Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/972
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Fluvoxamine Maleate (Tablet, Film Coated)
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Dosage for Adults: The recommended starting dose for fluvoxamine maleate tablets in adult patients is 50 mg, administered as a single daily dose at bedtime. In the controlled clinical trials establishing the effectiveness of fluvoxamine maleate tablets in OCD, patients were titrated within a dose range of 100 to 300 mg/day. Consequently, the dose should be increased in 50 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved, not to exceed 300 mg per day. It is advisable that a total daily dose of more than 100 mg should be given in two divided doses. If the doses are not equal, the larger dose should be given at bedtime.<br/>Dosage for Pediatric Population (children and adolescents): The recommended starting dose for fluvoxamine maleate tablets in pediatric populations (ages 8 to 17 years) is 25 mg, administered as a single daily dose at bedtime. In a controlled clinical trial establishing the effectiveness of fluvoxamine maleate tablets in OCD, pediatric patients (ages 8 to 17) were titrated within a dose range of 50 to 200 mg/day. Physicians should consider age and gender differences when dosing pediatric patients. The maximum dose in children up to age 11 should not exceed 200 mg/day. Therapeutic effect in female children may be achieved with lower doses. Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. The dose should be increased in 25 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved. It is advisable that a total daily dose of more than 50 mg should be given in two divided doses. If the two divided doses are not equal, the larger dose should be given at bedtime.<br/>Special Populations:<br/>Dosage for Elderly or Hepatically Impaired Patients: Elderly patients and those with hepatic impairment have been observed to have a decreased clearance of fluvoxamine maleate. Consequently, it may be appropriate to modify the initial dose and the subsequent dose titration for these patient groups.<br/>Treatment of Pregnant Women During the Third Trimester: Neonates exposed to fluvoxamine maleate tablets and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with fluvoxamine maleate tablets during the third trimester, the physician shouldcarefully consider the potential risks and benefits of treatment. The physician may consider tapering fluvoxamine maleate tablets in the third trimester.<br/>Maintenance/Continuation Extended Treatment: Although the efficacy of fluvoxamine maleate tablets beyond 10 weeks of dosing for OCD has not been documented in controlled trials, OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment.<br/>Discontinuation of Treatment with Fluvoxamine Maleate Tablets: Symptoms associated with discontinuation of other SSRIs and SNRIs have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.<br/>Switching Patients To or From a Monoamine Oxidase Inhibitor: At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with fluvoxamine. Similarly, at least 14 days should be allowed after stopping fluvoxamine before starting an MAOI.
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Fluvoxamine maleate is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the distinct chemical series, the 2-aminoethyl oxime ethers of aralkylketones. Fluvoxamine maleate is chemically unrelated to other SSRIs and clomipramine. It is chemically designated as 5-methoxy-4'-(trifluoromethyl)valerophenone-(E)-O-(2-aminoethyl)oxime maleate (1:1) and has the following empirical formula: CHONF���CHOM.W. 434.41 Fluvoxamine maleate is a white to off white, odorless, crystalline powder which is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diethyl ether. Fluvoxamine maleate tablets are available in 25 mg, 50 mg or 100 mg strengths for oral administration. In addition to the active ingredient, fluvoxamine maleate, each tablet contains the following inactive ingredients: hypromellose, mannitol, microcrystalline cellulose, pregelatinized starch, polyethylene glycol, polysorbate 80, sodium starch glycolate, sodium stearyl fumarate and titanium dioxide. The 50 mg also contains synthetic yellow iron oxide and the 100 mg also contains synthetic brown iron oxide and synthetic yellow iron oxide.
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Pharmacodynamics: The mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. Receptor binding studies have demonstrated that fluvoxamine is a potent serotonin reuptake inhibitor in vitro as well as in vivo. In preclinical studies, it was found that fluvoxamine inhibited neuronal uptake of serotonin. In in vitro studies fluvoxamine maleate had no significant affinity for histaminergic, alpha or beta adrenergic, muscarinic, or dopaminergic receptors. Antagonism of some of these receptors is thought to be associated with various sedative, cardiovascular, anticholinergic, and extrapyramidal effects of some psychotropic drugs.<br/>Pharmacokinetics:<br/>Bioavailability: The absolute bioavailability of fluvoxamine maleate is 53%. Oral bioavailability is not significantly affected by food. In a dose proportionality study involving fluvoxamine maleate at 100, 200 and 300 mg/day for 10 consecutive days in 30 normal volunteers, steady state was achieved after about a week of dosing. Maximum plasma concentrations at steady state occurred within 3 to 8 hours of dosing and reached concentrations averaging 88, 283 and 546 ng/mL, respectively. Thus, fluvoxamine had nonlinear pharmacokinetics over this dose range, i.e., higher doses of fluvoxamine maleate produced disproportionately higher concentrations than predicted from the lower dose.<br/>Distribution/Protein Binding: The mean apparent volume of distribution for fluvoxamine is approximately 25 L/kg, suggesting extensive tissue distribution. Approximately 80% of fluvoxamine is bound to plasma protein, mostly albumin, over a concentration range of 20 to 2000 ng/mL.<br/>Metabolism: Fluvoxamine maleate is extensively metabolized by the liver; the main metabolic routes are oxidative demethylation and deamination. Nine metabolites were identified following a 5 mg radiolabeled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. A third metabolite, fluvoxethanol, formed by oxidative deamination, accounted for about 10%. Fluvoxamine acid and fluvoxethanol were tested in an in vitro assay of serotonin and norepinephrine reuptake inhibition in rats; they were inactive except for a weak effect of the former metabolite on inhibition of serotonin uptake (1 to 2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged (see PRECAUTIONS, Drug Interactions).<br/>Elimination: Following aC-labeled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours. The mean plasma half-life of fluvoxamine at steady state after multiple oral doses of 100 mg/day in healthy, young volunteers was 15.6 hours.<br/>Elderly Subjects: In a study of fluvoxamine maleate tablets at 50 and 100 mg comparing elderly (ages 66 to 73) and young subjects (ages 19 to 35), mean maximum plasma concentrations in the elderly were 40% higher. The multiple dose elimination half-life of fluvoxamine was 17.4 and 25.9 hours in the elderly compared to 13.6 and 15.6 hours in the young subjects at steady state for 50 and 100 mg doses, respectively. In elderly patients, the clearance of fluvoxamine was reduced by about 50% and, therefore, fluvoxamine maleate tablets should be slowly titrated during initiation of therapy.<br/>Pediatric Subjects: The multiple-dose pharmacokinetics of fluvoxamine were determined in male and female children (ages 6 to 11) and adolescents (ages 12 to 17). Steady state plasma fluvoxamine concentrations were 2 to 3 fold higher in children than in adolescents. AUC and Cin children were 1.5 to 2.7 fold higher than that in adolescents (see Table 1). As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC (0 to 12) and Ccompared to male children and, therefore, lower doses of fluvoxamine maleate tablets may produce therapeutic benefit (see Table 2). No gender differences were observed in adolescents. Steady state plasma fluvoxamine concentrations were similar in adults and adolescents at a dose of 300 mg/day, indicating that fluvoxamine exposure was similar in these two populations (see Table 1). Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) maybe indicated to achieve therapeutic benefit.<br/>Hepatic and Renal Disease: A cross study comparison (healthy subjects vs. patients with hepatic dysfunction) suggested a 30% decrease in fluvoxamine clearance in association with hepatic dysfunction. The mean minimum plasma concentrations in renally impaired patients (creatinine clearance of 5 to 45 mL/min) after 4 and 6 weeks of treatment (50 mg b.i.d., N = 13) were comparable to each other, suggesting no accumulation of fluvoxamine in these patients (see PRECAUTIONS, Use in Patients with Concomitant Illness).<br/>Clinical Trials:<br/>Adult OCD Studies: The effectiveness of fluvoxamine maleate tablets for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 10 week multicenter, parallel group studies of adult outpatients. Patients in these trials were titrated to a total daily fluvoxamine maleate dose of 150 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 100 to 300 mg/day (on a b.i.d. schedule), on the basis of response and tolerance. Patients in these studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), totalscore of 23. Patients receiving fluvoxamine maleate experienced mean reductions of approximately 4 to 5 units on the Y-BOCS total score, compared to a 2 unit reduction for placebo patients. Table 3 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impressions (CGI) scale for both studies combined. Exploratory analyses for age and gender effects on outcomes did not suggest any differential responsiveness on the basis of age or sex.<br/>Pediatric OCD Study: The effectiveness of fluvoxamine maleate tablets for the treatment of OCD was also demonstrated in a 10 week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages 8 to 17). Patients in this study were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 50 to 200 mg/day (on a b.i.d. schedule) on the basis of response and tolerance. All patients had moderate-to-severe OCD (DSM-III-R) with mean baselineratings on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score of 24. Patients receiving fluvoxamine maleate experienced mean reductions of approximately six units on the CY-BOCS total score, compared to a three-unit reduction for placebo patients. Table 4 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study. Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender. Further exploratory analyses revealed a prominent treatment effect in the 8 to 11 age group and essentially no effect in the 12 to 17 age group. While the significance of these results is not clear, the 2 to 3 fold higher steady state plasma fluvoxamine concentrations in children compared to adolescents (see Pharmacokinetics) is suggestive that decreased exposure in adolescents may have been a factor, and dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.
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Coadministration of tizanidine, thioridazine, alosetron, or pimozide with fluvoxamine maleate is contraindicated (see WARNINGS and PRECAUTIONS). The use of MAO inhibitors within 14 days of treatment with fluvoxamine maleate is contraindicated (see WARNINGS and PRECAUTIONS). Fluvoxamine maleate tablets are contraindicated in patients with a history of hypersensitivity to the active substance or to any of the excipients.
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Fluvoxamine maleate tablets USP are available as white, round, film-coated tablets, debossed and���4389���on one side and plain on the other side containing 25 mg fluvoxamine maleate, packaged in bottles of 100 and 500 tablets and unit-dose boxes of 100 tablets. Fluvoxamine maleate tablets USP are available as yellow, round, film-coated tablets, debossed and���4391���on one side and scored on the other side containing 50 mg fluvoxamine maleate, packaged in bottles of 100, 500 and 1000 tablets and unit-dose boxes of 100 tablets. Fluvoxamine maleate tablets USP are available as beige, round, film-coated tablets, debossed and���4392���on one side and scored on the other side containing 100 mg fluvoxamine maleate, packaged in bottles of 100, 500 and 1000 tablets and unit-dose boxes of 60 tablets. PHARMACIST: Dispense in a tight container as defined in the USP. Use child-resistant closure (as required). PROTECT FROM HIGH HUMIDITY Store at 20��to 25��C (68��to 77��F) [See USP Controlled Room Temperature]. Lotronex���is a registered trademark of GlaxoSmithKline. MANUFACTURED BY IVAX PHARMACEUTICALS, INC. MIAMI, FL 33137 0172 02/08 B12 FLUVOXAMINE MALEATE TABLETS USP
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Suicidality and Antidepressant Drugs: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of fluvoxamine maleate tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patientsof all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Fluvoxamine is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD). (See WARNINGS, Clinical Worsening and Suicide Risk, PRECAUTIONS, Information for Patients, and PRECAUTIONS, Pediatric Use.)
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dailymed-ingredient:hypromellose,
dailymed-ingredient:mannitol,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:polysorbate_80,
dailymed-ingredient:pregelatinized_starch,
dailymed-ingredient:sodium_starch_glycolate,
dailymed-ingredient:sodium_stearyl_fumarate,
dailymed-ingredient:titanium_dioxide
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General:<br/>Discontinuation of Treatment with Fluvoxamine Maleate Tablets: During marketing of fluvoxamine maleate tablets and other SSRIs and SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluvoxamine maleate tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate (see DOSAGE AND ADMINISTRATION).<br/>Abnormal Bleeding: Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both 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. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of fluvoxamine with NSAIDs, aspirin, or other drugs that affect coagulation.<br/>Activation of Mania/Hypomania: During premarketing studies involving primarily depressed patients, hypomania or mania occurred in approximately 1% of patients treated with fluvoxamine. In a ten week pediatric OCD study, 2 out of 57 patients (4%) treated with fluvoxamine experienced manic reactions, compared to none of 63 placebopatients. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, fluvoxamine maleate tablets should be used cautiously in patients with a history of mania.<br/>Seizures: During premarketing studies, 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 if seizure frequency increases.<br/>Hyponatremia: Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluvoxamine. 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 GeriatricUse). Discontinuation of fluvoxamine 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.<br/>Use in Patients with Concomitant Illness: Closely monitored clinical experience with fluvoxamine maleate tablets in patients with concomitant systemic illness is limited. Caution is advised in administering fluvoxamine maleate tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism. Fluvoxamine maleate tablets 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 the product's premarketing testing. Evaluation of the electrocardiograms 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, fluvoxamine clearance was decreased by approximately 30%. Patients with liver dysfunction should begin with a low dose of fluvoxamine maleate tablets and increase it slowly with careful monitoring.<br/>Information for Patients: Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluvoxamine maleate tablets and should counsel them in its appropriate use. A patient Medication Guide about���Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions���is available for fluvoxamine maleate tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluvoxamine maleate tablets.<br/>Clinical Worsening and Suicide Risk: Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate the need for very close monitoring and possibly changes in the medication. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluvoxamine and triptans, tramadol or other serotonergic agents.<br/>Interference with Cognitive or Motor Performance: Since any psychoactive drug may impair judgement, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain that fluvoxamine maleate tablet therapy does not adversely affect their ability to engage in such activities.<br/>Pregnancy: Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy with fluvoxamine maleate tablets.<br/>Nursing: Patients receiving fluvoxamine maleate tablets should be advised to notify their physicians if they are breast feeding an infant (see PRECAUTIONS, Nursing Mothers).<br/>Concomitant Medication: Patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for clinically important interactions with fluvoxamine maleate tablets. Patients should be cautioned about the concomitant use of fluvoxamine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when fluvoxamine and tizanidine are used together, fluvoxamine should not be used with tizanidine. Because of the potential for the increased risk of serious adverse reactions when fluvoxamine and alosetron are used together, fluvoxamine should not be used with Lotronex(alosetron).<br/>Alcohol: As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets.<br/>Allergic Reactions: Patients should be advised to notify their physicians if they develop a rash, hives, or a related allergic phenomenon during therapy with fluvoxamine maleate tablets.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions: As with all drugs, the potential for interaction by a variety of mechanisms is a possibility.<br/>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. 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, 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 and WARNINGS).<br/>CNS Active Drugs:<br/>Other Drugs:<br/>Theophylline: See WARNINGS<br/>Warfarin: See WARNINGS<br/>Alosetron: Because alosetron is metabolized by a variety of hepatic CYP drug-metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known potent inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentration (AUC) approximately 6 fold and prolonged the half-life by approximately 3 fold (see CONTRAINDICATIONS, PRECAUTIONS, and Lotronex���(alosetron) package insert).<br/>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.<br/>Diltiazem: Bradycardia has been reported with the coadministration of fluvoxamine maleate and diltiazem.<br/>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 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 fluvoxamine maleate and metoprolol. If propranolol or metoprolol is coadministered with fluvoxamine maleate tablets, a reduction in the initial beta-blocker dose and more cautious dose titration are recommended. No dosage adjustment is required for fluvoxamine maleate tablets. Coadministration of fluvoxamine maleate 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.<br/>Drugs that Interfere with Hemostasis (NSAIDs, Aspirin, Warfarin, etc.): Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluvoxamine.<br/>Effects of Smoking on Fluvoxamine Metabolism: Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers.<br/>Electroconvulsive Therapy (ECT): There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility:<br/>Carcinogenesis: There was no evidence of carcinogenicity in rats treated orally with fluvoxamine maleate for 30 months or hamsters treated orally with fluvoxamine maleate for 20 (females) or 26 (males) months. The daily doses in the high dose groups in these studies were increased over the course of the study from a minimum of 160 mg/kg to a maximum of 240 mg/kg in rats, and from a minimum of 135 mg/kgto a maximum of 240 mg/kg in hamsters. The maximum dose of 240 mg/kg is approximately 6 times the maximum human daily dose on a mg/mbasis.<br/>Mutagenesis: No evidence of mutagenic potential was observed in a mouse micronucleus test, an in vitro chromosome aberration test, or the Ames microbial mutagen test with or without metabolic activation.<br/>Impairment of Fertility: In a study in which male and female rats were administered fluvoxamine (60, 120, or 240 mg/kg) prior to and during mating and gestation, fertility was impaired at oral doses of 120 mg/kg or greater, as evidenced by increased latency to mating, decreased sperm count, decreased epididymal weight, and decreased pregnancy rate. In addition, the numbers of implantations and embryos were decreased at the highest dose. The no effect dose for fertility impairment was 60 mg/kg (approximately 2 times the maximum recommended human dose [MRHD] on a mg/mbasis).<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Nonteratogenic Effects: Neonates exposed to fluvoxamine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. These findings are based on postmarketing reports. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical pictureis consistent with serotonin syndrome (see WARNINGS). Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN is associated with substantial neonatal morbidity and mortality. In a case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. PPHN occurs in 1 to 2 per 1000 live births in the general population. When treating a pregnant woman with fluvoxamine maleate during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.<br/>Labor and Delivery: The effect of fluvoxamine on labor and delivery in humans is unknown.<br/>Nursing Mothers: As with many other drugs, fluvoxamine is secreted in human breast milk. The decision of whether to discontinue nursing or to discontinue the drug should take into account the potential for serious adverse effects from exposure to fluvoxamine in the nursing infant as well as the potential benefits of fluvoxamine maleate tablets therapy to the mother.<br/>Pediatric Use: The efficacy of fluvoxamine maleate for the treatment of obsessive compulsive disorder was demonstrated in a 10 week multicenter placebo-controlled study with 120 outpatients ages 8 to 17. In addition, 99 of these outpatients continued open-label fluvoxamine maleate treatment for up to another one to three years, equivalent to 94 patient years. The adverse event profile observed in that study was generally similar to that observed in adult studies with fluvoxamine (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION). Decreased appetite and weight loss have been observed in association with the use of fluvoxamine as well as other SSRIs. Consequently, regular monitoring of weight and growth is recommended if treatment of a child with an SSRI is to be continued long-term. The risks, if any, that may be associated with fluvoxamine's extended use in children and adolescents with OCD have not been systematically assessed. The prescriber should be mindful that the evidence relied upon to conclude that fluvoxamine is safe for use in children and adolescents derives from relatively short-term clinical studies and from extrapolation of experience gained with adult patients. In particular, there are no studies that directly evaluate the effects of long-term fluvoxamine use on the growth, cognitive behavioral development, and maturation of children and adolescents. Although there is no affirmative finding to suggest that fluvoxamine possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of fluvoxamine to have adverse effectsin chronic use (see WARNINGS, Clinical Worsening and Suicide Risk). Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established (see BOXED WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of fluvoxamine maleate tablets in a child or adolescent must balance the potential risks with the clinical need.<br/>Geriatric Use: Approximately 230 patients participating in controlled premarketing studies with fluvoxamine maleate tablets were 65 years of age or over. No overall differences in safety were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients. However, SSRIs and SNRIs, including fluvoxamine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS, Hyponatremia). Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients (see CLINICAL PHARMACOLOGY, Pharmacokinetics), and greater sensitivity of some older individuals also cannot be ruled out. Consequently, fluvoxamine maleate tablets should be slowly titrated during initiation of therapy.
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Human Experience: Worldwide exposure to fluvoxamine 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 fluvoxamine 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 fluvoxamineinvolved 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. 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 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.<br/>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 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 PRECAUTIONS, Tricyclic Antidepressants (TCAs). In managing overdosage, consider the possibility of multiple drug involvement. The physician 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).
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Fluvoxamine Maleate
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Fluvoxamine Maleate (Tablet, Film Coated)
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Associated with Discontinuation of Treatment: Of the 1087 OCD and depressed patients treated with fluvoxamine maleate in controlled clinical trials conducted in North America, 22% discontinued treatment due to an adverse event. The most common events (���1%) associated with discontinuation and considered to be drug-related (i.e., those events associated with dropout at a rate at least twice that of placebo) included:<br/>Incidence in Controlled Trials:<br/>Commonly Observed Adverse Events in Controlled Clinical Trials: Fluvoxamine maleate tablets have been studied in 10 week short-term controlled trials of OCD (N = 320) and depression (N = 1350). In general, adverse event rates were similar in the two data sets as well as in the pediatric OCD study. The most commonly observed adverse events associated with the use of fluvoxamine maleate tablets and likely to be drug-related (incidence of 5% or greater and at least twice that for placebo) derived from Table 7 were: abnormal ejaculation, anorexia, asthenia, dyspepsia, insomnia, nausea, nervousness, somnolence, sweating, tremor and vomiting. In a pool of two studies involving only patients with OCD, the following additional events were identified using the above rule: anorgasmia, decreased libido, dry mouth, rhinitis, taste perversion and urinary frequency. In a study of pediatric patients with OCD, the following additional events were identified using the above rule: agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash.<br/>Adverse Events Occurring at an Incidence of 1%: Table 7 enumerates adverse events that occurred in adults at a frequency of 1% or more, and were more frequent than in the placebo group, among patients treated with fluvoxamine maleate tablets in two short-term placebo-controlled OCD trials (10 week) and depression trials (6 week) in which patients were dosed in a range of generally 100 to 300 mg/day. This table shows the percentage of patients in each group who had at least one occurrence of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based Dictionary terminology. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors may differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.<br/>Adverse Events in OCD Placebo-Controlled Studies Which are Markedly Different (defined as at least a two-fold difference) in Rate from the Pooled Event Rates in OCD and Depression Placebo-Controlled Studies: The events in OCD studies with a two-fold decrease in rate compared to event rates in OCD and depression studies were dysphagia and amblyopia (mostly blurred vision). Additionally, there was an approximate 25% decrease in nausea. The events in OCD studies with a two-fold increase in rate compared to event rates in OCD and depression studies were: asthenia, abnormal ejaculation (mostly delayed ejaculation), anxiety, infection, rhinitis, anorgasmia (in males), depression, libido decreased, pharyngitis, agitation, impotence, myoclonus/twitch, thirst, weight loss, leg cramps, myalgia and urinary retention. These events arelisted in order of decreasing rates in the OCD trials.<br/>Other Adverse Events in OCD Pediatric Population: In pediatric patients (N = 57) treated with fluvoxamine maleate tablets, the overall profile of adverse events was generally similar to that seen in adult studies, as shown in Table 7. However, the following adverse events, not appearing in Table 7, were reported in two or more of the pediatric patients and were more frequent with fluvoxamine maleate tablets than with placebo: abnormal thinking, cough increase, dysmenorrhea, ecchymosis, emotional lability, epistaxis, hyperkinesia, infection, manic reaction, rash,sinusitis, and weight decrease.<br/>Male and Female Sexual Dysfunction with SSRIs: Although changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of a psychiatric disorder and with aging, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that selective serotonin reuptake inhibitors (SSRIs) can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence. Table 8 displays the incidence of sexual side effects reported by at least 2% of patients taking fluvoxamine tablets in placebo-controlled trials in depression and OCD. There are no adequate and well-controlled studies examining sexual dysfunction with fluvoxamine treatment. Fluvoxamine treatment has been associated with several cases of priapism. In those cases with a known outcome, patients recovered without sequelae and upon discontinuation of fluvoxamine. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.<br/>Vital Sign Changes: Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various vital signs variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various vital signs variables revealed no important differences between fluvoxamine maleate and placebo.<br/>Laboratory Changes: Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) median change from baseline on various serum chemistry, hematology, and urinalysis variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various serum chemistry, hematology, and urinalysis variables revealed no important differences between fluvoxamine maleate and placebo.<br/>ECG Changes: Comparisons of fluvoxamine maleate and placebo groups in separate pools of short-term OCD and depression trials on (1) mean change from baseline on various ECG variables and on (2) incidence of patients meeting criteria for potentially important changes from baseline on various ECG variables revealed no important differences between fluvoxamine maleate and placebo.<br/>Other Events Observed During the Premarketing Evaluation of Fluvoxamine Maleate Tablets: During premarketing clinical trials conducted in North America and Europe, multiple doses of fluvoxamine maleate were administered for a combined total of 2737 patient exposures in patients suffering OCD or major depressive disorder. Untoward events associated with this exposure were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a limited (i.e., reduced) number of standard event categories. In the tabulations which follow, a standard COSTART-based Dictionary terminology has been used to classify reported adverse events. If the COSTART term for an event was so general as to be uninformative, it was replaced with a more informative term. The frequencies presented, therefore, represent the proportion of the 2737 patient exposures to multipledoses of fluvoxamine maleate who experienced an event of the type cited on at least one occasion while receiving fluvoxamine maleate. All reported events are included in the list below, with the following exceptions: 1) those events already listed in Table 7, which tabulates incidence rates of common adverse experiences in placebo-controlled OCD and depression clinical trials, are excluded; 2) those events for which a drug cause was considered remote (i.e., neoplasia, gastrointestinal carcinoma, herpes simplex, herpes zoster, application site reaction, and unintended pregnancy) are omitted; and 3) events which were reported in only one patient and judged to not be potentially serious are not included. It is important to emphasize that, although the events reported did occur during treatment with fluvoxamine maleate, a causal relationship to fluvoxamine maleate has not been established. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring between 1/100 and 1/1000 patients; and rare adverse events are those occurring in less than 1/1000 patients.<br/>Body as a Whole: Frequent: Accidental injury, malaise Infrequent: Allergic reaction, neck pain, neck rigidity, overdose, photosensitivity reaction, suicide attempt Rare: Cyst, pelvic pain, sudden death<br/>Cardiovascular System: Frequent: Hypertension, hypotension, syncope, tachycardia Infrequent: Angina pectoris, bradycardia, cardiomyopathy, cardiovascular disease, cold extremities, conduction delay, heart failure, myocardial infarction, pallor, pulse irregular, ST segment changes Rare: AV block, cerebrovascular accident, coronary artery disease, embolus, pericarditis, phlebitis, pulmonary infarction, supraventricular extrasystoles<br/>Digestive System: Frequent: Elevated liver transaminases Infrequent: Colitis, eructation, esophagitis, gastritis, gastroenteritis, gastrointestinal hemorrhage, gastrointestinal ulcer, gingivitis, glossitis, hemorrhoids, melena, rectal hemorrhage, stomatitis Rare: Biliary pain, cholecystitis, cholelithiasis, fecal incontinence, hematemesis, intestinal obstruction, jaundice<br/>Endocrine System: Infrequent: Hypothyroidism Rare: Goiter<br/>Hemic and Lymphatic Systems: Infrequent: Anemia, ecchymosis, leukocytosis, lymphadenopathy, thrombocytopenia Rare: Leukopenia, purpura<br/>Metabolic and Nutritional Systems: Frequent: Edema, weight gain, weight loss Infrequent: Dehydration, hypercholesterolemia Rare: Diabetes mellitus, hyperglycemia, hyperlipidemia, hypoglycemia, hypokalemia, lactate dehydrogenase increased<br/>Musculoskeletal System: Infrequent: Arthralgia, arthritis, bursitis, generalized muscle spasm, myasthenia, tendinous contracture, tenosynovitis Rare: Arthrosis, myopathy, pathological fracture<br/>Nervous System: Frequent: Amnesia, apathy, hyperkinesia, hypokinesia, manic reaction, myoclonus, psychotic reaction Infrequent: Agoraphobia, akathisia, ataxia, CNS depression, convulsion, delirium, delusion, depersonalization, drug dependence, dyskinesia, dystonia, emotional lability, euphoria, extrapyramidal syndrome, gait unsteady, hallucinations, hemiplegia, hostility, hypersomnia, hypochondriasis, hypotonia, hysteria, incoordination, increased salivation, increased libido, neuralgia, paralysis, paranoid reaction, phobia, psychosis, sleep disorder, stupor, twitching, vertigo Rare: Akinesia, coma, fibrillations, mutism, obsessions, reflexes decreased, slurred speech, tardive dyskinesia, torticollis, trismus, withdrawal syndrome<br/>Respiratory System: Frequent: Cough increased, sinusitis Infrequent: Asthma, bronchitis, epistaxis, hoarseness, hyperventilation Rare: Apnea, congestion of upper airway, hemoptysis, hiccups, laryngismus, obstructive pulmonary disease, pneumonia<br/>Skin: Infrequent: Acne, alopecia, dry skin, eczema, exfoliative dermatitis, furunculosis, seborrhea, skin discoloration, urticaria<br/>Special Senses: Infrequent: Accommodation abnormal, conjunctivitis, deafness, diplopia, dry eyes, ear pain, eye pain, mydriasis, otitis media, parosmia, photophobia, taste loss, visual field defect Rare: Corneal ulcer, retinal detachment<br/>Urogenital System: Infrequent: Anuria, breast pain, cystitis, delayed menstruation, dysuria, female lactation, hematuria, menopause, menorrhagia, metrorrhagia, nocturia, polyuria, premenstrual syndrome, urinary incontinence, urinary tract infection, urinary urgency, urination impaired, vaginal hemorrhage, vaginitis Rare: Kidney calculus, hematospermia, oliguria<br/>Postmarketing Reports: Voluntary reports of adverse events in patients taking fluvoxamine maleate tablets that have been received since market introduction and are of unknown causal relationship to fluvoxamine maleate tablets use include: acute renal failure, agranulocytosis, amenorrhea, anaphylactic reaction, angioedema, aplastic anemia, bullous eruption, Henoch-Schoenlein purpura, hepatitis, hyponatremia, ileus, laryngismus, neuropathy, pancreatitis, porphyria, priapism, serotonin syndrome, severe akinesia with fever when fluvoxamine was coadministered with antipsychotic medication, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsade de pointes).
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Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo inadults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 5. No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with Fluvoxamine Maleate Tablets, for a description of the risks of discontinuation of fluvoxamine maleate tablets). Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation byfamilies and caregivers. Prescriptions for fluvoxamine maleate tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.<br/>Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above representsuch a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that fluvoxamine maleate tablets are not approved for use in treating bipolar depression.<br/>Potential for Monoamine Oxidase Inhibitors Interaction: In patients receiving another serotonin reuptake inhibitor drug in combination with monoamine oxidase inhibitors (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have discontinued that drug and have been started on a MAOI. Some cases presented with features resembling a serotonin syndrome or neuroleptic malignant syndrome. Therefore, fluvoxamine maleate tablets should not be used in combination with a MAOI, or within 14 days of discontinuing treatment with a MAOI (see CONTRAINDICATIONS).<br/>Potential Thioridazine Interaction: The effect of fluvoxamine (25 mg b.i.d. 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 three-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 torsade 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 and thioridazine should not be coadministered (see CONTRAINDICATIONS and PRECAUTIONS).<br/>Potential Tizanidine Interaction: Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in 10 healthy male subjects. Tizanidine Cwas 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 and tizanidine should not be used together (see CONTRAINDICATIONS and PRECAUTIONS).<br/>Potential Pimozide Interaction: Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, 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 torsade 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 CYP3A4. 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 and PRECAUTIONS).<br/>Potential Alosetron Interaction: Fluvoxamine, an inhibitor of several CYP isozymes, has been shown to increase mean alosetron plasma concentrations (AUC) approximately 6 fold and prolonged the half-life by approximately 3 fold. Consequently, it is recommended that fluvoxamine not be used in combination with alosetron (see CONTRAINDICATIONS, PRECAUTIONS, and Lotronex(alosetron) package insert).<br/>Other Potentially Important Drug Interactions: (Also see PRECAUTIONS, Drug Interactions.)<br/>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.<br/>Mexiletine: The effect of steady state fluvoxamine (50 mg b.i.d. for 7 days) on the single dose pharmacokinetics of mexiletene (200 mg) was evaluated in 6 healthy Japanese males. The clearance of mexiletene was reduced by 38% following coadministration with fluvoxamine compared to mexiletene alone. If fluvoxamine and mexiletene are coadministered, serum mexiletene levels should be monitored.<br/>Neuroleptic Malignant Syndrome (NMS) or NMS-Like Events: Rare instances of neuroleptic malignant syndrome (NMS) or NMS-like events have been reported in association with fluvoxamine treatment when coadministered with antipsychotics. Additionally, a small number of such cases have been reported with fluvoxamine treatment in the absence of antipsychotic coadministration. These serious and sometimes fatal events can include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuations of vital signs, and mentalstatus changes. As these events may result in potentially life-threatening conditions, patients receiving this combination of therapy should be monitored for the emergence of NMS-like signs and symptoms. Treatment with fluvoxamine and any concomitant antipsychotic agent should be discontinued immediately if such events occur and supportive symptomatic treatment should be initiated.<br/>Ramelteon: Should not be used in combination with fluvoxamine (see PRECAUTIONS, Drug Interactions).<br/>Theophylline: The effect of steady state fluvoxamine (50 mg b.i.d.) 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 three-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 tablets.<br/>Warfarin: When fluvoxamine maleate (50 mg t.i.d.) was 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 tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for fluvoxamine maleate tablets.<br/>Serotonin Syndrome: The development of a potentially life-threatening serotonin syndrome may occur with fluvoxamine treatment, particularly with concomitant use of serotonergic drugs (including triptans) and with drugs which impair metabolism of serotonin (including MAOIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of fluvoxamine with MAOIs intended to treat depression is contraindicated (see CONTRAINDICATIONS and WARNINGS, Potential for Monoamine Oxidase Inhibitors Interaction). If concomitant treatment of fluvoxamine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see PRECAUTIONS, Drug Interactions). The concomitant use of fluvoxamine with serotonin precursors (such as tryptophan) is not recommended (see PRECAUTIONS, Drug Interactions).
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Fluvoxamine maleate tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in the DSM-III-R. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of fluvoxamine maleate tablets was established in three 10 week trials with obsessive compulsive outpatients with the diagnosis of obsessive compulsive disorder as defined in DSM-III-R (see CLINICAL PHARMACOLOGY, Clinical Trials). Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. The effectiveness of fluvoxamine maleate tablets for long-term use, i.e., for more than 10 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use fluvoxamine maleate tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).
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Fluvoxamine Maleate
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