PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

DRUG: fluvoxamine maleate

GENERIC: Fluvoxamine maleate

DOSAGE: TABLET, COATED

ADMINSTRATION: ORAL

NDC: 70518-1057-0

COLOR: white

SHAPE: OVAL

SCORE: Two even pieces

SIZE: 15 mm

IMPRINT: 1221

PACKAGING: 30 in 1 BLISTER PACK

ACTIVE INGREDIENT(S):

• FLUVOXAMINE MALEATE 100mg in 1

INACTIVE INGREDIENT(S):

• MANNITOL
• POLYETHYLENE GLYCOL 3350
• POLYVINYL ALCOHOL, UNSPECIFIED
• SILICON DIOXIDE
• SODIUM STEARYL FUMARATE
• STARCH, CORN
• STARCH, POTATO
• TALC
• TITANIUM DIOXIDE
• FERRIC OXIDE RED
• FERRIC OXIDE YELLOW
• FERROSOFERRIC OXIDE

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RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

Warnings and Precautions ( 5.2, 5.10) 8/2023

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CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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. Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitroand in vivo.

12.2 Pharmacodynamics

In in vitrostudies, 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 Pharmacokinetics

**Absorption:**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.

**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 a 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 a 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. A third metabolite, fluvoxethanol, formed by oxidative deamination, accounted for about 10%. Fluvoxamine acid and fluvoxethanol were tested in an in vitroassay 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 (1-2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged [see Drug Interactions ( 7)] .

**Elimination:**Following a 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 a 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 C maxin 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 C maxcompared 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 a 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)] .

TABLE 4 COMPARISON OF MEAN (SD) FLUVOXAMINE PHARMACOKINETIC PARAMETERS BETWEEN CHILDREN, ADOLESCENTS, AND ADULTS TABLE 5 COMPARISON OF MEAN (SD) FLUVOXAMINE PHARMACOKINETIC PARAMETERS BETWEEN MALE AND FEMALE CHILDREN (6-11 YEARS)

**Hepatic and Renal Disease:**A cross study comparison (healthy subjects versus 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 Warnings and Precautions ( 5.14)] .

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DOSAGE & ADMINISTRATION SECTION

Highlight: * Adults: Recommended starting dose is 50 mg at bedtime, with increases of 50 mg every 4 to 7 days as tolerated to maximum effect, not to exceed 300 mg/day. Daily doses over 100 mg should be divided. ( 2.1).

• Children and adolescents (8 -17 years): Recommended starting dose is 25 mg at bedtime, with increases of 25 mg every 4 to 7 days as tolerated to maximum effect, not to exceed 200 mg/day (8 -11 years) or 300 mg/day (12 -17 years). Daily doses over 50 mg should be divided ( 2.2).
• Hepatically impaired: Decreased clearance may require modified dose and titration ( 2.3).
• Extended treatment: Adjust dose to maintain lowest effective dose; reassess patients periodically ( 2.6).
• Discontinuation: Gradual dose reduction is recommended ( 2.7, 5.9).

2 DOSAGE AND ADMINISTRATION

2.1 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.

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 a single daily dose at bedtime. In a controlled clinical trial establishing the effectiveness of Fluvoxamine Maleate Tablets in OCD, pediatric patients (ages 8-17) 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.

2.3 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.

2.4 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI)

Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Fluvoxamine Maleate Tablets. Conversely, at least 14 days should be allowed after stopping Fluvoxamine Maleate Tablets before starting an MAOI intended to treat psychiatric disorders [see Contraindications ( 4)] .

2.5 Use of Fluvoxamine Maleate Tablets with Other MAOIs such as Linezolid

or Methylene Blue

Do not start Fluvoxamine Maleate Tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications ( 4)] .

In some cases, a patient already receiving Fluvoxamine Maleate Tablets therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Fluvoxamine Maleate Tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Fluvoxamine Maleate Tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions ( 5.2)] .

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Fluvoxamine Maleate Tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions ( 5.2)] .

2.6 Maintenance/Continuation Extended Treatment

It 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 a response for an average duration of about 4 weeks in a 10-week single-blind phase during which patients were titrated to effect was demonstrated in a 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 Tablets

Symptoms associated with discontinuation of other SSRIs or SNRIs have been reported [see Warnings and Precautions ( 5.9)] . 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.

DOSAGE FORMS & STRENGTHS SECTION

Highlight: * 100 mg Tablets ( 3)

3 DOSAGE FORMS AND STRENGTHS

Fluvoxamine Maleate Tablets USP are available as:
Tablets 100 mg: scored, beige, elliptical, film-coated (debossed “1221” on one side and scored on the other)

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CONTRAINDICATIONS SECTION

Highlight: * Coadministration of tizanidine, thioridazine, alosteron, pimozide ( 4) ***Serotonin Syndrome and MAOIs:**Do not use MAOIs intended to treat psychiatric disorders with Fluvoxamine Maleate Tablets or within 14 days of stopping treatment with Fluvoxamine Maleate Tablets. Do not use Fluvoxamine Maleate Tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start Fluvoxamine Maleate Tablets in a patient who is being treated with linezolid or intravenous methylene blue ( 4)

4 CONTRAINDICATIONS

Coadministration

Coadministration of tizanidine, thioridazine, alosetron, or pimozide with Fluvoxamine Maleate Tablets is contraindicated [see Warnings and Precautions ( 5.4, 5.5, 5.6, 5.7)] .

Serotonin Syndrome and Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with Fluvoxamine Maleate Tablets or within 14 days of stopping treatment with Fluvoxamine Maleate Tablets is contraindicated because of an increased risk of serotonin syndrome. The use of Fluvoxamine Maleate Tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.4), Warnings and Precautions ( 5.2)] .

Starting Fluvoxamine Maleate Tablets in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.5), Warnings and Precautions ( 5.2)] .

BOXED WARNING SECTION

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS

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ADVERSE REACTIONS SECTION

Highlight: * Most common reactions in controlled trials with adult OCD and depression patients (incidence ≥ 5% and at least twice that for placebo) were nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor, and vomiting( 6.2). Using the above rule, the following events were also identified: anorgasmia, decreased libido, dry mouth, rhinitis, taste perversion,and urinary frequencyin patients with OCD; and agitation, depression, dysmenorrhea, flatulence, hyperkinesia,and rashin pediatric patients with OCD.

To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6 ADVERSE REACTIONS

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.1 Adverse Reactions Leading to Treatment Discontinuation

Of 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 Trials

**Commonly 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 2were: nausea, somnolence, insomnia, asthenia, nervousness, dyspepsia, abnormal ejaculation, sweating, anorexia, tremor,and vomiting.In a 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 a 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 Occurring at an Incidence of 1%:**Table 2enumerates adverse reactions 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 a reaction at some time during their treatment. Reported adverse reactions 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.

TABLE 2 TREATMENT-EMERGENT ADVERSE REACTION INCIDENCE RATES BY BODY SYSTEM IN ADULT OCD AND DEPRESSION POPULATIONS COMBINED 1

**Adverse Reactions in OCD Placebo Controlled Studies Which are Markedly Different (defined as at least a two-fold difference) in Rate from the Pooled Reaction Rates in OCD and Depression Placebo Controlled Studies:**The reactions in OCD studies with a 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 a 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 Population

In 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 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 3displays 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.

TABLE 3 PERCENTAGE OF PATIENTS REPORTING SEXUAL ADVERSE REACTIONS IN ADULT PLACEBO-CONTROLLED TRIALS IN OCD AND DEPRESSION

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.

6.5 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.

6.6 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.

6.7 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.

6.8 Other Reactions 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 reactions 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 reactions without first grouping similar types of untoward reactions into a limited (i.e., reduced) number of standard reaction categories.

In the tabulations which follow, a standard COSTART-based Dictionary terminology has been used to classify reported adverse reactions. If the COSTART term for a reaction 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 multiple doses of fluvoxamine maleate who experienced a 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 a 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 a 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, a 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 a 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 Reports

The following adverse reactions have been identified during post-approval use of Fluvoxamine Maleate Tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Voluntary 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, anosmia, aplastic anemia, bullous eruption, Henoch-Schoenlein purpura, hepatitis, hyposmia, ileus, pancreatitis, porphyria, Stevens-Johnson syndrome, toxic epidermal necrolysis, vasculitis, and ventricular tachycardia (including torsades de pointes).

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

14.1 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 100-300 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), total score 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 6provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impressions (CGI) scale for both studies combined.

TABLE 6 OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN POOL OF TWO ADULT OCD STUDIES

Exploratory analyses for age and gender effects on outcomes did not suggest any differential responsiveness on the basis of age or sex.

14.2 Adult OCD Maintenance Study

In a maintenance trial of adult outpatients with OCD, 114 patients meeting DSM-IV criteria for OCD and with a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score ≥18 were titrated to an effective dose of Fluvoxamine Maleate Tablets 100 to 300 mg/day as part of an initial 10-week single-blind treatment phase. Treatment response during this single-blind phase was defined as Y-BOCS scores at least 30% lower than baseline at the end of weeks 8 and 10. Of the patients who responded, their average duration of response was 4 weeks. Patients who responded during this initial phase were randomized either to continuation of Fluvoxamine Maleate Tablets (N=56) or to placebo (N=58) in a double-blind phase for observation of relapse. Relapse during the double-blind phase was defined as an increase in the Y-BOCS score of at least 30% over the baseline for that phase or patient refusal to continue treatment due to a substantial increase in OCD symptoms. In the double-blind phase, patients receiving continued Fluvoxamine Maleate Tablets treatment experienced, on average, a significantly lower relapse rate than those receiving placebo.

An examination of population subgroups from this trial did not reveal any clear evidence of a differential maintenance effect on the basis of age or gender.

14.3 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 8-17). 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 50-200 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 baseline ratings 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 7provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study.

TABLE 7 OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN 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 8-11 age group and essentially no effect in the 12-17 age group. While the significance of these results is not clear, the 2-3 fold higher steady-state plasma fluvoxamine concentrations in children compared to adolescents [see Clinical Pharmacology ( 12.3)] 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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OVERDOSAGE SECTION

10 OVERDOSAGE

The following have been reported with fluvoxamine tablet overdosage:

• Seizures, which may be delayed, and altered mental status including coma.
• Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.
• Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk).

Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a fluvoxamine overdose.

Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for overdosage management recommendations.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

**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/kg to a maximum of 240 mg/kg in hamsters. The maximum dose of 240 mg/kg is approximately 5 and 6 times, respectively (in hamsters and rats), the MRHD given to children on a mg/m 2basis.

**Mutagenesis:**No evidence of genotoxic potential was observed in a mouse micronucleus test, an in vitrochromosome aberration test, or the Ames microbial mutagen test with or without metabolic activation.

**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 (3 times the MRHD given to adolescents on a mg/m 2basis) 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 (6 times the MRHD in adolescents on a mg/m 2basis). The no effect dose for fertility impairment was 60 mg/kg (1.6 times the MRHD given to adolescents on a mg/m 2basis).

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

Tablets 100 mg: scored, beige, elliptical, film-coated (debossed “1221” on one side and scored on the other)

NDC: 70518-1057-00

PACKAGING: 30 in 1 BLISTER PACK

Keep out of reach of children.

Fluvoxamine Maleate Tablets should be protected from high humidity and stored at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Dispense in tight containers.

Repackaged and Distributed By:

Remedy Repack, Inc.

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

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