7 Drug Interactions (not described in Contraindications or Warnings And Precautions) include the following: Drugs Inhibiting or Metabolized by Cytochrome P450: Fluvoxamine inhibits several cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP3A4, and CYP2C19).
Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity with coadministration ( 7.2 ).
Sumatriptan: Rare postmarketing reports of weakness, hyperreflexia, and incoordination following use of an SSRI and sumatriptan.
Monitor appropriately if concomitant treatment is clinically warranted ( 7.2 ).
Tacrine: Coadministration increased tacrine C max and AUC five-and eight-fold and caused nausea, vomiting, sweating, and diarrhea ( 7.2 ).
Tricyclic Antidepressants (TCAs): Coadministration significantly increased plasma TCA levels.
Use caution; monitor plasma TCA levels; reduce TCA dose if indicated ( 7.2 ).
Tryptophan: Severe vomiting with coadministration ( 7.2 ).
Diltiazem: Bradycardia with coadministration ( 7.3 ).
Propranolol or metoprolol: Reduce dose if coadministered and titrate more cautiously ( 7.3 ).
7.1 Potential Interactions with Drugs that Inhibit or are Metabolized by Cytochrome P450 Isoenzymes Multiple hepatic cytochrome P450 isoenzymes are involved in the oxidative biotransformation of a large number of structurally different drugs and endogenous compounds.
The available knowledge concerning the relationship of fluvoxamine and the cytochrome P450 isoenzyme system has been obtained mostly from pharmacokinetic interaction studies conducted in healthy volunteers, but some preliminary in vitro data are also available.
Based on a finding of substantial interactions of fluvoxamine with certain of these drugs [see later parts of this section and also WARNINGS AND PRECAUTIONS (5) ] and limited in vitro data for CYP3A4, it appears that fluvoxamine inhibits several cytochrome P450 isoenzymes that are known to be involved in the metabolism of other drugs such as: CYP1A2 (e.g., warfarin, theophylline, propranolol, tizanidine), CYP2C9 (e.g., warfarin), CYP3A4 (e.g., alprazolam), and CYP2C19 (e.g., omeprazole).
In vitro data suggest that fluvoxamine is a relatively weak inhibitor of CYP2D6.
Approximately 7% of the normal population has a genetic code that leads to reduced levels of activity of CYP2D6.
Such individuals have been referred to as “poor metabolizers” (PM) of drugs such as debrisoquin, dextromethorphan, and tricyclic antidepressants.
While none of the drugs studied for drug interactions significantly affected the pharmacokinetics of fluvoxamine, an in vivo study of fluvoxamine single-dose pharmacokinetics in 13 PM subjects demonstrated altered pharmacokinetic properties compared to 16 “extensive metabolizers” (EM): mean C max , AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group.
This suggests that fluvoxamine is metabolized, at least in part, by CYP2D6.
Caution is indicated in patients known to have reduced levels of CYP2D6 activity and those receiving concomitant drugs known to inhibit this cytochrome P450 isoenzyme (e.g., quinidine).
The metabolism of fluvoxamine has not been fully characterized and the effects of potent cytochrome P450 isoenzyme inhibition, such as the ketoconazole inhibition of CYP3A4, on fluvoxamine metabolism have not been studied.
A clinically significant fluvoxamine interaction is possible with drugs having a narrow therapeutic ratio such as pimozide, warfarin, theophylline, certain benzodiazepines, omeprazole and phenytoin.
If fluvoxamine maleate tablets are to be administered together with a drug that is eliminated via oxidative metabolism and has a narrow therapeutic window, plasma levels and/or pharmacodynamic effects of the latter drug should be monitored closely, at least until steady-state conditions are reached.
[see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5) .] 7.2 CNS Active Drugs Antipsychotics See WARNINGS AND PRECAUTIONS (5.2).
Benzodiazepines See WARNINGS AND PRECAUTIONS (5.8).
Alprazolam See WARNINGS AND PRECAUTIONS (5.8).
Diazepam See WARNINGS AND PRECAUTIONS (5.8).
Lorazepam A study of multiple doses of fluvoxamine maleate (50 mg b.i.d.) in healthy male volunteers (N=12) and a single dose of lorazepam (4 mg single dose) indicated no significant pharmacokinetic interaction.
On average, both lorazepam alone and lorazepam with fluvoxamine produced substantial decrements in cognitive functioning; however, the coadministration of fluvoxamine and lorazepam did not produce larger mean decrements compared to lorazepam alone.
Alcohol Studies involving single 40 g doses of ethanol (oral administration in one study and intravenous in the other) and multiple dosing with fluvoxamine maleate (50 mg b.i.d.) revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of the other.
As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets.
Carbamazepine Elevated carbamazepine levels and symptoms of toxicity have been reported with the coadministration of fluvoxamine maleate and carbamazepine.
Clozapine See WARNINGS AND PRECAUTIONS (5.8).
Lithium As with other serotonergic drugs, lithium may enhance the serotonergic effects of fluvoxamine and, therefore, the combination should be used with caution.
Seizures have been reported with the coadministration of fluvoxamine maleate and lithium.
Methadone See WARNINGS AND PRECAUTIONS (5.8).
Monoamine Oxidase Inhibitors See DOSAGE AND ADMINISTRATION ( 2.5 and 2.6 ), CONTRAINDICATIONS (4.2) and WARNINGS AND PRECAUTIONS (5.2) .
Pimozide See CONTRAINDICATIONS (4.1) and WARNINGS AND PRECAUTIONS (5.6) .
Ramelteon See WARNINGS AND PRECAUTIONS (5.8) .
Serotonergic Drugs See DOSAGE AND ADMINISTRATION ( 2.5 and 2.6 ), CONTRAINDICATIONS (4.2) and WARNINGS AND PRECAUTIONS (5.2) .
Tacrine In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five-and eight-fold increases in tacrine C max and AUC, respectively, compared to the administration of tacrine alone.
Five subjects experienced nausea, vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine.
Thioridazine See CONTRAINDICATIONS (4.1) and WARNINGS AND PRECAUTIONS (5.4) .
Tizanidine See CONTRAINDICATIONS (4.1) and WARNINGS AND PRECAUTIONS (5.5) .
Tricyclic Antidepressants (TCAs) Significantly increased plasma TCA levels have been reported with the coadministration of fluvoxamine maleate and amitriptyline, clomipramine or imipramine.
Caution is indicated with the coadministration of fluvoxamine maleate tablets and TCAs; plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced.
Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan.
If concomitant treatment of fluvoxamine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see WARNINGS AND PRECAUTIONS (5.2) ].
Sumatriptan There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan.
If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.
Tryptophan Tryptophan may enhance the serotonergic effects of fluvoxamine, and the combination should, therefore, be used with caution.
Severe vomiting has been reported with the coadministration of fluvoxamine maleate and tryptophan [see WARNINGS AND PRECAUTIONS (5.2) ].
7.3 Other Drugs Alosetron See CONTRAINDICATIONS (4.1) , 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 and 5.10 ).
7.4 Effects of Smoking on Fluvoxamine Metabolism Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers.
7.5 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate.
10 10.1 Human Experience Worldwide exposure to fluvoxamine includes over 45,000 patients treated in clinical trials and an estimated exposure of 50,000,000 patients treated during worldwide marketing experience (end of 2005).
Of the 539 cases of deliberate or accidental overdose involving fluvoxamine reported from this population, there were 55 deaths.
Of these, 9 were in patients thought to be taking fluvoxamine alone and the remaining 46 were in patients taking fluvoxamine along with other drugs.
Among non-fatal overdose cases, 404 patients recovered completely.
Five patients experienced adverse sequelae of overdosage, to include persistent mydriasis, unsteady gait, hypoxic encephalopathy, kidney complications (from trauma associated with overdose), bowel infarction requiring a hemicolectomy, and vegetative state.
In 13 patients, the outcome was provided as abating at the time of reporting.
In the remaining 62 patients, the outcome was unknown.
The largest known ingestion of fluvoxamine involved 12,000 mg (equivalent to 2 to 3 months’ dosage).
The patient fully recovered.
However, ingestions as low as 1,400 mg have been associated with lethal outcome, indicating considerable prognostic variability.
Commonly (≥5%) observed adverse events associated with fluvoxamine maleate overdose include gastrointestinal complaints (nausea, vomiting and diarrhea), coma, hypokalemia, hypotension, respiratory difficulties, somnolence, and tachycardia.
Other notable signs and symptoms seen with fluvoxamine maleate overdose (single or multiple drugs) include bradycardia, ECG abnormalities (such as heart arrest, QT interval prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm), convulsions, dizziness, liver function disturbances, tremor, and increased reflexes.
10.2 Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.
Ensure an adequate airway, oxygenation, and ventilation.
Monitor cardiac rhythm and vital signs.
General supportive and symptomatic measures are also recommended.
Induction of emesis is not recommended.
Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered.
Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.
No specific antidotes for fluvoxamine are known.
A specific caution involves patients taking, or recently having taken, fluvoxamine who might ingest excessive quantities of a tricyclic antidepressant.
In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation.
[see DRUG INTERACTIONS (7.2) .] In managing overdosage, consider the possibility of multiple drug involvement.
The physician should consider contacting a poison control center for additional information on the treatment of any overdose.
Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).
11 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 unrelated to other SSRIs and clomipramine.
It is chemically designated as 5-methoxy-4′-(trifluoromethyl) valerophenone (E)-O-(2-aminoethyl) oxime maleate (1:1) and has the molecular formula C 15 H 21 O 2 N 2 F 3 •C 4 H 4 O 4 .
Its molecular weight is 434.4.
The structural formula is: Fluvoxamine maleate 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: hydroxyethyl cellulose, magnesium stearate, mannitol, polyethylene glycol and titanium dioxide.
The 50 mg and 100 mg tablets also contain synthetic iron oxides.
14 14.1 Adult OCD Studies The effectiveness of fluvoxamine maleate tablets for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 10-week multicenter, parallel group studies of adult outpatients.
Patients in these trials were titrated to a total daily fluvoxamine maleate dose of 150 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 100-300 mg/day (on a b.i.d.
schedule), on the basis of response and tolerance.
Patients in these studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), total score of 23.
Patients receiving fluvoxamine maleate experienced mean reductions of approximately 4 to 5 units on the Y-BOCS total score, compared to a 2 unit reduction for placebo patients.
Table 6 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impressions (CGI) scale for both studies combined.
TABLE 6 OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN POOL OF TWO ADULT OCD STUDIES Outcome Classification Fluvoxamine (N=120) Placebo (N=134) Very Much Improved 13% 2% Much Improved 30% 10% Minimally Improved 22% 32% No Change 31% 51% Worse 4% 6% Exploratory analyses for age and gender effects on outcomes did not suggest any differential responsiveness on the basis of age or sex.
14.2 Adult OCD Maintenance Study In a maintenance trial of adult outpatients with OCD, 114 patients meeting DSM-IV criteria for OCD and with a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score ≥18 were titrated to an effective dose of fluvoxamine maleate tablets 100 to 300 mg/day as part of an initial 10-week single-blind treatment phase.
Treatment response during this single-blind phase was defined as Y-BOCS scores at least 30% lower than baseline at the end of weeks 8 and 10.
Of the patients who responded, their average duration of response was 4 weeks.
Patients who responded during this initial phase were randomized either to continuation of fluvoxamine maleate tablets (N=56) or to placebo (N=58) in a double-blind phase for observation of relapse.
Relapse during the double-blind phase was defined as an increase in the Y-BOCS score of at least 30% over the baseline for that phase or patient refusal to continue treatment due to a substantial increase in OCD symptoms.
In the double-blind phase, patients receiving continued fluvoxamine maleate tablets treatment experienced, on average, a significantly lower relapse rate than those receiving placebo.
An examination of population subgroups from this trial did not reveal any clear evidence of a differential maintenance effect on the basis of age or gender.
14.3 Pediatric OCD Study The effectiveness of fluvoxamine maleate tablets for the treatment of OCD was also demonstrated in a 10-week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages 8 to 17).
Patients in this study were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 50 to 200 mg/day (on a b.i.d.
schedule) on the basis of response and tolerance.
All patients had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score of 24.
Patients receiving fluvoxamine maleate experienced mean reductions of approximately six units on the CY-BOCS total score, compared to a three-unit reduction for placebo patients.
Table 7 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study.
TABLE 7 OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN PEDIATRIC STUDY Outcome Classification Fluvoxamine (N=38) Placebo (N=36) Very Much Improved 21% 11% Much Improved 18% 17% Minimally Improved 37% 22% No Change 16% 44% Worse 8% 6% Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender.
Further exploratory analyses revealed a prominent treatment effect in the 8 to 11 age group and essentially no effect in the 12 to 17 age group.
While the significance of these results is not clear, the 2 to 3 fold higher steady-state plasma fluvoxamine concentrations in children compared to adolescents [see CLINICAL PHARMACOLOGY -Pediatric Subjects (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.
16 /STORAGE AND HANDLING 16.1 How Supplied Fluvoxamine maleate tablets, USP are available in the following strengths, colors, imprints, and presentations: Tablets 50 mg: Golden, round, scored, film coated tablets, imprinted “APO” on one side and “F50” with a partial bisect on the other side.
Unit dose packages of 30 (3 × 10) NDC 68084-837-21 16.2 Storage Keep out of reach of children.
Fluvoxamine maleate tablets, USP should be protected from high humidity and stored at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
FOR YOUR PROTECTION: Do not use if blister is torn or broken.
RECENT MAJOR CHANGES
Warnings and Precautions ( 5.3 ) 7/2014
8.5 Geriatric Use Approximately 230 patients participating in controlled premarketing studies with fluvoxamine maleate tablets were 65 years of age or over.
No overall differences in safety were observed between these patients and younger patients.
Other reported clinical experience has not identified differences in response between the elderly and younger patients.
However, SSRIs and SNRIs, including fluvoxamine maleate tablets, have been associated with several cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see WARNINGS AND PRECAUTIONS (5.13) ] .
Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients [see CLINICAL PHARMACOLOGY-Elderly (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.
DOSAGE FORMS AND STRENGTHS
3 Fluvoxamine maleate tablets are available as: Tablets 25 mg: White to off-white, round, unscored, film coated tablets, imprinted “APO” on one side and “F25” on the other side.
Tablets 50 mg: Golden, round, scored, film coated tablets, imprinted “APO” on one side and “F50” with a partial bisect on the other side.
Tablets 100 mg: Reddish-brown, pillow shaped, scored, film coated tablets, imprinted “APO” on one side and “FLU” bisect “100” on the other side.
25 mg, 50 mg, and 100 mg Tablets ( 3 )
MECHANISM OF ACTION
12.1 Mechanism of Action The mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons.
Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitro and in vivo .
INDICATIONS AND USAGE
1 Fluvoxamine maleate tablets, USP are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) ( 1 ).
1.1 Obsessive-Compulsive Disorder Fluvoxamine maleate tablets, USP 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, USP was established in four trials in outpatients with OCD: two 10-week trials in adults, one 10-week trial in pediatric patients (ages 8 to 17) and one maintenance trial in adults.
[see CLINICAL STUDIES (14).
8.4 Pediatric Use The efficacy of fluvoxamine maleate for the treatment of obsessive compulsive disorder was demonstrated in a 10-week multicenter placebo controlled study with 120 outpatients ages 8 to 17.
In addition, 99 of these outpatients continued open-label fluvoxamine maleate treatment for up to another one to three years, equivalent to 94 patient years.
The adverse event profile observed in that study was generally similar to that observed in adult studies with fluvoxamine.
[see ADVERSE REACTIONS (6.3) and 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-Clinical Worsening and Suicide Risk (5.1) ].
Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established.
[see BOXED WARNING and WARNINGS AND PRECAUTIONS -Clinical Worsening and Suicide Risk (5.1) .] Anyone considering the use of fluvoxamine maleate tablets in a child or adolescent must balance the potential risks with the clinical need.
8.1 Pregnancy Teratogenic Effects Pregnancy Category C 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.
Decreased fetal body weight was seen at the high dose.
The no effect dose for developmental toxicity in this study was 60 mg/kg (approximately 2 times the MRHD on a mg/m 2 basis).
In a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2 times the MRHD on a mg/m 2 basis) during 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 or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.1 times the MRHD on a mg/m 2 basis).
Nonteratogenic Effects Neonates exposed to fluvoxamine maleate tablets and other SSRIs or serotonin and norepinephrine reuptake inhibitors (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) ].
Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN).PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality.
Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including fluvoxamine maleate tablets) in pregnancy and PPHN.
Other studies do not show a significant statistical association.
Physicians should also note in the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission.
Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.
When treating a pregnant woman with fluvoxamine maleate tablets, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant.
This decision can only be made on a case by case basis .
[see DOSAGE AND ADMINISTRATION (2.4) .]
8.3 Nursing Mothers As for many other drugs, fluvoxamine is secreted in human breast milk.
The decision of whether to discontinue nursing or to discontinue the drug should take into account the potential for serious adverse effects from exposure to fluvoxamine in the nursing infant as well as the potential benefits of fluvoxamine maleate tablets therapy to the mother.
Suicidality and AntidepressantS 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-Clinical Worsening and Suicide Risk (5.1) .] Warning: Suicidality and Antidepressants See full prescribing information for complete boxed warning.
Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders.
Fluvoxamine maleate tablets are not approved for use in pediatric patients except those with obsessive compulsive disorder ( 5.1 ).
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.
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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION 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 Medication Guide is provided as a pull-out in the middle of this booklet.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluvoxamine maleate tablets.
17.1 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 and WARNINGS AND PRECAUTIONS (5.1) ].
17.2 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, fentanyl, lithium, tramadol, tryptophan, buspirone and St.
John’s Wort) [see WARNINGS AND PRECAUTIONS-Serotonin Syndrome (5.2) ].
17.3 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) ] .
17.4 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.
17.5 Pregnancy Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy with fluvoxamine maleate tablets [see USE IN SPECIFIC POPULATIONS (8.1) .] 17.6 Nursing Patients receiving fluvoxamine maleate tablets should be advised to notify their physicians if they are breast-feeding an infant.
[ see USE IN SPECIFIC POPULATIONS-Nursing Mothers (8.3) .] 17.7 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-Warfarin and Other Drugs That Interfere With Hemostasis (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) ].
17.8 Alcohol As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets.
17.9 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.
PACKAGING INFORMATION American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Apotex Corp.
as follows: (50 mg / 30 UD) NDC 68084-837-25 packaged from NDC 60505-0165 Distributed by: American Health Packaging Columbus, OH 43217 8283721/1015OS 17.10 FDA Approved Medication Guide 8283721/1015OS
DOSAGE AND ADMINISTRATION
2 Adults: Recommended starting dose is 50 mg at bedtime, with increases of 50 mg every 4 to 7 days as tolerated to maximum effect, not to exceed 300 mg/day.
Daily doses over 100 mg should be divided ( 2.1 ).
Children and adolescents (8 to 17 years): Recommended starting dose is 25 mg at bedtime, with increases of 25 mg every 4 to 7 days as tolerated to maximum effect, not to exceed 200 mg/day (8 to 11 years) or 300 mg/day (12 to 17 years).
Daily doses over 50 mg should be divided ( 2.2 ).
Hepatically impaired: Decreased clearance may require modified dose and titration ( 2.3 ).
Extended treatment: Adjust dose to maintain lowest effective dose; reassess patients periodically ( 2.7 ).
Discontinuation: Gradual dose reduction is recommended ( 2.8 , see Warnings And Precautions [5.9] ).
2.1 Adults The recommended starting dose for fluvoxamine maleate tablets in adult patients is 50 mg, administered as a single daily dose at bedtime.
In the controlled clinical trials establishing the effectiveness of fluvoxamine maleate tablets in OCD, patients were titrated within a dose range of 100 to 300 mg/day.
Consequently, the dose should be increased in 50 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved, not to exceed 300 mg per day.
It is advisable that a total daily dose of more than 100 mg should be given in two divided doses.
If the doses are not equal, the larger dose should be given at bedtime.
2.2 Pediatric Population (children and adolescents) The recommended starting dose for fluvoxamine maleate tablets in pediatric populations (ages 8 to 17 years) is 25 mg, administered as a single daily dose at bedtime.
In a controlled clinical trial establishing the effectiveness of fluvoxamine maleate tablets in OCD, pediatric patients (ages 8 to 17) were titrated within a dose range of 50 to 200 mg/day.
Physicians should consider age and gender differences when dosing pediatric patients.
The maximum dose in children up to age 11 should not exceed 200 mg/day.
Therapeutic effect in female children may be achieved with lower doses.
Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.
The dose should be increased in 25 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved.
It is advisable that a total daily dose of more than 50 mg should be given in two divided doses.
If the two divided doses are not equal, the larger dose should be given at bedtime.
2.3 Elderly or Hepatically Impaired Patients Elderly patients and those with hepatic impairment have been observed to have a decreased clearance of fluvoxamine maleate.
Consequently, it may be appropriate to modify the initial dose and the subsequent dose titration for these patient groups.
2.4 Pregnant Women During the Third Trimester 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 and may be at risk for persistent pulmonary hypertension of the newborn (PPHN).
[see USE IN SPECIFIC POPULATIONS (8.1) .] When treating pregnant women with fluvoxamine maleate tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.
2.5 Switching Patients To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluvoxamine maleate tablets.
Conversely, at least 14 days should be allowed after stopping fluvoxamine maleate tablets before starting an MAOI intended to treat psychiatric disorders.
[see CONTRAINDICATIONS (4.2) .] 2.6 Use of Fluvoxamine Maleate Tablets with Other MAOIs such as Linezolid or Methylene Blue Do not start fluvoxamine maleate tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome.
In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.
[see CONTRAINDICATIONS (4.2) .] In some cases, a patient already receiving fluvoxamine maleate tablets therapy may require urgent treatment with linezolid or intravenous methylene blue.
If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, fluvoxamine maleate tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered.
The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.
Therapy with fluvoxamine maleate tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.
[See WARNINGS AND PRECAUTIONS (5.2) .] The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluvoxamine maleate tablets is unclear.
The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.
[See WARNINGS AND PRECAUTIONS (5.2) .] 2.7 Maintenance/Continuation Extended Treatment It is generally agreed that obsessive compulsive disorder requires several months or longer of sustained pharmacologic therapy.
The benefit of maintaining patients with OCD on fluvoxamine maleate tablets after achieving a response for an average duration of about 4 weeks in a 10-week single-blind phase during which patients were titrated to effect was demonstrated in a controlled trial [ see CLINICAL TRIALS (14.2) ].
The physician who elects to use fluvoxamine maleate tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.
2.8 Discontinuation of Treatment with Fluvoxamine Maleate Tablets Symptoms associated with discontinuation of other SSRIs or SNRIs have been reported.
[see WARNINGS AND PRECAUTIONS (5.9) .] Patients should be monitored for these symptoms when discontinuing treatment.
A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.
If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.
Subsequently, the physician may continue decreasing the dose but at a more gradual rate.