme. A clinically significant fluvoxamine interaction is possible with drugs having a narrow therapeutic ratio such as terfenadine, astemizole, cisapride, or pimozide, warfarin, theophylline, certain benzodiazepines and phenytoin If Fluvoxamine Maleate Tablets are to be administered together with a drug that is eliminated via oxidative metabolism and has a narrow therapeutic window, plasma levels and/or pharmacodynamic effects of the latter drug should be monitored closely, at least until steady-state conditions are reached CNS Active Drugs Alcohol Studies involving single 40 g doses of ethanol (oral administration in one study and intravenous in the other) and multiple dosing with fluvoxamine maleate (50 mg bid) revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of the other. Alprazolam See WARNINGS Antipsychotics See WARNINGS-Other Potentially Important Drug Interactions – Neuroleptic Malignant Syndrome (NMS) or NMS-Like Events. Diazepam See WARNINGS. Carbamazepine Elevated carbamazepine levels and symptoms of toxicity have been reported with the co-administration of fluvoxamine maleate and carbamazepine Clozapine Elevated serum levels of clozapine have been reported in patients taking fluvoxamine maleate and clozapine. Lithium As with other serotonergic drugs, lithium may enhance the serotonergic effects of fluvoxamine and, therefore, the combination should be used with caution. Lorazepam A study of multiple doses of fluvoxamine maleate (50 mg bid) in healthy male volunteers (N=12) and a single dose of lorazepam (4 mg single dose) indicated no significant pharmacokinetic interaction Methadone Significantly increased methadone (plasma level:dose) ratios have been reported when fluvoxamine maleate was administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient. Monoamine Oxidase Inhibitors See WARNINGS Serotonergic Drugs Based on the mechanism of action of fluvoxamine and the potential for serotonin syndrome, caution is advised when fluvoxamine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St John's Wort (see WARNINGS – Serotonin Syndrome). The concomitant use of fluvoxamine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS – Drug Interactions). Sumatriptan There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan If concomitant treatment with sumatriptan and an SSRI (eg. fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised Tacrine In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five- and eight-fold increases in tacrine Cmax and AUC, respectively, compared to the administration of tacrine alone Five subjects experienced nausea, vomiting, sweating, and diarrhea following co-administration, consistent with the cholinergic effects of tacrine

Fluvoxamine Drug Interactions:

• Contraindications:
  • Tizanidine
  • Alosetron
  • MAOIs
  • Thioridazine
  • Terfenadine
  • Astemizole
  • Cisapride
  • Pimozide
• Caution:
  • NSAIDs
  • Aspirin
  • Other drugs that affect coagulation
  • Lithium
  • Serotonergic drugs
  • Sumatriptan
  • Tacrine
• Monitor closely:
  • Warfarin
  • Theophylline
  • Certain benzodiazepines
  • Phenytoin
  • Carbamazepine
  • Clozapine
  • Methadone 2 2 2

From the Research

Fluvoxamine Drug Interactions

• Fluvoxamine is a potent and selective serotonin reuptake inhibitor (SSRI) that has little or no effect on other monoamine reuptake mechanisms 3.
• It is a weak inhibitor of cytochrome P450 (CYP) 2D6, a moderate inhibitor of CYP2C19 and CYP3A4, and a potent inhibitor of CYP1A2 3.
• Fluvoxamine can increase plasma concentrations of tricyclic antidepressants, particularly those of clomipramine, by varying extents 4.
• The drug can also interact with anti-epileptic or antidepressant drugs, resulting in elevated plasma concentrations of the target drug and/or clinical symptoms 4.
• Agents metabolized by cytochrome P450 1A2 isoenzyme appear most likely to be involved in drug-drug interactions with fluvoxamine 4.
• Fluvoxamine has the potential to inhibit CYP1A2, CYP2C9, CYP2C19, and CYP3A4 to a significant degree, which can result in an increase in the anticoagulant effect of warfarin 5.
• The coadministration of warfarin and fluvoxamine can result in an elevated international normalized ratio (INR) that can persist for several days after the discontinuation of fluvoxamine 5.
• Fluvoxamine shows minimal in vivo pharmacokinetic interaction with desipramine, but does interact with imipramine through inhibition of CYP3A3/4, CYP1A2, and CYP2C19 6.
• The extent of the in vivo interaction between fluvoxamine and tricyclic antidepressants mirrors to a large extent their in vitro inhibitory potencies against CYP2D6 and other isoenzyme systems 6.

Specific Interactions

• Fluvoxamine and warfarin: coadministration can result in an increased anticoagulant effect of warfarin 5.
• Fluvoxamine and tricyclic antidepressants: can increase plasma concentrations of tricyclic antidepressants, particularly those of clomipramine 4.
• Fluvoxamine and desipramine: shows minimal in vivo pharmacokinetic interaction 6.
• Fluvoxamine and imipramine: can interact through inhibition of CYP3A3/4, CYP1A2, and CYP2C19 6.