Fluvoxamine Maleate (Page 3 of 12)

5.3 Angle Closure Glaucoma

​Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including fluvoxamine maleate extended-release capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

5.4 Potential Thioridazine Interaction

The effect of fluvoxamine (25 mg immediate-release tablets given twice daily for one week) on thioridazine steady-state concentrations was evaluated in 10 male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased 3-fold following coadministration of fluvoxamine.

Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. It is likely that this experience underestimates the degree of risk that might occur with higher doses of thioridazine. Moreover, the effect of fluvoxamine may be even more pronounced when it is administered at higher doses.

Therefore, fluvoxamine maleate extended-release capsules should not be coadministered with thioridazine (see Contraindications [4]).

5.5 Potential Tizanidine Interaction

Fluvoxamine is a potent inhibitor of CYP1A2, and tizanidine is a CYP1A2 substrate. The effect of immediate-release fluvoxamine maleate tablets (100 mg daily for four days) on the pharmacokinetics and pharmacodynamics of a single dose of tizanidine has been studied in 10 healthy male subjects. Tizanidine Cmax was increased approximately 12-fold (range 5-fold to 32-fold), elimination half-life was increased by almost 3-fold, and AUC increased 33-fold (range 14-fold to 103-fold). The mean maximal effect on blood pressure was a 35 mm Hg decrease in systolic blood pressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased, and performance on the psychomotor task was significantly impaired. Fluvoxamine maleate extended-release capsules and tizanidine should not be used together (see Contraindications [4]).

5.6 Potential Pimozide Interaction

Pimozide is metabolized by the CYP3A4 isozyme and it has been demonstrated that ketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma concentrations of parent drug. An increased plasma concentration of pimozide causes QT prolongation and has been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal. As noted below, a substantial pharmacokinetic interaction has been observed for fluvoxamine in combination with alprazolam, a drug that is known to be metabolized by the CYP3A4 isozyme. Although it has not been definitively demonstrated that fluvoxamine is a potent CYP3A4 inhibitor, it is likely to be, given the substantial interaction of fluvoxamine with alprazolam. Consequently, it is recommended that fluvoxamine not be used in combination with pimozide (see Contraindications [4]).

5.7 Potential Alosetron Interaction

In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 to 200 mg/day for 16 days with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentrations (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. Consequently, it is recommended that fluvoxamine maleate extended-release capsules not be used in combination with alosetron (see Contraindications [4] and Lotronex® (alosetron) package insert).

5.8 Potential Ramelteon Interaction

When immediate-release fluvoxamine maleate tablets 100 mg twice daily were administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and immediate-release fluvoxamine maleate tablets, the AUC for ramelteon increased approximately 190-fold and the Cmax increased approximately 70-fold compared to ramelteon administered alone. Ramelteon should not be used in combination with fluvoxamine maleate extended-release capsules (see Contraindications [4]).

5.9 Other Potentially Important Drug Interactions

Benzodiazepines: Benzodiazepines metabolized by hepatic oxidation (e.g., alprazolam, midazolam, triazolam, etc.) should be used with caution because the clearance of these drugs is likely to be reduced by fluvoxamine. The clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine.

Alprazolam — When immediate-release fluvoxamine maleate tablets (100 mg given once daily) and alprazolam (1 mg given 4 times per day) were coadministered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, Cmax , T½ ) of alprazolam were approximately twice those observed when alprazolam was administered alone; oral clearance was reduced by about 50%. The elevated plasma alprazolam concentrations resulted in decreased psychomotor performance and memory. This interaction, which has not been investigated using higher doses of fluvoxamine, may be more pronounced if a 300 mg daily dose is coadministered, particularly since fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100 to 300 mg. If alprazolam is coadministered with fluvoxamine maleate extended-release capsules, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended. No dosage adjustment is required for fluvoxamine maleate extended-release capsules.

Diazepam — The coadministration of fluvoxamine maleate extended-release capsules and diazepam is generally not advisable. Because fluvoxamine reduces the clearance of both diazepam and its active metabolite, N-desmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic coadministration.

Evidence supporting the conclusion that it is inadvisable to coadminister fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of immediate-release fluvoxamine maleate tablets were administered a single oral dose of 10 mg of diazepam. In these subjects (N=8), the clearance of diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was too low to measure over the course of the 2-week-long study.

It is likely that this experience significantly underestimates the degree of accumulation that might occur with repeated diazepam administration. Moreover, as noted with alprazolam, the effect of fluvoxamine may even be more pronounced when it is administered at higher doses.

Accordingly, diazepam and fluvoxamine should not ordinarily be coadministered.

Clozapine: Elevated serum levels of clozapine have been reported in patients taking immediate-release fluvoxamine maleate tablets and clozapine. Since clozapine-related seizures and orthostatic hypotension appear to be dose related, the risk of these adverse reactions may be higher when fluvoxamine and clozapine are coadministered. Patients should be closely monitored when fluvoxamine maleate extended-release capsules and clozapine are used concurrently.

Methadone: Significantly increased methadone (plasma level:dose) ratios have been reported when immediate-release fluvoxamine maleate tablets were administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient. Opioid withdrawal symptoms were reported following fluvoxamine maleate discontinuation in another patient.

Mexiletine: The effect of steady-state fluvoxamine (50 mg given twice daily for 7 days) on the single dose pharmacokinetics of mexiletine (200 mg) was evaluated in 6 healthy Japanese males. The clearance of mexiletine was reduced by 38% following coadministration with fluvoxamine compared to mexiletine alone. If fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored.

Theophylline: The effect of steady-state immediate-release fluvoxamine maleate tablets (50 mg tablets given twice daily) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is coadministered with fluvoxamine maleate, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for fluvoxamine maleate extended-release capsules.

Warfarin and Other Drugs that Interfere with Hemostasis (NSAIDs, Aspirin, etc.): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluvoxamine (see Warnings and Precautions-Abnormal Bleeding [5.11]).

Warfarin — When immediate-release fluvoxamine maleate tablets (50 mg given three times daily) were administered concomitantly with warfarin for two weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and fluvoxamine maleate extended-release capsules should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for fluvoxamine maleate extended-release capsules.

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