|
|
DRUG INTERACTIONS Drug Interactions
As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.
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 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 warfarin or theophylline, certain benzodiazepines 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 and WARNINGS).
|
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 events 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 Overdose
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 Tricyclic Antidepressants (TCAs) under PRECAUTIONS).
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
Co-administration of alosetron, tizanidine, thioridazine, or pimozide with LUVOX CR Capsules is contraindicated (see WARNINGS and PRECAUTIONS).
The use of MAO inhibitors used in combination with LUVOX CR Capsules, or within 14 days of discontinuing treatment with LUVOX CR Capsules, is contraindicated (see WARNINGS and PRECAUTIONS).
LUVOX CR Capsules are contraindicated in patients with a history of hypersensitivity to fluvoxamine maleate or any of the excipients.
|
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
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).
|
|
|
|
-- advertisement --
|
