Fluvoxamine maleate extended-release

1 INDICATIONS AND USAGE Fluvoxamine maleate extended-release capsules are a selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of obsessive compulsive disorder (OCD) ( 1 ). Efficacy was demonstrated in: One 12-week study with fluvoxamine maleate extended-release capsules in adults ( 14.1 ) . Two 10-week studies with immediate-release (IR) fluvoxamine tablets in adults and one 10-week study with IR fluvoxamine tablets in children and adolescents ( 14.1 , 14.3 ) . One maintenance study with IR fluvoxamine tablets ( 14.2 ) . 1.1 Obsessive Compulsive Disorder Fluvoxamine maleate extended-release capsules are indicated for the treatment of obsessive compulsive disorder (OCD), as defined in the DSM-IV. 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 obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of fluvoxamine maleate extended-release capsules was demonstrated in one 12-week trial in adults with fluvoxamine maleate extended-release capsules as well as in two 10-week trials in adults and in one 10-week trial in children and adolescents (ages 8 years to 17 years) with immediate-release fluvoxamine tablets in outpatients with the diagnosis of OCD as defined in DSM-IV or DSM-III-R (see Clinical Studies [ 14.1 , 14.3 ]) . The efficacy of fluvoxamine for long-term use was established in one maintenance study in adults with immediate-release fluvoxamine tablets (see Clinical Studies [ 14.2 ] ). The health care provider who elects to prescribe fluvoxamine maleate extended-release capsules for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see Dosage and Administration [ 2.4 ]) .

2 DOSAGE AND ADMINISTRATION Adults: Recommended starting dose is 100 mg at bedtime, with weekly increases of 50 mg as tolerated to maximum effect, not to exceed 300 mg/day ( 2.1 ) . Pediatric patients naïve to fluvoxamine maleate: The lowest available dose of fluvoxamine maleate extended-release capsules may not be appropriate ( 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 ( 2.4 ) . Discontinuation: Gradual dose reduction is recommended ( 2.7 , see Warnings and Precautions [ 5.10 ] ). 2.1 OCD (Obsessive Compulsive Disorder) The recommended starting dose is 100 mg at bedtime, with weekly increases of 50 mg as tolerated to maximum therapeutic benefit, not to exceed 300 mg per day. Capsules should not be crushed or chewed. 2.2 Pediatric Patients Naïve to Fluvoxamine Maleate Physicians should consider that the lowest available dose of fluvoxamine maleate extended-release capsules may not be appropriate for pediatric patients naïve to fluvoxamine maleate. 2.3 Dosage for 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 titrate slowly following the initial dose of 100 mg in these patient groups. 2.4 Maintenance/Continuation of Extended Treatment Although the efficacy of fluvoxamine maleate extended-release capsules beyond 12 weeks of dosing has not been documented in controlled trials, OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. The benefit of maintaining patients with OCD on immediate-release 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 Studies [ 14.2 ]) . Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. 2.5 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 extended-release capsules. Conversely, at least 14 days should be allowed after stopping fluvoxamine maleate extended-release capsules before starting an MAOI intended to treat psychiatric disorders (see Contraindications [ 4.1 ] ). 2.6 Use of Fluvoxamine Maleate Extended-Release Capsules with Other MAOIs such as Linezolid or Methylene Blue Do not start fluvoxamine maleate extended-release capsules 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 [ 4.1 ] ). In some cases, a patient already receiving fluvoxamine maleate extended-release capsules 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 extended-release capsules 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 extended-release capsu …

3 DOSAGE FORMS AND STRENGTHS Fluvoxamine maleate extended-release capsules are available as: 100 mg strength: Off white to yellow colored pellets filled in size "2" hard gelatin capsules with blue opaque cap printed with "1847" in black ink and a white opaque body. 150 mg strength: Off white to yellow colored pellets filled in size "1" hard gelatin capsules with blue opaque cap printed with "1848" in black ink and a white opaque body. Extended-Release Capsules: 100 mg and 150 mg ( 3 )

4 CONTRAINDICATIONS Coadministration of thioridazine, tizanidine, pimozide, alosetron, or ramelteon with fluvoxamine maleate extended-release capsules is contraindicated (see Warnings and Precautions [ 5.4 to 5.8 ] ). Coadministration of thioridazine, tizanidine, pimozide, alosetron or ramelteon ( 4 ) . Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with fluvoxamine maleate extended-release capsules or within 14 days of stopping treatment with fluvoxamine maleate extended-release capsules. Do not use fluvoxamine maleate extended-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start fluvoxamine maleate extended-release capsules in a patient who is being treated with linezolid or intravenous methylene blue ( 4.1 ) . 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with fluvoxamine maleate extended-release capsules or within 14 days of stopping treatment with fluvoxamine maleate extended-release capsules is contraindicated because of an increased risk of serotonin syndrome. The use of fluvoxamine maleate extended-release capsules within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see Dosage and Administration [ 2.5 ] and Warnings and Precautions [ 5.2 ] ) . Starting fluvoxamine maleate extended-release capsules in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see Dosage and Administration [ 2.6 ] and Warnings and Precautions [ 5.2 ] ) .

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Most common reactions in controlled trials with OCD patients and patients from another studied population (incidence ≥ 5% and at least twice that for placebo) were abnormal ejaculation, anorexia, anorgasmia, asthenia, diarrhea, nausea, somnolence, sweating and tremor (6.2) . The following additional reactions occurred: anxiety, decreased libido, myalgia, pharyngitis, and vomiting in the OCD population; and dyspepsia, dizziness, insomnia and yawning in another studied population. To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trial Data Sources Fluvoxamine maleate extended-release capsules were studied in one 12-week controlled trial in patients with OCD (N = 124; mean exposure 66.6 days) and in two 12-week controlled trials for another condition (N = 279; mean exposure 59.2 days). Patients in these trials were initiated on 100 mg/day and were titrated in 50 mg increments over the first 6 weeks to within a range of 100 mg to 300 mg/day. The reactions listed in Table 2 show reactions from the two populations separately. Table 3 shows reactions from the three controlled studies combined. 6.2 Adverse Reactions Observed in Controlled Trials Adverse Reactions Associated with Discontinuation of Treatment: Of the 124 patients with OCD and 279 patients in other studies treated with fluvoxamine maleate extended-release capsules in controlled clinical trials, 19% and 26% discontinued treatment due to an adverse reaction. The most common reactions (≥ 1%) associated with discontinuation and considered to be drug related (i.e., those reactions associated with dropout at a rate at least twice that of placebo) were anorexi a (including, but not limited to, loss of appetite and decreased appetite) (1%), anxiety (3%), asthenia (3%), diarrhea (2%), dizziness (4%), headache (2%), insomnia (5%), nausea (7%), nervousness (1%), somnolence (5%) and thinking abnormal (1%) . Commonly Observed Adverse Reactions: Fluvoxamine maleate extended-release capsules have been studied in one controlled trial in patients with OCD (N = 124) and two controlled trials for another condition (N = 279). In general, adverse reaction rates were similar in the two data sets as well as in a study of pediatric patients with OCD treated with immediate- release fluvoxamine maleate tablets. The most commonly observed treatment-emergent adverse reactions associated with the use of fluvoxamine maleate extended-release capsules and likely to be drug-related (incidence of 5% or greater and at least twice that for placebo) and derived from Table 2 were: abnormal ejaculation, anorexia, anorgasmia, asthenia, diarrhea, nausea, somnolence, sweating and tremor . In the one controlled trial in patients with OCD, the following additional reactions occurred at an incidence of 5% or greater and at least twice that for placebo: anxiety, decreased libido, myalgia, pharyngitis and vomiting . The following additional reactions occurred in another studied population: dyspepsia, dizziness, insomnia and yawning . In a study evaluating immediate-release fluvoxamine maleate tablets in pediatric patients with OCD, the following additional reactions were identified using the above rule: agitation, depression, dysmenorrhea, flatulence, hyperkinesia and rash. Adverse Reactions Occurring at an Incidence of ≥ 2%: Table 2 enumerates adverse reactions that occurred in adults at a frequency of 2% or more, and were more frequent than in the placebo group, among patients treated with fluvoxamine maleate extended-release capsules in two short-term, placebo-controlled trials (12 weeks) in another population and one …

7 DRUG INTERACTIONS Drug Interactions (not described in Contraindications or Warnings and Precautions) include the following: Drugs Inhibiting or Metabolized by Cytochrome P450: Fluvoxamine inhibits several cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP3A4, and CYP2C19) ( 7.1 ) . 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 with fluvoxamine 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 ] for details) 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 enzyme. 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 cytochrome P450 2D6 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 extended-release capsules 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 …

8 USE IN SPECIFIC POPULATIONS Specific populations not discussed in Dosage and Administration or Warnings and Precautions include: Pregnancy: Consider both potential risks and benefits when treating a pregnant woman. Infants exposed to SSRIs in pregnancy have developed various complications and may be at risk for persistent pulmonary hypertension of the newborn (PPHN) ( 2.7 , 8.1 ). Nursing mothers: Fluvoxamine is secreted in human breast milk ( 8.3 ). Geriatric: Use of a lower starting dose may be warranted. Titrate slowly during initiation of therapy ( 2.3 , 8.5 ). Smokers: Smokers had a 25% increase in fluvoxamine metabolism ( 7.4 ). 8.1 Pregnancy Teratogenic Effects – When pregnant rats were given daily doses of fluvoxamine (60 mg/kg, 120 mg/kg or 240 mg/kg) orally 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 maximum recommended human dose [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) orally 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 mg/kg, 20 mg/kg, 80 mg/kg 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: Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.11 ) and Clinical Considerations]. 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 or 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-Serotonin Syndrome [ 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 (fluvoxamine maleate and fluvoxamine maleate extended-release are SSRIs) in pregnancy and PPHN. Other studies do not show a significant statistical association. Physicians should also note 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 …

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 .

11 DESCRIPTION Fluvoxamine maleate extended-release capsules for oral administration that contains fluvoxamine maleate, USP a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the chemical series, the 2-aminoethyl oxime ethers of aralkylketones. Fluvoxamine maleate, USP 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 434.41. The structural formula is: Fluvoxamine maleate, USP is a white to off-white, odorless, crystalline powder that is sparingly soluble in water, freely soluble in ethanol and chloroform, and practically insoluble in diethyl ether. Each fluvoxamine maleate extended-release capsule intended oral administration contains 100 mg or 150 mg of fluvoxamine maleate. In addition, each capsule contains the following inactive ingredients: D&C Red#28, ethyl cellulose, FD&C Blue#1, ferric oxide yellow, gelatin, hydroxypropyl cellulose, purified water, sugar spheres, talc, titanium dioxide and triethyl citrate. All capsule shells are imprinted with black pharmaceutical ink that contains black iron oxide, potassium hydroxide, propylene glycol and shellac. Image

10 OVERDOSAGE 10.1 Human Experience Exposure to immediate-release fluvoxamine maleate tablets 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 immediate-release fluvoxamine tablets 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 immediate-release tablets 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. In the controlled clinical trials with 403 patients treated with fluvoxamine maleate extended-release capsules, there was one nonfatal intentional overdose. Commonly (≥ 5%) observed adverse reactions 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 immediate-release 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 maleate 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 health care provider 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).

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fluvoxamine maleate extended-release capsules are available as follows: 100 mg strength: Off white to yellow colored pellets filled in size "2" hard gelatin capsules with blue opaque cap printed with "1847" in black ink and a white opaque body and are supplied as follows: NDC 70710-1847-3 in bottle of 30 capsules with child-resistant closure 150 mg strength: Off white to yellow colored pellets filled in size "1" hard gelatin capsules with blue opaque cap printed with "1848" in black ink and a white opaque body and are supplied as follows: NDC 70710-1848-3 in bottle of 30 capsules with child-resistant closure 16.2 Storage Keep out of reach of children. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature] Protect from high humidity and avoid exposure to temperatures above 30°C (86°F). Dispense in tight, light-resistant container as defined in the USP.

16.1 How Supplied Fluvoxamine maleate extended-release capsules are available as follows: 100 mg strength: Off white to yellow colored pellets filled in size "2" hard gelatin capsules with blue opaque cap printed with "1847" in black ink and a white opaque body and are supplied as follows: NDC 70710-1847-3 in bottle of 30 capsules with child-resistant closure 150 mg strength: Off white to yellow colored pellets filled in size "1" hard gelatin capsules with blue opaque cap printed with "1848" in black ink and a white opaque body and are supplied as follows: NDC 70710-1848-3 in bottle of 30 capsules with child-resistant closure