Fluvoxamine Maleate

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. 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 frequency in patients with OCD; and agitation, depression, dysmenorrhea, flatulence, hyperkinesia, and rash in pediatric patients with OCD. To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 2 were: 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 2 enumerates 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 BODY SYSTEM/ ADVERSE REACTION Percentage of Patients Reporting Reaction FLUVOXAMINE N=892 PLACEBO N=778 BODY AS WHOLE Headache 22 20 Asthenia 14 6 Flu Syndrome 3 2 Chills 2 1 CARDIOVASCULAR Palpitations 3 2 DIGESTIVE SYSTEM Nausea 40 14 Diarrhea 11 7 Constipation 10 8 Dyspepsia 10 5 Anorexia 6 2 Vomiting 5 2 Flatulence 4 3 Tooth Disorder 2 3 1 Dysphagia 2 1 NERVOUS SYSTEM Somnolence 22 8 Insomnia 21 10 Dry Mouth 14 10 Nervousness 12 5 Dizziness 11 6 Tremor 5 1 Anxiety 5 3 Vasodilatation 3 3 1 Hypertonia 2 1 Agitation 2 1 Decreased Libido 2 1 Depression 2 1 CNS Stimulation 2 1 RESPIRATORY SYSTEM Upper Respiratory Infection 9 5 Dyspnea 2 1 Yawn 2 0 SKIN Sweating 7 3 SPECIAL SENSES Taste Perversion 3 1 Amblyopia 4 3 2 UROGENITAL Abnormal Ejaculation 5,6 8 1 Urinary Frequency 3 2 Impotence 6 2 1 Anorgasmia 2 0 Urinary Retention 1 0 1 Reactions for which fluvoxamine maleate incidence was equal to or less than placebo are not listed in the table above. 2 Includes "toothache," "tooth extraction and abscess," and "caries." 3 Mostly feeling warm, hot, or flushed. 4" Mostly "blurred vision." 5" Mostly "delayed ejaculation." 6 Incidence based on number of male patients. 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 3 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. TABLE 3 PERCENTAGE OF PATIENTS REPORTING SEXUAL ADVERSE REACTIONS IN ADULT PLACEBO-CONTROLLED TRIALS IN OCD AND DEPRESSION Fluvoxamine maleate tablets N=892 Placebo N=778 Abnormal Ejaculation* 8% 1% Impotence* 2% 1% Decreased Libido 2% 1% Anorgasmia 2% 0% * Based on the number of male patients. 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 1/1,000 patients; and rare adverse reactions are those occurring in less than 1/1,000 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).

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 )]. Coadministration of tizanidine, thioridazine, alosetron, pimozide ( 4 ) S erotonin 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 )

11 DESCRIPTION Fluvoxamine maleate, USP is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the chemical series, the 2-aminoethyl oxime ethers of aralkylketones. It 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 molecular formula C 15 H 21 O 2 N 2 F 3 •C 4 H 4 O 4 . Its molecular weight is 434.4. The structural formula is: Fluvoxamine maleate, USP is a white to off-white powder which is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diethyl ether. Fluvoxamine maleate tablets, USP are available in 25 mg, 50 mg and 100 mg strengths for oral administration. In addition to the active ingredient, fluvoxamine maleate USP, each tablet contains the following inactive ingredients: hydroxyethyl cellulose (25 mg and 50 mg), hydroxypropyl cellulose (100 mg), hypromellose (100 mg), iron oxide black (100 mg), iron oxide red (100 mg), iron oxide yellow (50 mg and 100 mg), magnesium stearate, mannitol, polyethylene glycol and titanium dioxide. Meets USP Organic Impurities Test 2. fluvoxamine-malea-01

2 DOSAGE AND ADMINISTRATION 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 to 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 to 11 years) or 300 mg/day (12 to 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 ). 2.1 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 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. 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.

1 INDICATIONS AND USAGE Fluvoxamine maleate tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) ( 1 ). 1.1 Obsessive-Compulsive Disorder Fluvoxamine maleate tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in DSM-III-R or DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. 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 efficacy of fluvoxamine maleate tablets was established in four trials in outpatients with OCD: two 10-week trials in adults, one 10-week trial in pediatric patients (ages 8 to 17), and one maintenance trial in adults [see Clinical Studies ( 14 )].

9.1 Controlled Substance Fluvoxamine maleate tablets are not a controlled substance.

9.3 Dependence The potential for abuse, tolerance and physical dependence with fluvoxamine maleate has been studied in a nonhuman primate model. No evidence of dependency phenomena was found. The discontinuation effects of fluvoxamine maleate tablets were not systematically evaluated in controlled clinical trials. Fluvoxamine maleate tablets were not systematically studied in clinical trials for potential for abuse, but there was no indication of drug-seeking behavior in clinical trials. It should be noted, however, that patients at risk for drug dependency were systematically excluded from investigational studies of fluvoxamine maleate. Generally, it is not possible to predict on the basis of preclinical or premarketing clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of fluvoxamine maleate misuse or abuse (i.e., development of tolerance, incrementation of dose, drug-seeking behavior).

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Fluvoxamine maleate tablets are not a controlled substance. 9.3 Dependence The potential for abuse, tolerance and physical dependence with fluvoxamine maleate has been studied in a nonhuman primate model. No evidence of dependency phenomena was found. The discontinuation effects of fluvoxamine maleate tablets were not systematically evaluated in controlled clinical trials. Fluvoxamine maleate tablets were not systematically studied in clinical trials for potential for abuse, but there was no indication of drug-seeking behavior in clinical trials. It should be noted, however, that patients at risk for drug dependency were systematically excluded from investigational studies of fluvoxamine maleate. Generally, it is not possible to predict on the basis of preclinical or premarketing clinical experience the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of fluvoxamine maleate misuse or abuse (i.e., development of tolerance, incrementation of dose, drug-seeking behavior).

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.

7 DRUG INTERACTIONS Drug Interactions (not described in Contraindications or Warnings And Precautions ) include the following: Drugs Inhibiting or Metabolized by Cytochrome P450: Fluvoxamine inhibits several cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP3A4, and CYP2C19). Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity with coadministration ( 7.2 ). Sumatriptan: Rare postmarketing reports of weakness, hyperreflexia, and incoordination following use of an SSRI and sumatriptan. Monitor appropriately if concomitant treatment is clinically warranted ( 7.2 ). Tacrine: Coadministration increased tacrine C max and AUC five- and eight-fold and caused nausea, vomiting, sweating, and diarrhea ( 7.2 ). Tricyclic Antidepressants (TCAs): Coadministration significantly increased plasma TCA levels. Use caution; monitor plasma TCA levels; reduce TCA dose if indicated ( 7.2 ). Tryptophan: Severe vomiting with coadministration ( 7.2 ). Diltiazem: Bradycardia with coadministration ( 7.3 ). Propranolol or metoprolol: Reduce dose if coadministered and titrate more cautiously ( 7.3 ). 7.1 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 and Precautions ( 5 )] 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 max , 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 (4 ), Warnings and Precautions ( 5 )]. 7.2 CNS Active Drugs Antipsychotics : See Warnings and Precautions ( 5.2 ). Benzodiazepines: See Warnings and Precautions ( 5.8 ). Alprazolam : See Warnings and Precautions ( 5.8 ). Diazepam : See Warnings and Precautions ( 5.8 ). Lorazepam: A study of multiple doses of fluvoxamine maleate (50 mg b.i.d.) in healthy male volunteers (N=12) and a single dose of lorazepam (4 mg single dose) indicated no significant pharmacokinetic interaction. On average, both lorazepam alone and lorazepam with fluvoxamine produced substantial decrements in cognitive functioning; however, the coadministration of fluvoxamine and lorazepam did not produce larger mean decrements compared to lorazepam alone. Alcohol : Studies involving single 40 g doses of ethanol (oral administration in one study and intravenous in the other) and multiple dosing with fluvoxamine maleate (50 mg b.i.d.) revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of the other. As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets. Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity have been reported with the coadministration of fluvoxamine maleate and carbamazepine. Clozapine : See Warnings and Precautions ( 5.8 ). Lithium : As with other serotonergic drugs, lithium may enhance the serotonergic effects of fluvoxamine and, therefore, the combination should be used with caution. Seizures have been reported with the coadministration of fluvoxamine maleate and lithium. Methadone: See Warnings and Precautions ( 5.8 ). Monoamine Oxidase Inhibitors: See Dosage and Administration ( 2.4 , 2.5 ), Contraindications ( 4), Warnings and Precautions (5.2 ). Pimozide : See Contraindications ( 4), Warnings and Precautions (5.6 ). Ramelteon: See Warnings and Precautions ( 5.8 ). Other Serotonergic Drugs: The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) with Fluvoxamine Maleate Tablets increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of Fluvoxamine Maleate Tablets and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.2 )] . Tacrine : In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five-and eight-fold increases in tacrine C max and AUC, respectively, compared to the administration of tacrine alone. Five subjects experienced nausea, vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine. Thioridazine: See Contraindications ( 4 ), Warnings and Precautions ( 5.4 ) . Tizanidine : See Contraindications ( 4 ), Warnings and Precautions (5.5 ). Tricyclic Antidepressants (TCAs) : Significantly increased plasma TCA levels have been reported with the coadministration of fluvoxamine maleate and amitriptyline, clomipramine or imipramine. Caution is indicated with the coadministration of fluvoxamine maleate tablets and TCAs; plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced. Triptans : There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of fluvoxamine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions ( 5.2 )]. Sumatriptan: There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised. Tryptophan : Tryptophan may enhance the serotonergic effects of fluvoxamine, and the combination should, therefore, be used with caution. Severe vomiting has been reported with the coadministration of fluvoxamine maleate and tryptophan [ see Warnings and Precautions ( 5.2 )]. 7.3 Other Drugs Alosetron: See Contraindications ( 4 ), Warnings and Precautions ( 5.7 ), and Lotronex TM (alosetron) package insert. 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. Diltiazem: Bradycardia has been reported with the coadministration of fluvoxamine maleate and diltiazem. Mexiletine : See Warnings and Precautions ( 5.8 ). 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. Theophylline: See Warnings and Precautions ( 5.8 ). Warfarin and Other Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, etc.) : See Warnings and Precautions ( 5.8 , 5.10 ). 7.4 Effects of Smoking on Fluvoxamine Metabolism Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers. 7.5 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate.

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 vitro and in vivo . 12.2 Pharmacodynamics 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. 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 2,000 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 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 Drug Interactions ( 7 )]. Elimination: Following a 14 C-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 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 [see Dosage and Administration ( 2.3 )]. 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 C max 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 C max 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 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 Pharmacokinetic Parameter (body weight corrected) Dose = 200 mg/day (100 mg b.i.d.) Dose = 300 mg/day (150 mg b.i.d.) Children (N=10) Adolescent (N=17) Adolescent (N=13) Adult (N=16) AUC 0-12 (ng • h/mL/kg) 155.1 (160.9) 43.9 (27.9) 69.6 (46.6) 59.4 (40.9) C max (ng/mL/kg) 14.8 (14.9) 4.2 (2.6) 6.7 (4.2) 5.7 (3.9) C min (ng/mL/kg) 11 (11.9) 2.9 (2) 4.8 (3.8) 4.6 (3.2) TABLE 5 COMPARISON OF MEAN (SD) FLUVOXAMINE PHARMACOKINETIC PARAMETERS BETWEEN MALE AND FEMALE CHILDREN (6-11 YEARS) Pharmacokinetic Parameter (body weight corrected) Dose = 200 mg/day (100 mg b.i.d.) Male Children (N=7) Female Children (N=3) AUC 0-12 (ng • h/mL/kg) 95.8 (83.9) 293.5 (233) C max (ng/mL/kg) 9.1 (7.6) 28.1 (21.1) C min (ng/mL/kg) 6.6 (6.1) 21.2 (17.6) 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 )].

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 vitro and in vivo .

12.2 Pharmacodynamics 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.

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 2,000 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 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 Drug Interactions ( 7 )]. Elimination: Following a 14 C-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 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 [see Dosage and Administration ( 2.3 )]. 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 C max 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 C max 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 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 Pharmacokinetic Parameter (body weight corrected) Dose = 200 mg/day (100 mg b.i.d.) Dose = 300 mg/day (150 mg b.i.d.) Children (N=10) Adolescent (N=17) Adolescent (N=13) Adult (N=16) AUC 0-12 (ng • h/mL/kg) 155.1 (160.9) 43.9 (27.9) 69.6 (46.6) 59.4 (40.9) C max (ng/mL/kg) 14.8 (14.9) 4.2 (2.6) 6.7 (4.2) 5.7 (3.9) C min (ng/mL/kg) 11 (11.9) 2.9 (2) 4.8 (3.8) 4.6 (3.2) TABLE 5 COMPARISON OF MEAN (SD) FLUVOXAMINE PHARMACOKINETIC PARAMETERS BETWEEN MALE AND FEMALE CHILDREN (6-11 YEARS) Pharmacokinetic Parameter (body weight corrected) Dose = 200 mg/day (100 mg b.i.d.) Male Children (N=7) Female Children (N=3) AUC 0-12 (ng • h/mL/kg) 95.8 (83.9) 293.5 (233) C max (ng/mL/kg) 9.1 (7.6) 28.1 (21.1) C min (ng/mL/kg) 6.6 (6.1) 21.2 (17.6) 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 )].

20230925

13

3 DOSAGE FORMS AND STRENGTHS Fluvoxamine maleate tablets, USP are available as: Tablets 25 mg: White to off-white, round, unscored, film coated tablets, engraved “APO” on one side and “F25” on the other side. Tablets 50 mg: Golden, round, scored, film coated tablets, engraved “APO” on one side and “F50” with a partial bisect on the other side. Tablets 100 mg: Reddish-brown, pillow shaped, scored, film coated tablets, engraved “APO” on one side and “FLU” bisect “100” on the other side. 25 mg tablets, 50 mg tablets, and 100 mg tablets ( 3 )

Fluvoxamine Maleate Fluvoxamine Maleate FLUVOXAMINE MALEATE FLUVOXAMINE HYDROXYETHYL CELLULOSE (140 MPA.S AT 5%) MAGNESIUM STEARATE MANNITOL POLYETHYLENE GLYCOL 8000 TITANIUM DIOXIDE APO;F25 Fluvoxamine Maleate Fluvoxamine Maleate FLUVOXAMINE MALEATE FLUVOXAMINE HYDROXYETHYL CELLULOSE (140 MPA.S AT 5%) MAGNESIUM STEARATE MANNITOL POLYETHYLENE GLYCOL 8000 TITANIUM DIOXIDE FERRIC OXIDE YELLOW APO;F50 Fluvoxamine Maleate Fluvoxamine Maleate FLUVOXAMINE MALEATE FLUVOXAMINE HYDROXYPROPYL CELLULOSE, UNSPECIFIED MAGNESIUM STEARATE MANNITOL POLYETHYLENE GLYCOL 8000 TITANIUM DIOXIDE FERRIC OXIDE RED FERRIC OXIDE YELLOW FERROSOFERRIC OXIDE HYPROMELLOSE, UNSPECIFIED APO;FLU100 25mg-100btl.jpg 50mg-100btl.jpg 100mg-100btl.jpg

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 2 basis. Mutagenesis: No evidence of genotoxic 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. 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 2 basis) 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 2 basis). The no effect dose for fertility impairment was 60 mg/kg (1.6 times the MRHD given to adolescents on a mg/m 2 basis).

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 2 basis. Mutagenesis: No evidence of genotoxic 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. 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 2 basis) 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 2 basis). The no effect dose for fertility impairment was 60 mg/kg (1.6 times the MRHD given to adolescents on a mg/m 2 basis).

ANDA075902

Fluvoxamine Maleate

Fluvoxamine Maleate

60505-0165

HUMAN PRESCRIPTION DRUG

ORAL

5.15 Laboratory Tests There are no specific laboratory tests recommended.

PRINCIPAL DISPLAY PANEL - 25 mg Representative sample of labeling (see HOW SUPPLIED section for complete listing) APOTEX CORP. NDC 60505-0164-1 Fluvoxamine Maleate Tablets, USP 25 mg Rx 100 bottle count

Warnings and Precautions ( 5.2 , 5.10 ) 8/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). 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 the 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. 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 [see Boxed Warning, Warnings and Precautions ( 5.1 )]. Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome particularly with the concomitant use of fluvoxamine with other serotonergic agents (including triptans, tricyclic antidepressants, opioids, lithium, tryptophan, buspirone, amphetamines, and St. John's Wort) [see Warnings and Precautions ( 5.2 )]. Angle Closure Glaucoma Patients should be advised that taking Fluvoxamine Maleate Tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions ( 5.3 )]. Interference with Cognitive or Motor Performance Since 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. Pregnancy Advise pregnant women to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with Fluvoxamine Maleate Tablets. Advise patients that Fluvoxamine Maleate Tablets use late in pregnancy may lead to an increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension of the newborn (PPHN). Advise women that there is a risk of relapse with discontinuation of antidepressants. Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Fluvoxamine Maleate Tablets during pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise breastfeeding women using Fluvoxamine Maleate Tablets to monitor infants for diarrhea, vomiting, decreased sleep, and agitation and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )]. 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 [see Warnings and Precautions ( 5.8 )]. 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 ( 5.5 )]. 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 TM (alosetron) [see Warnings and Precautions ( 5.7 )]. Sexual Dysfunction Advise patients that use of fluvoxamine maleate tablets may cause symptoms of sexual dysfunction in both male and female patients. Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions ( 5.16 )]. Alcohol As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets. 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. All registered trademarks in this document are the property of their respective owners. Dispense with Medication Guide available at www1.apotex.com/products/us APOTEX INC. FLUVOXAMINE MALEATE TABLETS, USP 25 mg, 50 mg and 100 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L1T9 USA 33326 Revision: 16

MEDICATION GUIDE Fluvoxamine (Flu VOX ah meen) Tablets , USP Medication Guide available at www1.apotex.com/products/us Read the Medication Guide that comes with fluvoxamine maleate tablets before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about fluvoxamine maleate tablets? Fluvoxamine is the same kind of medicine as those used to treat depression and may cause serious side effects, including: 1. Suicidal thoughts or actions: Fluvoxamine maleate tablets and antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed . Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice: New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. Pay particular attention to such changes when fluvoxamine maleate tablets is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: attempts to commit suicide acting on dangerous impulses acting aggressive or violent thoughts about suicide or dying new or worse depression new or worse anxiety or panic attacks feeling agitated, restless, angry or irritable trouble sleeping an increase in activity or talking more than what is normal for you other unusual changes in behavior or mood Tell your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluvoxamine maleate tablets may be associated with these serious side effects: 2. Serotonin Syndrome: This condition can be life-threatening and may include : agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) racing heartbeat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity 3. Visual problems eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. 4. Severe allergic reactions: trouble breathing swelling of the face, tongue, eyes, or mouth rash, itchy welts (hives) or blisters, alone or with fever or joint pain 5. Abnormal bleeding : fluvoxamine maleate tablets and antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin ® , Jantoven ® ), or a non-steroidal anti-inflammatory drug (NSAIDs, like ibuprofen, naproxen, or aspirin). 6. Seizures or convulsions 7. Manic episodes: greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual 8. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment. 9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include: headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 10. Sexual problems (dysfunction). Taking selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine maleate tablets, may cause sexual problems. Symptoms in males may include: Delayed ejaculation or inability to have an ejaculation Decreased sex drive Problems getting or keeping an erection Symptoms in females may include: Decreased sex drive Delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with fluvoxamine maleate tablets. There may be treatments your healthcare provider can suggest. Do not stop fluvoxamine maleate tablets without first talking to your healthcare provider . Stopping fluvoxamine maleate tablets too quickly may cause serious symptoms including: anxiety, irritability, high or low mood, feeling restless or changes in sleep habits headache, sweating, nausea, dizziness electric shock-like sensations, shaking, confusion What are fluvoxamine maleate tablets? Fluvoxamine maleate tablets are a prescription medicine used to treat obsessive compulsive disorder (OCD). It is important to talk with your healthcare provider about the risks of treating OCD and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Talk to your healthcare provider if you do not think that your condition is getting better with fluvoxamine maleate tablets treatment. Who should not take fluvoxamine maleate tablets? Do not take fluvoxamine maleate tablets if you: are allergic to fluvoxamine maleate or any of the ingredients in fluvoxamine maleate tablets. See the end of this Medication Guide for a complete list of ingredients in fluvoxamine maleate tablets. take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 2 weeks of stopping fluvoxamine maleate tablets unless directed to do so by your physician. Do not start fluvoxamine maleate tablets if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take fluvoxamine maleate tablets close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: high fever uncontrolled muscle spasms stiff muscles rapid changes in heart rate or blood pressure confusion loss of consciousness (pass out) take Mellaril ® (thioridazine). Do not take Mellaril ® within 2 weeks of stopping Fluvoxamine Maleate Tablets because this can cause serious heart rhythm problems or sudden death. take Orap ® (pimozide) because taking this drug with Fluvoxamine Maleate Tablets can cause serious heart rhythm problems or sudden death. take Zanaflex ® (tizanidine). Fluvoxamine maleate tablets could increase the amount of Zanaflex in your body, which could increase its actions and side effects. This could include drowsiness and a drop in blood pressure and affecting how well you do things that require alertness. Take Lotronex ® (alosetron). Fluvoxamine maleate tablets may increase the amount of Lotronex in your body, which could increase its actions and side effects. What should I tell my healthcare provider before taking fluvoxamine maleate tablets? Ask if you are not sure. Before starting fluvoxamine maleate tablets, tell your healthcare provider if you: Are taking certain drugs such as: Monoamine oxidase inhibitors (MAOIs) such as Emsam ® (selegiline), Nardil ® (phenelzine), or Parnate ® (tranylcypromine) Mellaril ® (thioridazine): used to treat mental or mood problems Zanaflex ® (tizanidine): used to treat spasticity (a condition in which muscles keep tightening and cramping) Orap ® (pimozide): used to treat Tourette Syndrome (a brain condition causing tics) Lotronex ® (alosetron): used to treat a condition with diarrhea, continuing stomach pain, cramps, and bloating Triptans: used to treat migraine headache Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, or antipsychotics Tramadol, fentanyl, meperidine, methadone, or other opioids Benzodiazepines: used to reduce anxiety, stress, emotional upset, or seizures; helps you sleep; helps with alcohol withdrawal; reduces restlessness; and relaxes muscles Clozapine: used to treat mental disorders Mexiletine: used to treat abnormalities in heart rhythm Theophylline: used to treat swollen air passages in your lungs, to relax the muscles in your chest to ease shortness of breath, often to treat asthma Warfarin and other drugs that affect how your blood clots Diuretics to treat high blood pressure, congestive heart failure, or swelling Over-the-counter supplements such as tryptophan or St. John’s Wort have liver problems have kidney problems have heart problems have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have a history of a stroke have high blood pressure have or had bleeding problems are pregnant or plan to become pregnant. Talk to your healthcare provider about the risk to your unborn baby if you take Fluvoxamine Maleate Tablets. Talk to your healthcare provider about the benefits and risks of treating OCD during pregnancy. If you become pregnant during treatment with Fluvoxamine Maleate Tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-­844-405-6185. are breast-feeding or plan to breast-feed. Some fluvoxamine maleate tablets may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking fluvoxamine maleate tablets. Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. fluvoxamine maleate tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects. Your healthcare provider or pharmacist can tell you if it is safe to take fluvoxamine maleate tablets with your other medicines. Do not start or stop any medicine while taking fluvoxamine maleate tablets without talking to your healthcare provider first. If you take fluvoxamine maleate tablets, you should not take any other medicines that contain fluvoxamine including: Fluvoxamine maleate extended-release capsules. How should I take fluvoxamine maleate tablets? Take fluvoxamine maleate tablets exactly as prescribed. Your healthcare provider may need to change the dose of fluvoxamine maleate tablets until it is the right dose for you. Fluvoxamine maleate tablets may be taken with or without food. If you miss a dose of fluvoxamine maleate tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of fluvoxamine maleate tablets at the same time. If you take too much fluvoxamine maleate tablets, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking fluvoxamine maleate tablets? Fluvoxamine maleate tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how fluvoxamine maleate tablets affects you. Do not drink alcohol while using fluvoxamine maleate tablets. What are the possible side effects of fluvoxamine maleate tablets? Fluvoxamine maleate tablets may cause serious side effects, including: See “What is the most important information I should know about fluvoxamine maleate tablets?” Feeling anxious or trouble sleeping Common possible side effects in people who take fluvoxamine maleate Tablets include: nausea sleepiness weakness indigestion sweating loss of appetite shaking vomiting delayed ejaculation inability to have an orgasm decreased sex drive dry mouth stuffy nose unusual taste frequent urination Other side effects in children and adolescents include: agitation or abnormal increase in activity feeling depressed or sad excessive gas heavy menstrual periods rash possible slowed growth rate and weight change. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of fluvoxamine maleate tablets. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO APOTEX AT 1-800-706-5575 OR FDA AT 1-800-FDA-1088. How should I store fluvoxamine maleate tablets? Store fluvoxamine maleate tablets at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Keep Fluvoxamine Maleate Tablets away from high humidity. Keep Fluvoxamine Maleate Tablets in a tight, light-resistant container. Keep fluvoxamine maleate tablets and all medicines out of the reach of children. General information about fluvoxamine maleate Tablets Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluvoxamine maleate tablets for a condition for which it was not prescribed. Do not give fluvoxamine maleate tablets to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about fluvoxamine maleate tablets. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluvoxamine maleate tablets that is written for healthcare professionals. For more information about Fluvoxamine Maleate Tablets call toll free at 1-800-706-5575 or go to www.apotex.com What are the ingredients in fluvoxamine maleate tablets? Active ingredient: Fluvoxamine maleate Inactive ingredients: hydroxyethyl cellulose (25 mg and 50 mg), hydroxypropyl cellulose (100 mg), hypromellose (100 mg), iron oxide black (100 mg), iron oxide red (100 mg), iron oxide yellow (50 mg and 100 mg), magnesium stearate, mannitol, polyethylene glycol and titanium dioxide. All registered trademarks in this document are the property of their respective owners. APOTEX INC. FLUVOXAMINE MALEATE TABLETS, USP 25 mg, 50 mg and 100 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L1T9 USA 33326 Revised: September 2023 This Medication Guide has been approved by the U.S. Food and Drug Administration.

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 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), 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 6 provides 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 Outcome Classification Fluvoxamine (N=120) Placebo (N=134) Very Much Improved 13% 2% Much Improved 30% 10% Minimally Improved 22% 32% No Change 31% 51% Worse 4% 6% 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 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 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 7 provides 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 Outcome Classification Fluvoxamine (N=38) Placebo (N=36) Very Much Improved 21% 11% Much Improved 18% 17% Minimally Improved 37% 22% No Change 16% 44% Worse 8% 6% 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 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.

8.5 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 maleate tablets, have been associated with several cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions ( 5.13 )] . Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients [see Clinical Pharmacology ( 12.3 )], and greater sensitivity of some older individuals also cannot be ruled out. Consequently, a lower starting dose should be considered in elderly patients and fluvoxamine maleate tablets should be slowly titrated during initiation of therapy.

8.4 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 (6.3), Dosage and Administration (2.2 )]. 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 effects in chronic use [see Warnings and Precautions (5.1 )]. Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established [see Boxed Warning; Warnings and Precautions (5.1 )] . Anyone considering the use of fluvoxamine maleate tablets in a child or adolescent must balance the potential risks with the clinical need.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ . Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.10 ) and Clinical Considerations]. Prolonged experience with fluvoxamine in pregnant women over decades, based on published observational studies, have not identified a clear drug-associated risk of major birth defects or miscarriage (see Data). There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (PPHN) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, during pregnancy (see Clinical Considerations). When pregnant rats were treated orally with fluvoxamine throughout the period of organogenesis, increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses ≥3 times the maximum recommended human dose (MRHD) of 300 mg/day given to adolescents on a mg/m 2 basis. In addition, decreased fetal body weight was seen at a dose 6 times the MRHD given to adolescents on a mg/m 2 basis. There were no adverse developmental effects in rabbits treated with fluvoxamine during the period of organogenesis up to a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. When fluvoxamine was administered orally to rats during pregnancy and lactation, increased pup mortality at birth was seen at a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. In addition, decreases in pup body weight and survival were observed at doses that are ≥0.13 times the MRHD given to adolescents (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of Fluvoxamine Maleate Tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.10 )] . Fetal/Neonatal adverse reactions 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. 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 picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. Data Human Data Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data When pregnant rats were given oral doses of fluvoxamine (60, 120, or 240 mg/kg) throughout the period of organogenesis, developmental toxicity in the form of increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses of 120 mg/kg or greater (3 times the MRHD of 300 mg/day, given to adolescents on a mg/m 2 basis). Decreased fetal body weight was seen at the high dose of 240 mg/kg/day (6 times the MRHD given to adolescents on a mg/m 2 basis). The no effect dose for developmental toxicity in this study was 60 mg/kg/day (1.6 times the MRHD given to adolescents on a mg/m 2 basis). In a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2.1 times the MRHD given to adolescents on a mg/m 2 basis) during the period of organogenesis, no adverse effects on embryofetal development were observed. In other reproduction studies in which female rats were dosed orally during pregnancy and lactation (5, 20, 80, or 160 mg/kg), increased pup mortality at birth was seen at doses of 80 mg/kg/day (2 times the MRHD given to adolescents on a mg/m 2 basis) or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.13 times the MRHD given to adolescents on a mg/m 2 basis).

8 USE IN SPECIFIC POPULATIONS Specific populations not discussed in Dosage and Administration or Warnings and Precautions include: Pregnancy: Third trimester use may increase risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8.1 ). Pediatric: Monitor weight and growth; effects of long-term use on growth, cognitive behavioral development, and maturation have not been studied ( 8.4 ). Geriatric: Use of a lower starting dose may be warranted. Titrate slowly during initiation of therapy ( 2.3 , 8.5 ). Smokers: Smokers had a 25% increase in fluvoxamine metabolism ( 7.4 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/ . Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.10 ) and Clinical Considerations]. Prolonged experience with fluvoxamine in pregnant women over decades, based on published observational studies, have not identified a clear drug-associated risk of major birth defects or miscarriage (see Data). There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (PPHN) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine, during pregnancy (see Clinical Considerations). When pregnant rats were treated orally with fluvoxamine throughout the period of organogenesis, increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses ≥3 times the maximum recommended human dose (MRHD) of 300 mg/day given to adolescents on a mg/m 2 basis. In addition, decreased fetal body weight was seen at a dose 6 times the MRHD given to adolescents on a mg/m 2 basis. There were no adverse developmental effects in rabbits treated with fluvoxamine during the period of organogenesis up to a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. When fluvoxamine was administered orally to rats during pregnancy and lactation, increased pup mortality at birth was seen at a dose 2 times the MRHD given to adolescents on a mg/m 2 basis. In addition, decreases in pup body weight and survival were observed at doses that are ≥0.13 times the MRHD given to adolescents (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of Fluvoxamine Maleate Tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.10 )] . Fetal/Neonatal adverse reactions 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. 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 picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. Data Human Data Exposure during late pregnancy to SSRIs may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal Data When pregnant rats were given oral doses of fluvoxamine (60, 120, or 240 mg/kg) throughout the period of organogenesis, developmental toxicity in the form of increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses of 120 mg/kg or greater (3 times the MRHD of 300 mg/day, given to adolescents on a mg/m 2 basis). Decreased fetal body weight was seen at the high dose of 240 mg/kg/day (6 times the MRHD given to adolescents on a mg/m 2 basis). The no effect dose for developmental toxicity in this study was 60 mg/kg/day (1.6 times the MRHD given to adolescents on a mg/m 2 basis). In a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2.1 times the MRHD given to adolescents on a mg/m 2 basis) during the period of organogenesis, no adverse effects on embryofetal development were observed. In other reproduction studies in which female rats were dosed orally during pregnancy and lactation (5, 20, 80, or 160 mg/kg), increased pup mortality at birth was seen at doses of 80 mg/kg/day (2 times the MRHD given to adolescents on a mg/m 2 basis) or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.13 times the MRHD given to adolescents on a mg/m 2 basis). 8.2 Lactation Data from published literature report the presence of fluvoxamine is in human milk (see Data). No adverse effects on the breastfed infant have been reported in most cases of maternal use of fluvoxamine during breastfeeding. However, there are reports of diarrhea, vomiting, decreased sleep, and agitation (see Clinical Considerations). There are no data on the effect of fluvoxamine on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for fluvoxamine and any potential adverse effects on the breastfed child from fluvoxamine or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to fluvoxamine through breast milk for diarrhea, vomiting, decreased sleep, and agitation. Data Milk drug concentrations ≤ 425 ng/mL were observed following maternal dosing of fluvoxamine 25 mg/day to 300 mg/day in published case reports and case series. 8.3 Females and Males of Reproductive Potential Infertility Animal findings suggest fertility may be impaired while taking fluvoxamine [see Nonclinical Toxicology ( 13.1 )]. 8.4 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 (6.3), Dosage and Administration (2.2 )]. 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 effects in chronic use [see Warnings and Precautions (5.1 )]. Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established [see Boxed Warning; Warnings and Precautions (5.1 )] . Anyone considering the use of fluvoxamine maleate tablets in a child or adolescent must balance the potential risks with the clinical need. 8.5 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 maleate tablets, have been associated with several cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions ( 5.13 )] . Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients [see Clinical Pharmacology ( 12.3 )], and greater sensitivity of some older individuals also cannot be ruled out. Consequently, a lower starting dose should be considered in elderly patients and fluvoxamine maleate tablets should be slowly titrated during initiation of therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fluvoxamine maleate tablets, USP are available in the following strengths, colors, imprints, and presentations: Tablets 25 mg: White to off-white, round, unscored, film coated tablets, engraved “APO” on one side and “F25” on the other side. Bottles of 100...........................................................................NDC 60505-0164-1 Tablets 50 mg: Golden, round, scored, film coated tablets, engraved “APO” on one side and “F50” with a partial bisect on the other side. Bottles of 100...........................................................................NDC 60505-0165-1 Tablets 100 mg: Reddish-brown, pillow shaped, scored, film coated tablets, engraved “APO” on one side and “FLU” bisect “100” on the other side. Bottles of 100...........................................................................NDC 60505-0166-1 16.2 Storage Keep out of reach of children. Fluvoxamine maleate tablets, USP should be protected from high humidity and stored at 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container.

WARNING: 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. Patients of 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 maleate tablets are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD) [see Warnings and Precautions ( 5.1 )] . WARNING: SUICIDALITY AND ANTIDEPRESSANTS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders. Fluvoxamine maleate tablets are not approved for use in pediatric patients except those with obsessive compulsive disorder ( 5.1 ).