Fluvoxamine

Drug Interactions (not described in Contraindications or Warnings And Precautions ) include the following: Drugs Inhibiting or Metabolized by Cytochrome P450: Fluvoxamine inhibits several cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP3A4, and CYP2C19). Carbamazepine : Elevated carbamazepine levels and symptoms of toxicity with coadministration ( 7.2 ). Sumatriptan : Rare postmarketing reports of weakness, hyperreflexia, and incoordination following use of an SSRI and sumatriptan. Monitor appropriately if concomitant treatment is clinically warranted ( 7.2 ).

Tacrine : Coadministration increased tacrine C max and AUC five- and eight-fold and caused nausea, vomiting, sweating, and diarrhea ( 7.2 ). Tricyclic Antidepressants (TCAs) : Coadministration significantly increased plasma TCA levels. Use caution; monitor plasma TCA levels; reduce TCA dose if indicated ( 7.2 ). Tryptophan : Severe vomiting with coadministration ( 7.2 ). Diltiazem : Bradycardia with coadministration ( 7.3 ). Propranolol or metoprolol : Reduce dose if coadministered and titrate more cautiously ( 7.3 ).

7.1 Potential Interactions with Drugs that Inhibit or are Metabolized by Cytochrome P450 Isoenzymes Multiple hepatic cytochrome P450 isoenzymes 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 cytochrome P450 isoenzyme 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 and Precautions ( 5 ) ] and limited in vitro data for CYP3A4, it appears that fluvoxamine inhibits several cytochrome P450 isoenzymes that are known to be involved in the metabolism of other drugs such as: CYP1A2 (e.g., warfarin, theophylline, propranolol, tizanidine), CYP2C9 (e.g., warfarin), CYP3A4 (e.g., alprazolam), and CYP2C19 (e.g., omeprazole). In vitro data suggest that fluvoxamine is a relatively weak inhibitor of CYP2D6. Approximately 7% of the normal population has a genetic code that leads to reduced levels of activity of CYP2D6.

Such individuals have been referred to as "poor metabolizers" (PM) of drugs such as debrisoquin, dextromethorphan, and tricyclic antidepressants. While none of the drugs studied for drug interactions significantly affected the pharmacokinetics of fluvoxamine, an in vivo study of fluvoxamine single-dose pharmacokinetics in 13 PM subjects demonstrated altered pharmacokinetic properties compared to 16 "extensive metabolizers" (EM): mean C max , AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group. This suggests that fluvoxamine is metabolized, at least in part, by CYP2D6.

Caution is indicated in patients known to have reduced levels of CYP2D6 activity and those receiving concomitant drugs known to inhibit this cytochrome P450 isoenzyme (e.g., quinidine). The metabolism of fluvoxamine has not been fully characterized and the effects of potent cytochrome P450 isoenzyme inhibition, such as the ketoconazole inhibition of CYP3A4, on fluvoxamine metabolism have not been studied. A clinically significant fluvoxamine interaction is possible with drugs having a narrow therapeutic ratio such as pimozide, warfarin, theophylline, certain benzodiazepines, omeprazole 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 [see Contraindications ( 4 ), Warnings and Precautions ( 5 )] .

7.2 CNS Active Drugs Antipsychotics: See Warnings and Precautions ( 5.2 ) . Benzodiazepines: See Warnings and Precautions ( 5.8 ) . Alprazolam: See Warnings and Precautions ( 5.8 ) . Diazepam: See Warnings and Precautions ( 5.8 ) . Lorazepam: A study of multiple doses of fluvoxamine maleate (50 mg b.i.d.) in healthy male volunteers (N=12) and a single dose of lorazepam (4 mg single dose) indicated no significant pharmacokinetic interaction. On average, both lorazepam alone and lorazepam with fluvoxamine produced substantial decrements in cognitive functioning; however, the coadministration of fluvoxamine and lorazepam did not produce larger mean decrements compared to lorazepam alone.

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 b.i.d.) revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of the other. As with other psychotropic medications, patients should be advised to avoid alcohol while taking Fluvoxamine Maleate Tablets. Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity have been reported with the coadministration of fluvoxamine maleate and carbamazepine. Clozapine: See Warnings and Precautions ( 5.8 ) .

Lithium: As with other serotonergic drugs, lithium may enhance the serotonergic effects of fluvoxamine and, therefore, the combination should be used with caution. Seizures have been reported with the coadministration of fluvoxamine maleate and lithium. Methadone: See Warnings and Precautions ( 5.8 ) . Monoamine Oxidase Inhibitors: See Dosage and Administration ( 2.4 , 2.5 ), Contraindications ( 4 ), Warnings and Precautions ( 5.2 ) . Pimozide: See Contraindications ( 4 ), Warnings and Precautions ( 5.6 ) . Ramelteon: See Warnings and Precautions ( 5.8 ) .

Other Serotonergic Drugs: The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with Fluvoxamine Maleate Tablets increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Fluvoxamine Maleate Tablets and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.2 )] .

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 C max and AUC, respectively, compared to the administration of tacrine alone. Five subjects experienced nausea, vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine. Thioridazine: See Contraindications ( 4 ), Warnings and Precautions ( 5.4 ) . Tizanidine: See Contraindications ( 4 ), Warnings and Precautions ( 5.5 ) .

Tricyclic Antidepressants (TCAs): Significantly increased plasma TCA levels have been reported with the coadministration of fluvoxamine maleate and amitriptyline, clomipramine or imipramine. Caution is indicated with the coadministration of Fluvoxamine Maleate Tablets and TCAs; plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced. Triptans: There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan.

If concomitant treatment of fluvoxamine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions ( 5.2 )] . 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 (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.

Tryptophan: Tryptophan may enhance the serotonergic effects of fluvoxamine, and the combination should, therefore, be used with caution. Severe vomiting has been reported with the coadministration of fluvoxamine maleate and tryptophan [see Warnings and Precautions ( 5.2 )] .

7.3 Other Drugs Alosetron: See Contraindications ( 4 ), Warnings and Precautions ( 5.7 ) , and Lotronex TM (alosetron) package insert. Digoxin: Administration of fluvoxamine maleate 100 mg daily for 18 days (N=8) did not significantly affect the pharmacokinetics of a 1.25 mg single intravenous dose of digoxin. Diltiazem: Bradycardia has been reported with the coadministration of fluvoxamine maleate and diltiazem. Mexiletine: See Warnings and Precautions ( 5.8 ) . Propranolol and Other Beta-Blockers: Coadministration of fluvoxamine maleate 100 mg per day and propranolol 160 mg per day in normal volunteers resulted in a mean five-fold increase (range 2 to 17) in minimum…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.

Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.10 ) and Clinical Considerations] . Prolonged experience with fluvoxamine in pregnant women over decades, based on published observational studies, have not identified a clear drug-associated risk of major birth defects or miscarriage ( see Data ).

There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (PPHN) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, during pregnancy ( see Clinical Considerations ). When pregnant rats were treated orally with fluvoxamine throughout the period of organogenesis, increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses ≥3 times the maximum recommended human dose (MRHD) of 300 mg/day given to adolescents on a mg/m 2 basis.

In addition, decreased fetal body weight was seen at a dose 6 times the MRHD given to adolescents on a mg/m 2 basis. There were no adverse developmental effects in rabbits treated with fluvoxamine during the period of organogenesis up to a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. When fluvoxamine was administered orally to rats during pregnancy and lactation, increased pup mortality at birth was seen at a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. In addition, decreases in pup body weight and survival were observed at doses that are ≥0.13 times the MRHD given to adolescents (see Data) .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations…