Fluvoxamine Maleate Tablet, Film Coated
FDA Label NDC 62135-932

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)] .

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 8-17), and one maintenance trial in adults [see Clinical Studies (14)] .

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.

The recommended starting dose for fluvoxamine maleate tablets in pediatric populations (ages 8-17 years) is 25 mg, administered as a single daily dose at bedtime. In a controlled clinical trial establishing the effectiveness of fluvoxamine maleate tablets in OCD, pediatric patients (ages 8-17) were titrated within a dose range of 50 to 200 mg/day. Physicians should consider age and gender differences when dosing pediatric patients. The maximum dose in children up to age 11 should not exceed 200 mg/day. Therapeutic effect in female children may be achieved with lower doses. Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. The dose should be increased in 25 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved. It is advisable that a total daily dose of more than 50 mg should be given in two divided doses. If the two divided doses are not equal, the larger dose should be given at bedtime.

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.

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)] .

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)] .

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.

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.

Fluvoxamine Maleate Tablets, USP are available as:

Tablets 25 mg: White colored, oval shaped biconvex film-coated tablets with “ CE” above “ 239” debossed on one side and plain on the other side

Tablets 50 mg: White colored, oval shaped biconvex film-coated tablets debossed with bisect on one side and CE” above “ 240” on the other side

Tablets 100 mg: White colored, oval shaped biconvex film-coated tablets debossed with bisect on one side and “ CE” above “ 241” on the other side

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)] .

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1.

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about the drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms and risks [see Dosage and Administration (2.7)].

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers.Prescriptions for fluvoxamine maleate tablets should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder:A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that fluvoxamine maleate tablets are not approved for use in treating bipolar depression.

Selective serotonin reuptake inhibitors (SSRIs), including fluvoxamine maleate tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, meperidine, methadone, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7.1)] . Serotonin syndrome can also occur when these drugs are used alone.

Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of fluvoxamine maleate tablets with MAOIs is contraindicated. In addition, do not initiate fluvoxamine maleate tablets in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluvoxamine maleate tablets, discontinue fluvoxamine maleate tablets before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7.2)] .

Monitor all patients taking fluvoxamine maleate tablets for the emergence of serotonin syndrome. Discontinue treatment with fluvoxamine maleate tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of fluvoxamine maleate tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.

The pupillary dilation that occurs following use of many antidepressant drugs including fluvoxamine maleate tablets may trigger an angle closure attack in a patient with anatomically narrow angles who do not have a patent iridectomy.

The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady-state concentrations was evaluated in 10 male inpatients with schizophrenia. Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased threefold following coadministration of fluvoxamine.

Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death. It is likely that this experience underestimates the degree of risk that might occur with higher doses of thioridazine. Moreover, the effect of fluvoxamine may be even more pronounced when it is administered at higher doses.

Therefore, fluvoxamine and thioridazine should not be coadministered [see Contraindications (4)] .

Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate. The effect of fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in 10 healthy male subjects. Tizanidine C _maxwas increased approximately 12-fold (range 5-fold to 32-fold), elimination half-life was increased by almost 3-fold, and AUC increased 33-fold (range 14- fold to 103-fold). The mean maximal effect on blood pressure was a 35 mm Hg decrease in systolic blood pressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsiness was significantly increased and performance on the psychomotor task was significantly impaired. Fluvoxamine and tizanidine should not be used together [see Contraindications (4)] .

Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma concentrations of parent drug. An increased plasma concentration of pimozide causes QT prolongation and has been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal. As noted below, a substantial pharmacokinetic interaction has been observed for fluvoxamine in combination with alprazolam, a drug that is known to be metabolized by CYP3A4. Although it has not been definitively demonstrated that fluvoxamine is a potent CYP3A4 inhibitor, it is likely to be, given the substantial interaction of fluvoxamine with alprazolam. Consequently, it is recommended that fluvoxamine not be used in combination with pimozide [see Contraindications (4)] .

Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known potent inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, with coadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasma concentration (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold. [See Contraindications (4)and Lotronex ^TM(alosetron) package insert].

Benzodiazepines:Benzodiazepines metabolized by hepatic oxidation (e.g., alprazolam, midazolam, triazolam, etc.) should be used with caution because the clearance of these drugs is likely to be reduced by fluvoxamine. The clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine.

Alprazolam- When fluvoxamine maleate (100 mg q.d.) and alprazolam (1 mg q.i.d.) were coadministered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, C _max, T½) of alprazolam were approximately twice those observed when alprazolam was administered alone; oral clearance was reduced by about 50%. The elevated plasma alprazolam concentrations resulted in decreased psychomotor performance and memory. This interaction, which has not been investigated using higher doses of fluvoxamine, may be more pronounced if a 300 mg daily dose is coadministered, particularly since fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100-300 mg. If alprazolam is coadministered with fluvoxamine maleate tablets, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended. No dosage adjustment is required for fluvoxamine maleate tablets.

Diazepam- The coadministration of fluvoxamine maleate tablets and diazepam is generally not advisable. Because fluvoxamine reduces the clearance of both diazepam and its active metabolite, N-desmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic coadministration.

Evidence supporting the conclusion that it is inadvisable to coadminister fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of fluvoxamine were administered a single oral dose of 10 mg of diazepam. In these subjects (N=8), the clearance of diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was too low to measure over the course of the 2 week long study.

It is likely that this experience significantly underestimates the degree of accumulation that might occur with repeated diazepam administration. Moreover, as noted with alprazolam, the effect of fluvoxamine may even be more pronounced when it is administered at higher doses.

Accordingly, diazepam and fluvoxamine should not ordinarily be coadministered.

Clozapine -Elevated serum levels of clozapine have been reported in patients taking fluvoxamine maleate and clozapine. Since clozapine-related seizures and orthostatic hypotension appear to be dose related, the risk of these adverse events may be higher when fluvoxamine and clozapine are coadministered. Patients should be closely monitored when fluvoxamine maleate and clozapine are used concurrently.

Methadone: Significantly increased methadone (plasma level:dose) ratios have been reported when fluvoxamine maleate was administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient. Opioid withdrawal symptoms were reported following fluvoxamine maleate discontinuation in another patient.

Mexiletine:The effect of steady-state fluvoxamine (50 mg b.i.d. for 7 days) on the single dose pharmacokinetics of mexiletine (200 mg) was evaluated in 6 healthy Japanese males. The clearance of mexiletine was reduced by 38% following coadministration with fluvoxamine compared to mexiletine alone. If fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored.

Ramelteon:When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and fluvoxamine, the AUC for ramelteon increased approximately 190- fold and the C _maxincreased approximately 70-fold compared to ramelteon administered alone. Ramelteon should not be used in combination with fluvoxamine .

Theophylline:The effect of steady-state fluvoxamine (50 mg bid) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers. The clearance of theophylline was decreased approximately 3-fold. Therefore, if theophylline is coadministered with fluvoxamine maleate, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored. No dosage adjustment is required for fluvoxamine maleate tablets.

Warfarin and Other Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, etc.):Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with fluvoxamine [see Warnings and Precautions (5.10)] .

Warfarin -When fluvoxamine maleate (50 mg t.i.d.) was administered concomitantly with warfarin for two weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged. Thus patients receiving oral anticoagulants and fluvoxamine maleate tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly. No dosage adjustment is required for fluvoxamine maleate tablets.

During marketing of fluvoxamine maleate tablets and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with fluvoxamine maleate tablets. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration (2.7)] .

SSRIs and SNRIs, including fluvoxamine maleate tablets, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Based on data from the 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 Use in Specific Populations (8.1)] . Bleeding events related to SSRIs and SNRIs have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the increased risk of bleeding associated with the concomitant use of fluvoxamine maleate tablets and NSAIDs, aspirin, or other drugs that affect coagulation [see Warnings and Precautions (5.8)] .

During premarketing studies involving primarily depressed patients, hypomania or mania occurred in approximately 1% of patients treated with fluvoxamine. In a ten week pediatric OCD study, 2 out of 57 patients (4%) treated with fluvoxamine experienced manic reactions, compared to none of 63 placebo patients.
Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, fluvoxamine maleate tablets should be used cautiously in patients with a history of mania.

During premarketing studies, seizures were reported in 0.2% of fluvoxamine-treated patients. Caution is recommended when the drug is administered to patients with a history of convulsive disorders. Fluvoxamine should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Treatment with fluvoxamine should be discontinued if seizures occur or if seizure frequency increases.

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluvoxamine maleate tablets. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported.

Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs [see Use in Specific Populations (8.5)] . Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk. Discontinuation of fluvoxamine maleate tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Closely monitored clinical experience with fluvoxamine maleate tablets in patients with concomitant systemic illness is limited. Caution is advised in administering fluvoxamine maleate tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism.

Fluvoxamine maleate tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from many clinical studies during the product's premarketing testing. Evaluation of the electrocardiograms for patients with depression or OCD who participated in premarketing studies revealed no differences between fluvoxamine and placebo in the emergence of clinically important ECG changes.

Patients with Hepatic Impairment -In patients with liver dysfunction, fluvoxamine clearance was decreased by approximately 30%. Patients with liver dysfunction should begin with a low dose of fluvoxamine maleate tablets and increase it slowly with careful monitoring.

There are no specific laboratory tests recommended.

Use of SSRIs, including fluvoxamine maleate tablets, may cause symptoms of sexual dysfunction [see Adverse Reactions (6.4)] . In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction. In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.

It is important for prescribers to inquire about sexual function prior to initiation of fluvoxamine maleate tablets and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported. When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder. Discuss potential management strategies to support patients in making informed decisions about treatment.

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.

Of the 1,087 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).

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.

¹Reactions for which fluvoxamine maleate incidence was equal to or less than placebo are not listed in the table above.

²Includes “toothache,” “tooth extraction and abscess,” and “caries.”

³Mostly feeling warm, hot, or flushed.

⁴Mostly “blurred vision.”

⁵Mostly “delayed ejaculation.”

⁶Incidence 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 (mostlydelayed 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.

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.

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.

^*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.

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.

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.

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.

During premarketing clinical trials conducted in North America and Europe, multiple doses of fluvoxamine maleate were administered for a combined total of 2,737 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 2,737 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.

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).

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 vitrodata 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 vitrodata 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 vitrodata 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 vivostudy 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)] .

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 _maxand 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)] .

Alosetron:See Contrainidications (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) .

Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers.

There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate.

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 ²basis. In addition, decreased fetal body weight was seen at a dose 6 times the MRHD given to adolescents on a mg/m ²basis. 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 ²basis. 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 ²basis. 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 1-2 per 1,000 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).

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.

Infertility

Animal findings suggest fertility may be impaired while taking fluvoxamine [see Nonclinical Toxicology (13.1)] .

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.

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.

Fluvoxamine maleate tablets are not a controlled substance.

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).

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.

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 designated as 5-methoxy-4′-(trifluoromethyl)valerophenone-(E)-O-(2-aminoethyl)oxime maleate (1:1) and has the empirical formula C ₁₅H ₂₁O ₂N ₂F ₃·C ₄H ₄O ₄. Its molecular weight is 434.41.

The structural formula is:

"image Description" (Fluvoxamine Maleate Tabs Structure)

Fluvoxamine maleate is a white to off white, odorless, crystalline powder which is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diethyl ether.

Fluvoxamine Maleate Tablets, USP are available in 25 mg, 50 mg and 100 mg strengths for oral administration. In addition to the active ingredient, fluvoxamine maleate, each tablet contains the following inactive ingredients: colloidal silicon dioxide, hypromellose, mannitol, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium stearyl fumarate, starch (corn) and titanium dioxide.

The mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons. Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitroand in vivo.

In in vitrostudies, fluvoxamine maleate had no significant affinity for histaminergic, alpha or beta adrenergic, muscarinic, or dopaminergic receptors. Antagonism of some of these receptors is thought to be associated with various sedative, cardiovascular, anticholinergic, and extrapyramidal effects of some psychotropic drugs.

Absorption:The absolute bioavailability of fluvoxamine maleate is 53%. Oral bioavailability is not significantly affected by food.

In a dose proportionality study involving fluvoxamine maleate at 100, 200 and 300 mg/day for 10 consecutive days in 30 normal volunteers, steady state was achieved after about a week of dosing. Maximum plasma concentrations at steady state occurred within 3 to 8 hours of dosing and reached concentrations averaging 88, 283 and 546 ng/mL, respectively. Thus, fluvoxamine had nonlinear pharmacokinetics over this dose range, i.e., higher doses of fluvoxamine maleate produced disproportionately higher concentrations than predicted from the lower dose.

Distribution:The mean apparent volume of distribution for fluvoxamine is approximately 25 L/kg, suggesting extensive tissue distribution.

Approximately 80% of fluvoxamine is bound to plasma protein, mostly albumin, over a concentration range of 20 to 2000 ng/mL.

Metabolism:Fluvoxamine maleate is extensively metabolized by the liver; the main metabolic routes are oxidative demethylation and deamination. Nine metabolites were identified following a 5 mg radiolabelled dose of fluvoxamine maleate, constituting approximately 85% of the urinary excretion products of fluvoxamine. The main human metabolite was fluvoxamine acid which, together with its N-acetylated analog, accounted for about 60% of the urinary excretion products. A third metabolite, fluvoxethanol, formed by oxidative deamination, accounted for about 10%. Fluvoxamine acid and fluvoxethanol were tested in an in vitroassay of serotonin and norepinephrine reuptake inhibition in rats; they were inactive except for a weak effect of the former metabolite on inhibition of serotonin uptake (1-2 orders of magnitude less potent than the parent compound). Approximately 2% of fluvoxamine was excreted in urine unchanged [see Drug Interactions (7)] .

Elimination:Following a ¹⁴C-labelled oral dose of fluvoxamine maleate (5 mg), an average of 94% of drug-related products was recovered in the urine within 71 hours.

The mean plasma half-life of fluvoxamine at steady state after multiple oral doses of 100 mg/day in healthy, young volunteers was 15.6 hours.

Elderly Subjects:In a study of fluvoxamine maleate tablets at 50 and 100 mg comparing elderly (ages 66-73) and young subjects (ages 19-35), mean maximum plasma concentrations in the elderly were 40% higher. The multiple dose elimination half-life of fluvoxamine was 17.4 and 25.9 hours in the elderly compared to 13.6 and 15.6 hours in the young subjects at steady state for 50 and 100 mg doses, respectively. In elderly patients, the clearance of fluvoxamine was reduced by about 50% and, therefore, fluvoxamine maleate tablets should be slowly titrated during initiation of therapy [see Dosage and Administration (2.3)] .

Pediatric Subjects:The multiple-dose pharmacokinetics of fluvoxamine were determined in male and female children (ages 6-11) and adolescents (ages 12-17). Steady-state plasma fluvoxamine concentrations were 2-3 fold higher in children than in adolescents. AUC and C _maxin children were 1.5- to 2.7-fold higher than that in adolescents. (See Table 4.) As in adults, both children and adolescents exhibited nonlinear multiple-dose pharmacokinetics. Female children showed significantly higher AUC (0-12) and C _maxcompared to male children and, therefore, lower doses of fluvoxamine maleate tablets may produce therapeutic benefit. (See Table 5.) No gender differences were observed in adolescents. Steady-state plasma fluvoxamine concentrations were similar in adults and adolescents at a dose of 300 mg/day, indicating that fluvoxamine exposure was similar in these two populations. (See Table 4.) Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit [see Dosage and Administration (2.2)] .

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)] .

Carcinogenesis:There was no evidence of carcinogenicity in rats treated orally with fluvoxamine maleate for 30 months or hamsters treated orally with fluvoxamine maleate for 20 (females) or 26 (males) months. The daily doses in the high dose groups in these studies were increased over the course of the study from a minimum of 160 mg/kg to a maximum of 240 mg/kg in rats, and from a minimum of 135 mg/kg to a maximum of 240 mg/kg in hamsters. The maximum dose of 240 mg/kg is approximately 5 and 6 times, respectively (in hamsters and rats), the MRHD given to children on a mg/m ²basis.

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

Impairment of Fertility:In a study in which male and female rats were administered fluvoxamine (60, 120, or 240 mg/kg) prior to and during mating and gestation, fertility was impaired at oral doses of 120 mg/kg (3 times the MRHD given to adolescents on a mg/m ²basis) or greater, as evidenced by increased latency to mating, decreased sperm count, decreased epididymal weight, and decreased pregnancy rate. In addition, the numbers of implantations and embryos were decreased at the highest dose (6 times the MRHD in adolescents on a mg/m ²basis). The no effect dose for fertility impairment was 60 mg/kg (1.6 times the MRHD given to adolescents on a mg/m ²basis).

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.

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

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.

The effectiveness of fluvoxamine maleate tablets for the treatment of OCD was also demonstrated in a 10- week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages 8- 17). Patients in this study were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 50-200 mg/day (on a b.i.d.schedule) on the basis of response and tolerance. All patients had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score of 24. Patients receiving fluvoxamine maleate experienced mean reductions of approximately six units on the CY-BOCS total score, compared to a three-unit reduction for placebo patients.

Table 7 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study.

Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender. Further exploratory analyses revealed a prominent treatment effect in the 8 to 11 age group and essentially no effect in the 12 to 17 age group. While the significance of these results is not clear, the 2-3 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.

Fluvoxamine Maleate Tablets, USP, 25 mg are White colored, oval shaped biconvex film-coated tablets with “ CE” above “ 239” debossed on one side and plain on the other side are available as follows:

Bottles of 90.................................................................................................... NDC 62135-931-90

Fluvoxamine Maleate Tablets, USP, 50 mg are Whtie colored, oval shaped biconvex film-coated tablets debossed with bisect on one side and “ CE” above “ 240” on the other side are available as follows:

Bottles of 60................................................................................................... NDC 62135-932-60

Fluvoxamine Maleate Tablets, USP, 100 mg are White colored, oval shaped biconvex film-coated tablets debossed with bisect on one side and “ CE” above “ 241” on the other side are available as follows:

Bottles of 30................................................................................................... NDC 62135-933-30

Keep out of reach of children.

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

Dispense in tight containers.

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 brand names listed are the registered trademarks of their respective owners and are not trademarks of Chartwell RX, LLC.

Manufactured for:

Chartwell RX, LLC.

Congers, NY 10920

L72499

Rev. 12/2024

Print Medication Guides at: www.chartwellpharma.com/medguides.

Fluvoxamine Maleate Tablets, USP 25 mg - NDC 62135-931-90 - 90s Bottle label

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Fluvoxamine Maleate Tablets, USP 50 mg - NDC 62135-932-60 - 60s Bottle label

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Fluvoxamine Maleate Tablets, USP 100 mg - NDC 62135-933-30 - 30s Bottle label

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