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WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Suicidality: Monitor for clinical worsening and suicide risk ( 5.1 ).

Bipolar disorder: Screen for bipolar disorder ( 5.1 ).

S erotonin Syndrome: Serotonin syndrome has been reported with SSRIs, and SNRIs including fluvoxamine maleate tablets, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St.

John’s Wort).

If such symptoms occur, discontinue fluvoxamine maleate tablets and initiate supportive treatment.

If concomitant use of fluvoxamine maleate tablets with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

( 5.2 ).

Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.3 ).

Other potentially important drug interactions.

Benzodiazepines: Use with caution.

Coadministration with diazepam is generally not advisable ( 5.8 ).

Clozapine: Clozapine levels may be increased and produce orthostatic hypotension or seizures ( 5.9 ).

Methadone : Coadministration may produce opioid intoxication.

Discontinuation of fluvoxamine may produce opioid withdrawal ( 5.8 ).

Mexiletine: Monitor serum mexiletine levels ( 5.9 ).

Ramelteon: Should not be used in combination with fluvoxamine ( 5.8 ).

Theophylline: Clearance decreased; reduce theophylline dose by one-third ( 5.8 ).

Warfarin: Plasma concentrations increased and prothrombin times prolonged; monitor prothrombin time and adjust warfarin dose accordingly ( 5.8 ).

Other Drugs Affecting Hemostasis: Increased risk of bleeding with concomitant use of NSAIDs, aspirin, or other drugs affecting coagulation ( 5.8 , 5.10 ).

See Contraindications (4) .

Discontinuation: Symptoms associated with discontinuation have been reported ( 5.9 ).

Abrupt discontinuation not recommended.

See Dosage And Administration (2.8) .

Activation of mania/hypomania has occurred ( 5.11 ).

Seizures: Avoid administering fluvoxamine in patients with unstable epilepsy; monitor patients with controlled epilepsy; discontinue treatment if seizures occur or frequency increases ( 5.12 ).

Hyponatremia: May occur with SSRIs and SNRIs, including fluvoxamine maleate tablets.

The elderly may be at increased risk.

Consider discontinuing in patients with symptomatic hyponatremia ( 5.13 ).

Concomitant illness: Use caution in patients with diseases or conditions that affect hemodynamic responses or metabolism ( 5.14 ).

Patients with impaired liver function may require a lower starting dose and slower titration ( 2.3 ).

5.1 Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.

There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders.

Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo 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 4400 patients.

The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients.

There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.

There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD.

The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications.

These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 .

TABLE 1 DRUG-PLACEBO DIFFERENCES IN NUMBER OF CASES OF SUICIDALITY PER 1000 PATIENTS TREATED Age Range Increases Compared to Placebo <18 14 Additional Cases 18-24 5 Additional Cases Age Range Decreases Compared to Placebo 25-64 1 Fewer Case ≥ 65 6 Fewer Cases 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 [see DOSAGE AND ADMINISTRATION – Discontinuation of Treatment with fluvoxamine maleate tablets (2.8) , for a description of the risks of discontinuation of fluvoxamine maleate tablets] .

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to 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.

5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluvoxamine maleate tablets, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, busipirone, and St.

John’s Wort) and with drugs that impair metabolism of serotonin ( in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome 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 aberrations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or 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 intended to treat psychiatric disorders is contraindicated.

Fluvoxamine maleate tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluvoxamine maleate tablets.

Fluvoxamine maleate tablets should be discontinued before initiating treatment with the MAOI.

[see CONTRAINDICATIONS (4.2) and DOSAGE AND ADMINISTRATION ( 2.5 and 2.6 ).] If concomitant use of fluvoxamine maleate tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St.

John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with fluvoxamine maleate tablets and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.3 Angle Closure Glaucoma 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.

5.4 Potential Thioridazine Interaction The effect of fluvoxamine (25 mg b.i.d.

for one week) on thioridazine steady-state concentrations was evaluated in 10 male inpatients with schizophrenia.

Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased 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 (4.1) .] 5.5 Potential Tizanidine Interaction Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate.

The effect of fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in 10 healthy male subjects.

Tizanidine C max was 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 (4.1) .] 5.6 Potential Pimozide Interaction Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma concentrations of parent drug.

An increased plasma concentration of pimozide causes QT prolongation and has been associated with 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 (4.1) .] 5.7 Potential Alosetron Interaction 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 (4.1) and Lotronex TM (alosetron) package insert.] 5.8 Other Potentially Important Drug Interactions 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 , T ½ ) 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 to 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 max increased 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 b.i.d) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers.

The clearance of theophylline was decreased approximately 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, Abnormal Bleeding (5.9)] .

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.

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

While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with fluvoxamine maleate tablets.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

[see DOSAGE AND ADMINISTRATION (2.8) .] 5.10 Abnormal Bleeding 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.

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 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] ).

5.11 Activation of Mania/Hypomania During premarketing studies involving primarily depressed patients, hypomania or mania occurred in approximately 1% of patients treated with fluvoxamine.

In a ten week pediatric OCD study, 2 out of 57 patients (4%) treated with fluvoxamine experienced manic reactions, compared to none of 63 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.

5.12 Seizures During premarketing studies, seizures were reported in 0.2% of fluvoxamine-treated patients.

Caution is recommended when the drug is administered to patients with a history of convulsive disorders.

Fluvoxamine should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored.

Treatment with fluvoxamine should be discontinued if seizures occur or if seizure frequency increases.

5.13 Hyponatremia 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 POPULATION, Geriatric Use (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.

5.14 Use in Patients with Concomitant Illness Closely monitored clinical experience with fluvoxamine maleate tablets in patients with concomitant systemic illness is limited.

Caution is advised in administering fluvoxamine maleate tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism.

Fluvoxamine maleate tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were systematically excluded from many clinical studies during the product’s premarketing testing.

Evaluation of the electrocardiograms for patients with depression or OCD who participated in premarketing studies revealed no differences between fluvoxamine and placebo in the emergence of clinically important ECG changes.

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.

5.15 Laboratory Tests There are no specific laboratory tests recommended.