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Luvox CR (Fluvoxamine Maleate) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

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 ] for details) 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 enzyme. 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 Cmax, 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 cytochrome P450 2D6 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 LUVOX CR Capsules 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 ] and WARNINGS AND PRECAUTIONS [ 5 ]).

CNS Active Drugs

      Antipsychotics: See WARNINGS AND PRECAUTIONS (5.2).

      Benzodiazepines: See WARNINGS AND PRECAUTIONS (5.9).

      Alprazolam: See WARNINGS AND PRECAUTIONS (5.9).

      Diazepam: See WARNINGS AND PRECAUTIONS (5.9).

           Lorazepam: A study of multiple doses of immediate-release fluvoxamine maleate tablets (50 mg given twice daily) 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 immediate-release fluvoxamine maleate tablets (50 mg given twice daily) 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 LUVOX CR Capsules.

      Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and carbamazepine.

      Clozapine: See WARNINGS AND PRECAUTIONS (5.9).

      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 immediate-release fluvoxamine maleate tablets and lithium.

      Methadone: See WARNINGS AND PRECAUTIONS (5.9).

      Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS (4.1) and WARNINGS AND PRECAUTIONS (5.2).

      Pimozide: See CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.6).

      Ramelteon: See CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.8).

      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 immediate-release fluvoxamine maleate tablets 100 mg/day administered at steady-state was associated with 5- and 8-fold increases in tacrine Cmax 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) and WARNINGS AND PRECAUTIONS (5.4).

      Tizanidine: See CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS ( 5.5 ).

      Tricyclic Antidepressants (TCAs): Significantly increased plasma TCA levels have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and amitriptyline, clomipramine or imipramine. Caution is indicated with the coadministration of LUVOX CR Capsules 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 LUVOX CR Capsules 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 immediate-release fluvoxamine maleate tablets and tryptophan (see WARNINGS AND PRECAUTIONS [ 5.2 ]).

Other Drugs

      Alosetron: See CONTRAINDICATIONS (4), WARNINGS AND PRECAUTIONS (5.7), and Lotronex® (alosetron) package insert.

      Digoxin: Administration of immediate-release fluvoxamine maleate tablets 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 immediate-release fluvoxamine maleate tablets and diltiazem.

      Mexiletine: See WARNINGS AND PRECAUTIONS (5.9).

      Propranolol and Other Beta-Blockers: Coadministration of immediate-release fluvoxamine maleate tablets 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 propranolol plasma concentrations. In this study, there was a slight potentiation of the propranolol-induced reduction in heart rate and reduction in the exercise diastolic pressure.

     One case of bradycardia and hypotension and a second case of orthostatic hypotension have been reported with the coadministration of immediate-release fluvoxamine maleate tablets and metoprolol.

     If propranolol or metoprolol is coadministered with LUVOX CR Capsules, a reduction in the initial beta-blocker dose and more cautious dose titration are recommended. No dosage adjustment is required for LUVOX CR Capsules.

     Coadministration of immediate-release fluvoxamine maleate tablets 100 mg per day with atenolol 100 mg per day (N=6) did not affect the plasma concentrations of atenolol. Unlike propranolol and metoprolol, which undergo hepatic metabolism, atenolol is eliminated primarily by renal excretion.

      Theophylline: See WARNINGS AND PRECAUTIONS (5.9).

      Warfarin and Other Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, etc.): See WARNINGS AND PRECAUTIONS (5.9, 5.11).

Effects of Smoking on Fluvoxamine Metabolism

     Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers.

Electroconvulsive Therapy (ECT)

     There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate.

Monoamine Oxidase Inhibitors (MAOIs) Serotonergic Drugs

     See DOSAGE AND ADMINISTRATION ( 2.6, 2.7 ), CONTRADICTIONS ( 4.1 ), WARNINGS AND PRECAUTIONS ( 5.2 ).

Serotonergic Drugs

     See DOSAGE AND ADMINISTRATION ( 2.6, 2.7 ), CONTRADICTIONS ( 4.1 ), WARNINGS AND PRECAUTIONS ( 5.2 ).

OVERDOSAGE

Human Experience

     Exposure to immediate-release fluvoxamine maleate tablets includes over 45,000 patients treated in clinical trials and an estimated exposure of 50,000,000 patients treated during worldwide marketing experience (end of 2005). Of the 539 cases of deliberate or accidental overdose involving fluvoxamine reported from this population, there were 55 deaths. Of these, 9 were in patients thought to be taking immediate-release fluvoxamine tablets alone and the remaining 46 were in patients taking fluvoxamine along with other drugs. Among non-fatal overdose cases, 404 patients recovered completely. Five patients experienced adverse sequelae of overdosage, to include persistent mydriasis, unsteady gait, hypoxic encephalopathy, kidney complications (from trauma associated with overdose), bowel infarction requiring a hemicolectomy, and vegetative state. In 13 patients, the outcome was provided as abating at the time of reporting. In the remaining 62 patients, the outcome was unknown. The largest known ingestion of fluvoxamine immediate-release tablets involved 12,000 mg (equivalent to 2 to 3 months' dosage). The patient fully recovered. However, ingestions as low as 1,400 mg have been associated with lethal outcome, indicating considerable prognostic variability.

     In the controlled clinical trials with 403 patients treated with LUVOX CR Capsules, there was one nonfatal intentional overdose.

     Commonly (≥5%) observed adverse reactions associated with fluvoxamine maleate overdose include gastrointestinal complaints (nausea, vomiting, and diarrhea), coma, hypokalemia, hypotension, respiratory difficulties, somnolence, and tachycardia. Other notable signs and symptoms seen with immediate-release fluvoxamine maleate overdose (single or multiple drugs) include bradycardia, ECG abnormalities (such as heart arrest, QT interval prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm), convulsions, dizziness, liver function disturbances, tremor, and increased reflexes.

Management of Overdosage

     Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

     Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

     Activated charcoal should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluvoxamine are known.

     A specific caution involves patients taking, or recently having taken, fluvoxamine maleate who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see DRUG INTERACTIONS [ 7.2 ]).

     In managing overdosage, consider the possibility of multiple drug involvement. The health care provider should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).

CONTRAINDICATIONS

     Coadministration of thioridazine, tizanidine, pimozide, alosetron, or ramelteon with LUVOX CR Capsules is contraindicated (see WARNINGS AND PRECAUTIONS [ 5.4 - 5.8 ]).

Monoamine Oxidase Inhibitors (MAOIs)

     The use of MAOIs intended to treat psychiatric disorders with LUVOX CR Capsules or within 14 days of stopping treatment with LUVOX CR is contraindicated because of an increased risk of serotonin syndrome. The use of LUVOX CR within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see DOSAGE AND ADMINISTRATION [ 2.5 ] and WARNINGS AND PRECAUTIONS [ 5.2 ]).

     Starting LUVOX CR in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see DOSAGE AND ADMINISTRATION [ 2.6 ] and WARNINGS AND PRECAUTIONS [ 5.2 ]).

DRUG ABUSE AND DEPENDENCE

Controlled Substance

     LUVOX CR is not a controlled substance.

Physical and Psychological Dependence

     The potential for abuse, tolerance, and physical dependence with immediate-release fluvoxamine maleate has been studied in a nonhuman primate model. No evidence of dependency phenomena was found. The discontinuation effects of LUVOX CR Capsules were not systematically evaluated in controlled clinical trials. LUVOX CR Capsules were not systematically studied in clinical trials for potential for abuse, but there was no indication of drug-seeking behavior in clinical trials. It should be noted, however, that patients at risk for drug dependency were systematically excluded from investigational studies of immediate-release fluvoxamine maleate. Generally, it is not possible to predict on the basis of preclinical or premarketing clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, health care providers should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of LUVOX CR misuse or abuse (i.e., development of tolerance, incrementation of dose, drug-seeking behavior).

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