FLUVOXAMINE MALEATE tablets

FLUVOXAMINE MALEATE tablets

FLUVOXAMINE MALEATE tablets

Fluvoxamine maleate 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 C15H21O2N2F3●C4H4O4. Its molecular weight is 434.41.

Fluvoxamine Maleate Tablets 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: carnauba wax, hypromellose, mannitol, polyethylene glycol, polysorbate 80, pregelatinized starch (potato), silicon dioxide, sodium stearyl fumarate, starch (corn), and titanium dioxide. The 50 mg and 100 mg tablets also contain synthetic iron oxides.

INDICATIONS AND USAGE

obsessive-compulsive disorder

Fluvoxamine Maleate Tablets are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in DSM-III-R or DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.

Mechanism of Action

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

DOSAGE AND ADMINISTRATION

Adults

The recommended starting dose for Fluvoxamine Maleate Tablets in adult patients is 50 mg, administered as a single daily dose at bedtime. In the controlled clinical trials establishing the effectiveness of Fluvoxamine Maleate Tablets in OCD, patients were titrated within a dose range of 100 to 300 mg/day.

Consequently, the dose should be increased in 50 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved, not to exceed 300 mg per day. It is advisable that a total daily dose of more than 100 mg should be given in two divided doses. If the doses are not equal, the larger dose should be given at bedtime.

Pediatric Population (children and adolescents)

The recommended starting dose for Fluvoxamine Maleate Tablets in pediatric populations (ages 8-17 years) is 25 mg, administered as a single daily dose at bedtime. In a controlled clinical trial establishing the effectiveness of Fluvoxamine Maleate Tablets in OCD, pediatric patients (ages 8-17) were titrated within a dose range of 50 to 200 mg/day. Physicians should consider age and gender differences when dosing pediatric patients.

The maximum dose in children up to age 11 should not exceed 200 mg/day. Therapeutic effect in female children may be achieved with lower doses. Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit. The dose should be increased in 25 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved. It is advisable that a total daily dose of more than 50 mg should be given in two divided doses. If the two divided doses are not equal, the larger dose should be given at bedtime.

Elderly or Hepatically Impaired Patients

Elderly patients and those with hepatic impairment have been observed to have a decreased clearance of fluvoxamine maleate. Consequently, it may be appropriate to modify the initial dose and the subsequent dose titration for these patient groups.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

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

Use of Fluvoxamine Maleate Tablets with Other MAOIs such as Linezolid or Methylene Blue

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

Discontinuation of Treatment with Fluvoxamine Maleate Tablets

Symptoms associated with discontinuation of other SSRIs or SNRIs have been reported. Patients should be monitored for these symptoms when discontinuing treatment. Agradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerablesymptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming thepreviously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dosebut at a more gradual rate.

CONTRAINDICATIONS

Coadministration

Coadministration of tizanidine, thioridazine, alosetron, or pimozide with Fluvoxamine Maleate Tablets is contraindicated.

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.

WARNINGS AND PRECAUTIONS

  • SUICIDALITY AND ANTIDEPRESSANT DRUGS: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Fluvoxamine Maleate Tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Fluvoxamine Maleate Tablets are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD)
  • Bipolar disorder: Screen for bipolar disorder.
  • Serotonin 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, amphetamines, 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.
  • Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.
  • Discontinuation: Symptoms associated with discontinuation have been reported. Abrupt discontinuation not recommended.
  • Activation of mania/hypomania has occurred.
  • Seizures: Avoid administering fluvoxamine in patients with unstable epilepsy; monitor patients with controlled epilepsy; discontinue treatment if seizures occur or frequency increases.
  • 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.
  • Concomitant illness: Use caution in patients with diseases or conditions that affect hemodynamic responses or metabolism. Patients with impaired liver function may require a lower starting dose and slower titration.
  • Sexual Dysfunction: Fluvoxamine Maleate Tablets may cause symptoms of sexual dysfunction

ADVERSE REACTIONS

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

DRUG INTERACTIONS

Potential Thioridazine Interaction: The effect of fluvoxamine (25 mg b.i.d. for one week) on thioridazine steady-state concentrations was evaluatedin 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

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 tizanidinehas been studied in 10 healthy male subjects. Tizanidine Cmax 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 bloodpressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate. Drowsinesswas significantly increased and performance on the psychomotor task was significantly impaired. Fluvoxamineand tizanidine should not be used together.

Potential Pimozide Interaction: Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, and it has been demonstrated thatketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasmaconcentrations of parent drug. An increased plasma concentration of pimozide causes QT prolongation and hasbeen associated with torsades de pointes-type ventricular tachycardia, sometimes fatal. As noted below, asubstantial pharmacokinetic interaction has been observed for fluvoxamine in combination with alprazolam, adrug that is known to be metabolized by CYP3A4. Although it has not been definitively demonstrated thatfluvoxamine is a potent CYP3A4 inhibitor, it is likely to be, given the substantial interaction of fluvoxaminewith alprazolam. Consequently, it is recommended that fluvoxamine not be used in combination with pimozide

Potential Alosetron Interaction: Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes, inducers orinhibitors of these enzymes may change the clearance of alosetron. Fluvoxamine is a known potent inhibitor ofCYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19. In a pharmacokinetic study, 40 healthy femalesubjects received fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, withcoadministration of alosetron 1 mg on the last day. Fluvoxamine increased mean alosetron plasmaconcentration (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold.

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, Cmax, 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, Ndesmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic coadministration.

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.

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.

USE IN SPECIFIC POPULATIONS

Pregnancy: 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. 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.

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.

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.

Lactation: Data from published literature report the presence of fluvoxamine is in human milk. No adverseeffects on the breastfed infant have been reported in most cases of maternal use of fluvoxamine duringbreastfeeding. However, there are reports of diarrhea, vomiting, decreased sleep, and agitation. 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.

Females and Males of Reproductive Potential: Animal findings suggest fertility may be impaired while taking fluvoxamine.

Pediatric Use: The efficacy of fluvoxamine maleate for the treatment of obsessive-compulsive disorder was demonstrated in a10-week multicenter placebo-controlled study with 120 outpatients ages 8-17. In addition, 99 of theseoutpatients continued open-label fluvoxamine maleate treatment for up to another one to three years, equivalentto 94 patient years. The adverse event profile observed in that study was generally similar to that observed inadult studies with fluvoxamine.

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.

OVERDOSAGE

The following have been reported with fluvoxamine tablet overdosage:

  • Seizures, which may be delayed, and altered mental status including coma.
  • Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation.

Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.

  • Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk).

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

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