ADVERSE REACTIONS SECTION.

6. ADVERSE REACTIONS6.1 Adverse Reactions Leading to Treatment DiscontinuationOf the 1087 OCD and depressed patients treated with fluvoxamine maleate in controlled clinical trials in North America, 22% discontinued due to an adverse reaction. Adverse reactions that led to discontinuation in at least 2% of fluvoxamine maleate-treated patients in these trials were: nausea (9%), insomnia (4%), somnolence (4%), headache (3%), and asthenia, vomiting, nervousness, agitation, and dizziness (2% each).6.2 Incidence in Controlled TrialsCommonly Observed Adverse Reactions 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 reaction rates were similar in the two data sets as well as in the pediatric OCD study. The most commonly observed adverse reactions 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 were: nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, and vomiting. In pool of two studies involving only patients with OCD, the following additional reactions were identified using the above rule: anorgasmia, decreased libido, dry mouth, rhinitis, taste perversion, and urinary frequency. In study of pediatric patients with OCD, the following additional reactions were identified using the above rule: agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash. Adverse Reactions Occuring at an Incidence of 1%: Table enumerates adverse reactions that occurred in adults at 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 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 reaction at some time during their treatment. Reported adverse reactions were classified using 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.Adverse Reactions in OCD Placebo Controlled Studies Which are Markedly Different (defined as at least two-fold difference) in Rate from the Pooled Reaction Rates in OCD and Depression Placebo Controlled Studies: The reactions in OCD studies with two-fold decrease in rate compared to reaction rates in OCD and depression studies were dysphagia and amblyopia (mostly blurred vision). Additionally, there was an approximate 25% decrease in nausea.The reactions in OCD studies with two-fold increase in rate compared to reaction rates in OCD and depression studies were: asthenia, abnormal ejaculation (mostly delayed ejaculation), anxiety, rhinitis, anorgasmia (in males), depression, libido decreased, pharyngitis, agitation, impotence, myoclonus/twitch, thirst, weight loss, leg cramps, myalgia, and urinary retention. These reactions are listed in order of decreasing rates in the OCD trials.6.3 Other Adverse Reactions in OCD Pediatric PopulationIn pediatric patients (N=57) treated with Fluvoxamine Maleate Tablets, the overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions, not appearing in Table 2, were reported in two or more of the pediatric patients and were more frequent with Fluvoxamine Maleate Tablets than with placebo: cough increase, dysmenorrhea, ecchymosis, emotional lability, epistaxis, hyperkinesia, manic reaction, rash, sinusitis, and weight decrease.6.4 Male and Female Sexual Dysfunction with SSRIsAlthough changes in sexual desire, sexual performance and sexual satisfaction often occur as manifestations of psychiatric disorder and with aging, they may also be 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 displays the incidence of sexual side effects reported by at least 2% of patients taking Fluvoxamine Maleate 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 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.6.5 Vital Sign ChangesComparisons 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.6.6 Laboratory ChangesComparisons 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.6.7 ECG ChangesComparisons 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.6.8 Other Reactions Observed During the Premarketing Evaluation of Fluvoxamine Maleate TabletsDuring premarketing clinical trials conducted in North America and Europe, multiple doses of fluvoxamine maleate were administered for combined total of 2737 patient exposures in patients suffering OCD or Major Depressive Disorder. Untoward reactions associated with this exposure were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of untoward reactions into limited (i.e., reduced) number of standard reaction categories.In the tabulations which follow, standard COSTART-based Dictionary terminology has been used to classify reported adverse reactions. If the COSTART term for reaction was so general as to be uninformative, it was replaced with more informative term. The frequencies presented, therefore, represent the proportion of the 2737 patient exposures to multiple doses of fluvoxamine maleate who experienced reaction of the type cited on at least one occasion while receiving fluvoxamine maleate. All reported reactions are included in the list below, with the following exceptions: 1) those reactions already listed in Table 2, which tabulates incidence rates of common adverse experiences in placebo-controlled OCD and depression clinical trials, are excluded; 2) those reactions for which drug cause was not considered likely are omitted; 3) reactions for which the COSTART term was too vague to be clinically meaningful and could not be replaced with more informative term; and 4) reactions 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 reactions reported did occur during treatment with fluvoxamine maleate, causal relationship to fluvoxamine maleate has not been established.Reactions are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse reactions are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring between 1/100 and 1/1000 patients; and rare adverse reactions are those occurring in less than 1/1000 patients.Body as Whole Frequent: malaise; Infrequent: photosensitivity reaction and suicide attempt.Cardiovascular System Frequent: syncope.Digestive System Infrequent: gastrointestinal hemorrhage and melena; Rare: hematemesis.Hemic and Lymphatic Systems Infrequent: anemia and ecchymosis; Rare: purpura.Metabolic and Nutritional Systems Frequent: weight gain and weight loss.Nervous System Frequent: hyperkinesia, manic reaction, and myoclonus; Infrequent: abnormal dreams, akathisia, convulsion, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, and twitching; Rare: withdrawal syndrome.Respiratory System Infrequent: epistaxis. Rare: hemoptysis and laryngismus.Skin Infrequent: urticaria.Urogenital System Infrequent: hematuria, menorrhagia, and vaginal hemorrhage; Rare: hematospermia. Based on the number of males or females, as appropriate.6.9 Postmarketing ReportsVoluntary reports of adverse reactions 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, ileus, pancreatitis, porphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsades de pointes).

CLINICAL PHARMACOLOGY SECTION.

12. CLINICAL PHARMACOLOGY12.1 Mechanism Of ActionThe mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. Fluvoxamine has been shown to be potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitro and in vivo.12.2 PharmacodynamicsIn 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.12.3 PharmacokineticsAbsorption: The absolute bioavailability of fluvoxamine maleate is 53%. Oral bioavailability is not significantly affected by food.In 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 week of dosing. Maximum plasma concentrations at steady state occurred within 3-8 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.Distribution: 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 concentration range of 20 to 2000 ng/mL.Metabolism: Fluvoxamine maleate is extensively metabolized by the liver; the main metabolic routes are oxidative demethylation and deamination. Nine metabolites were identified following 5 mg radiolabelled 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. 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 weak effect of the former metabolite on inhibition of serotonin uptake (1-2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged. (See DRUG INTERACTIONS [7].)Elimination: Following 14C-labelled 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.Elderly Subjects: In study of Fluvoxamine Maleate Tablets at 50 and 100 mg comparing elderly (ages 66-73) and young subjects (ages 19-35), 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. (See DOSAGE AND ADMINISTRATION [2.3].)Pediatric Subjects: The multiple-dose pharmacokinetics of fluvoxamine were determined in male and female children (ages 6-11) and adolescents (ages 12-17). Steady-state plasma fluvoxamine concentrations were 2-3 fold higher in children than in adolescents. AUC and Cmax in children were 1.5- to 2.7-fold higher than that in adolescents. (See Table 4.) As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC (0-12) and Cmax compared to male children and, therefore, lower doses of Fluvoxamine Maleate Tablets may produce therapeutic benefit. (See Table 5.) No gender differences were observed in adolescents. Steady-state plasma fluvoxamine concentrations were similar in adults and adolescents at dose of 300 mg/day, indicating that fluvoxamine exposure was similar in these two populations. (See Table 4.) Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. (See DOSAGE AND ADMINISTRATION [2.2].)Hepatic and Renal Disease: cross study comparison (healthy subjects versus patients with hepatic dysfunction) suggested 30% decrease in fluvoxamine clearance in association with hepatic dysfunction. The mean minimum plasma concentrations in renally impaired patients (creatinine clearance of to 45 mL/min) after and weeks of treatment (50 mg b.i.d., N=13) were comparable to each other, suggesting no accumulation of fluvoxamine in these patients. (See WARNINGS AND PRECAUTIONS Use in Patients with Concomitant Illness [5.13].).

DOSAGE & ADMINISTRATION SECTION.

2. DOSAGE AND ADMINISTRATION2.1 AdultsThe recommended starting dose for Fluvoxamine Maleate Tablets in adult patients is 50 mg, administered as single daily dose at bedtime. In the controlled clinical trials establishing the effectiveness of Fluvoxamine Maleate Tablets in OCD, patients were titrated within dose range of 100 to 300 mg/day. Consequently, the dose should be increased in 50 mg increments every to days, as tolerated, until maximum therapeutic benefit is achieved, not to exceed 300 mg per day. It is advisable that 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.2.2 Pediatric Population (children and adolescents)The recommended starting dose for Fluvoxamine Maleate Tablets in pediatric populations (ages 8-17 years) is 25 mg, administered as single daily dose at bedtime. In controlled clinical trial establishing the effectiveness of Fluvoxamine Maleate Tablets in OCD, pediatric patients (ages 8-17) were titrated within 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 to days, as tolerated, until maximum therapeutic benefit is achieved. It is advisable that total daily dose of more then 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.2.3 Elderly or Hepatically Impaired PatientsElderly patients and those with hepatic impairment have been observed to have decreased clearance of fluvoxamine maleate. Consequently, it may be appropriate to modify the initial dose and the subsequent dose titration for these patient groups.2.4 Pregnant Women During the Third TrimesterNeonates 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 and may be at risk for persistent pulmonary hypertension of the newborn (PPHN). (See USE IN SPECIFIC POPULATIONS [8.1].) When treating pregnant women with Fluvoxamine Maleate Tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering Fluvoxamine Maleate Tablets in the third trimester.2.5 Switching Patients To or From Monoamine Oxidase InhibitorAt least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with Fluvoxamine Maleate Tablets. Similarly, at least 14 days should be allowed after stopping Fluvoxamine Maleate Tablets before starting an MAOI.2.6 Maintenance/Continuation Extended TreatmentIt is generally agreed that obsessive compulsive disorder requires several months or longer of sustained pharmacologic therapy. The benefit of maintaining patients with OCD on Fluvoxamine Maleate Tablets after achieving response for an average duration of about weeks in 10-week single-blind phase during which patients were titrated to effect was demonstrated in controlled trial [see CLINICAL TRIALS (14.2)]. 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.2.7 Discontinuation of Treatment with Fluvoxamine Maleate TabletsSymptoms associated with discontinuation of other SSRIs or SNRIs have been reported. (See WARNINGS AND PRECAUTIONS [5.8].) Patients should be monitored for these symptoms when discontinuing treatment. gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following 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 more gradual rate.

INFORMATION FOR PATIENTS SECTION.

17. PATIENT COUNSELING INFORMATIONPrescribers 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 the appropriate use. 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.17.1 Clinical Worsening and Suicide RiskPatients, 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 day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patients prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patients 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 (see Boxed Warning and WARNINGS AND PRECAUTIONS [5.1]).17.2 Serotonin SyndromePatients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluvoxamine and triptans, tramadol, or other serotonergic agents (see WARNINGS AND PRECAUTIONS-Serotonergic Drugs [5.7]).17.3 Interference with Cognitive or Motor PerformanceSince any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain that Fluvoxamine Maleate Tablets therapy does not adversely affect their ability to engage in such activities.17.4 PregnancyPatients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy with Fluvoxamine Maleate Tablets (see USE IN SPECIFIC POPULATIONS [8.1]).17.5 NursingPatients receiving Fluvoxamine Maleate Tablets should be advised to notify their physicians if they are breast-feeding an infant. (See USE IN SPECIFIC POPULATIONS Nursing Mothers [8.3].)17.6 Concomitant MedicationPatients 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 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 (see WARNINGS AND PRECAUTIONS-Warfarin and Other Drugs That Interfere With Hemostasis [5.7]).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 (see WARNINGS AND PRECAUTIONS [5.4]).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 LotronexTM (alosetron) (see WARNINGS AND PRECAUTIONS [5.6]).17.7 AlcoholAs with other psychotropic medications, patients should be advised to avoid alcohol while taking Fluvoxamine Maleate Tablets.17.8 Allergic ReactionsPatients should be advised to notify their physicians if they develop rash, hives, or related allergic phenomenon during therapy with Fluvoxamine Maleate Tablets.LotronexTM is registrered trademark of GlaxoSmithKline.Manufactured forBayPharma, Inc.Baltimore, MD 21244.

OVERDOSAGE SECTION.

10. OVERDOSAGE10.1 Human ExperienceWorldwide 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, 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 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 involved 12,000 mg (equivalent to to 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.10.2 Management of OverdosageTreatment 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 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 tricyclic antidepressant. In such 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 physician should consider contacting 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).