Managed Care - April 2008 - (Page 3) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding. Bleeding events related to use of SSRIs and SNRIs have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of LUVOX CR and NSAIDs, aspirin, or other drugs that affect coagulation. Activation of Mania/Hypomania: During premarketing studies of IR fluvoxamine maleate involving primarily depressed patients, hypomania or mania occurred in ~1% of patients treated with fluvoxamine. In a 10-week pediatric OCD study, 2 out of 57 patients (4%) treated with fluvoxamine experienced manic reactions, compared to none of 63 placebo patients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, LUVOX CR should be used cautiously in patients with a history of mania. Seizures: During premarketing studies with IR fluvoxamine maleate, seizures were reported in 0.2% of fluvoxamine-treated patients. Caution is recommended when the drug is administered to patients with a history of convulsive disorders. Fluvoxamine should be avoided in patients with unstable epilepsy, and patients with controlled epilepsy should be carefully monitored. Treatment with fluvoxamine should be discontinued if seizures occur or seizure frequency increases. Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including LUVOX CR. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk (see Geriatric Use). Discontinuation of LUVOX CR should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Use in Patients with Concomitant Illness: Closely monitored clinical experience with IR fluvoxamine maleate in patients with concomitant systemic illness is limited. Caution is advised in administering LUVOX CR to patients with diseases or conditions that could affect hemodynamic responses or metabolism. LUVOX CR or IR fluvoxamine maleate have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during premarket testing. Evaluation of the electrocardiograms (ECGs) for patients with depression or OCD who participated in premarketing studies revealed no differences between fluvoxamine and placebo in the emergence of clinically important ECG changes. In patients with liver dysfunction, following administration of IR fluvoxamine maleate, fluvoxamine clearance was decreased by ~30%. Patients with liver dysfunction should begin with a low dose of LUVOX CR and increase it slowly with careful monitoring. Laboratory Tests: There are no specific laboratory tests recommended. 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 PK 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 WARNINGS) and limited in vitro data for CYP3A4, it appears that fluvoxamine inhibits several cytochrome P450 isoenzymes known to be involved in the metabolism of other drugs such as CYP1A2 (eg warfarin, theophylline, propranolol, tizanidine), CYP2C9 (eg warfarin), CYP3A4 (eg alprazolam), and CYP2C19 (eg 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 (PMs) of drugs such as debrisoquin, dextromethorphan, and tricyclic antidepressants. While none of the drugs studied for drug interactions significantly affected the PK of fluvoxamine, an in vivo study of fluvoxamine single-dose PK in 13 PM subjects demonstrated altered PK properties compared to 16 extensive metabolizers (EMs): mean Cmax, AUC, and T½ 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 or receiving concomitant drugs known to inhibit this cytochrome P450 isoenzyme (eg 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 is to be administered together with a drug that is eliminated via oxidative metabolism and has a narrow therapeutic window, plasma levels and/or PD effects of the latter drug should be monitored closely, at least until steady-state conditions are reached (see CONTRAINDICATIONS and WARNINGS). CNS Active Drugs: Antipsychotics: See WARNINGS—Other Potentially Important Drug Interactions, NMS or NMS-Like Events. MAOIs: See CONTRAINDICATIONS and WARNINGS. Alprazolam and Diazepam: See WARNINGS. Alcohol: Studies involving single 40 g doses of ethanol (oral administration in 1 study and intravenous in the other) and multiple dosing with IR fluvoxamine maleate (50 mg bid) revealed no effect of either drug on the PK or PD of the other. Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity have been reported with the co-administration of IR fluvoxamine maleate and carbamazepine. Clozapine: Elevated serum levels of clozapine have been reported in patients taking IR fluvoxamine maleate and clozapine. Since clozapine-related seizures and orthostatic hypotension appear to be dose related, the risk of these AEs may be higher when fluvoxamine and clozapine are co-administered. Patients should be closely monitored when LUVOX CR and clozapine are used concurrently. 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 co-administration of IR fluvoxamine maleate and lithium. Lorazepam: A study of multiple doses of IR fluvoxamine maleate (50 mg bid) and a 4 mg single dose of lorazepam in healthy male volunteers (n=12) indicated no significant PK interaction. On average, both lorazepam alone and lorazepam with fluvoxamine produced substantial decrements in cognitive functioning; however, the co-administration of fluvoxamine and lorazepam did not produce larger mean decrements compared to lorazepam alone. Methadone: Significantly increased methadone (plasma level:dose) ratios have been reported when IR fluvoxa mine maleate was administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in 1 patient. Opioid withdrawal symptoms were reported following fluvoxamine maleate discontinuation in another patient. Ramelteon: When IR fluvoxamine maleate 100 mg bid was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and IR fluvoxamine maleate, the AUC for ramelteon increased ~190-fold and the Cmax increased ~70-fold compared to ramelteon administered alone. Ramelteon should not be used in combination with LUVOX CR (see WARNINGS). Serotonergic Drugs: Based on the mechanism of action of LUVOX CR and the potential for serotonin syndrome, caution is advised when fluvoxamine is co-administered 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 LUVOX CR with other SSRIs, SNRIs, or tryptophan is not recommended. Sumatriptan: Rare postmarketing reports have described patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (eg fluoxetine, fluvoxamine, paroxetine, sertraline, etc.) 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 IR fluvoxamine maleate 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 co-administration, consistent with the cholinergic effects of tacrine. Thioridazine: See CONTRAINDI
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