FLUOXETINE

Fluoxetine tablets, USP are a selective serotonin reuptake inhibitor (SSRI) for oral administration. It is designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro- p -tolyl)oxy]propylamine hydrochloride and has the empirical formula of C 17 H 18 F 3 NO•HCl. Its molecular weight is 345.79. The structural formula is: Fluoxetine hydrochloride, USP is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Fluoxetine tablets, USP contains fluoxetine hydrochloride equivalent to 10 mg or 20 mg of fluoxetine. Each tablet also contains colloidal silicon dioxide, croscarmellose sodium, D&C yellow no. 10 lake, FD&C yellow no. 6 lake, magnesium stearate, microcrystalline cellulose, and povidone. Structure

Fluoxetine tablets, USP are selective serotonin reuptake inhibitor (SSRI) indicated for the treatment of Premenstrual Dysphoric Disorder (PMDD) ( 1.1 ) 1.1 Premenstrual Dysphoric Disorder (PMDD) Fluoxetine tablets, USP are indicated for the treatment of premenstrual dysphoric disorder (PMDD) [see Clinical Studies ( 14.1 )]. The effectiveness of fluoxetine tablets, USP in long-term use (that is, for more than 6 months) has not been systematically evaluated in placebo-controlled trials. The use of fluoxetine tablets, USP for extended periods should be periodically re-evaluated for the individual patient [ see Dosage and Administration ( 2.1 )].

20 mg/day continuously or intermittently ( 2.1 ) 2.1 Treatment The recommended dose of fluoxetine tablets for the treatment of PMDD is 20 mg/day given continuously (every day of the menstrual cycle) or intermittently (defined as starting a daily dose 14 days prior to the anticipated onset of menstruation through the first full day of menses and repeating with each new cycle). The dosing regimen should be based on individual patient characteristics. In a study comparing continuous dosing of fluoxetine 20 and 60 mg/day to placebo, both doses were proven to be effective, but there was no statistically significant added benefit for the 60 mg/day compared with the 20 mg/day dose. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with PMDD. The maximum fluoxetine dose should not exceed 80 mg/day [see Clinical Studies ( 14.1 )] . Systematic evaluation of fluoxetine tablets has shown that its efficacy in PMDD is maintained for periods of up to 6 months at a dose of 20 mg/day given continuously and up to 3 months at a dose of 20 mg/day given intermittently [see Clinical Studies ( 14.1 )] . Patients should be periodically re-assessed to determine the need for continued treatment. 2.2 Dosing in Specific Populations Treatment of Pregnant Women — PMDD does not exist in pregnancy. However, if there is a need to treat pregnant women with fluoxetine, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations ( 8.1 )] . Hepatic Impairment — A lower or less frequent dosage should be used in patients with hepatic impairment [see Clinical Pharmacology ( 12.3 ) and Use in Specific Populations ( 8.6 )]. Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Warnings and Precautions ( 5.11 ) and Clinical Pharmacology ( 12.3 )] . 2.3 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions ( 5.14 )] . 2.4 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 fluoxetine tablets. Conversely, at least 5 weeks should be allowed after stopping fluoxetine tablets before starting an MAOI intended to treat psychiatric disorders [ see Contraindications ( 4.1 )]. 2.5 Use of Fluoxetine Tablets with Other MAOIs such as Linezolid or Methylene Blue Do not start fluoxetine 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 ( 4.1 )]. In some cases, a patient already receiving fluoxetine 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, fluoxetine 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 five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine 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 fluoxetine 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 )] .

Serotonin Syndrome and MAOIs: Do not use with MAOIs intended to treat psychiatric disorders with fluoxetine tablet or within 5 weeks of stopping treatment with fluoxetine tablets. Do not use fluoxetine tablet within 14 days of stopping an MAIO intended to treat psychiatric disorders. In addition, do not start fluoxetine tablet in a patient who is being treated with linezolid or intravenous methylene blue ( 4.1 ) Do not use with pimozide due to risk of drug interaction or QTc prolongation ( 4.2 , 7.9 ) Do not use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing fluoxetine tablet ( 4.2 , 7.9 ) 4.1 Monoamine Oxidase Inhibitors The use of MAOIs intended to treat psychiatric disorders with fluoxetine tablet or within 5 weeks of stopping treatment with fluoxetine tablet is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine tablet within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.2 )]. Starting fluoxetine tablet in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [ see Dosage and Administration ( 2.5 ) and Warnings and Precautions ( 5.2 )]. 4.2 Other Contraindications The use of fluoxetine hydrochloride is contraindicated with the following: Pimozide [see Drug Interactions ( 7.9 )] Thioridazine [see Drug Interactions ( 7.9 )]

Most common adverse reactions (incidence rate greater than or equal to 5% and greater than placebo) associated with fluoxetine tablet 20 mg (either continuous or intermittent) for PMDD: Headache, asthenia, pain, accidental injury, infection, flu syndrome, nausea, diarrhea, insomnia, dizziness, nervousness, thinking abnormal, libido decreased, rhinitis, and pharyngitis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 or predict the rates observed in practice. Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in US clinical trials. Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (that is, reduced) number of standardized reaction categories. In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. The stated frequencies represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is important to emphasize that reactions reported during therapy were not necessarily caused by it. The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied. Incidence in placebo-controlled PMDD clinical trials — In 1 of 3 placebo-controlled, continuous-dosing trials and 1 placebo-controlled, intermittent-dosing trial of fluoxetine in PMDD, treatment-emergent adverse reactions reporting rates were assessed. The information contained in Table 5 enumerates the most common treatment-emergent adverse reactions associated with the use of fluoxetine tablet 20 mg (incidence of at least 5% for fluoxetine tablet 20 mg and greater than placebo) for the treatment of PMDD and is based on data from the continuous-dosing trial at the recommended dose of fluoxetine tablet (fluoxetine tablets 20 mg, N = 104; placebo, N = 108) and data from the intermittent-dosing trial of fluoxetine in PMDD (fluoxetine tablets 20 mg, N = 86; placebo, N = 88). Table 5: Most Common Treatment-Emergent Adverse Reactions: Incidence in PMDD Placebo-Controlled Clinical Trials Percentage of Patients Reporting Adverse Reaction Body System/Adverse Reaction 1 Fluoxetine tablet 20 mg/day Continuously (N = 104) Fluoxetine tablet 20 mg/day Intermittently (N = 86) Placebo (Pooled) (N = 196) Body as a Whole Headache 13 15 11 Asthenia 12 8 4 Pain 9 3 7 Accidental injury 8 1 5 Infection 7 0 3 Flu syndrome 12 3 7 Digestive System Nausea 13 9 6 Diarrhea 6 2 6 Nervous System Insomnia 9 10 7 Dizziness 7 2 3 Nervousness 7 3 3 Thinking abnormal 2 6 5 0 Libido decreased 3 9 1 Respiratory System Rhinitis 23 16 15 Pharyngitis 10 6 5 1 Included in the table are adverse reactions reported by at least 5% of patients taking fluoxetine tablet 20 mg either continuously or intermittently. For additional adverse reaction terms referenced in Warnings and Precautions, reporting rates for fluoxetine tablet 20 mg continuous and intermittent were, respectively: anxiety 4.8%, 1.2% and anorexia 3.8%, 3.5%. 2 Thinking abnormal is the COSTART term that captures concentration difficulties. Incidence in US depression, OCD, and bulimia placebo-controlled clinical trials (excluding data from extensions of trials) — Table 6 enumerates the most common treatment-emergent adverse reactions associated with the use of fluoxetine up to 80 mg (incidence of at least 2% for fluoxetine and greater than placebo) in female patients ages 18 to 45 years from US placebo-controlled clinical trials in the treatment of depression, OCD, and bulimia. Table 6: Treatment-Emergent Adverse Reactions: Incidence in Female Patients Ages 18 to 45 Years in Depression, OCD, and Bulimia Placebo-Controlled US Clinical Trials Percentage of Patients Reporting Adverse Reaction Body System/Adverse Reaction 1 Fluo x etine (N = 1,145) Pl a ceb o (N = 553) B o d y as a Whole Headache 24 21 Asthenia 14 6 Flu syndrome 7 3 Abdominal pain 6 5 Accidental injury 4 3 Fever 3 2 Cardiovascular System Palpitation 3 2 Vasodilatation 3 1 Digestive System Nausea 27 11 Anorexia 11 4 Dry mouth 11 8 Diarrhea 10 7 Dyspepsia 7 5 Constipation 5 3 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 3 1 Nervous System Insomnia 24 11 Nervousness 14 10 Anxiety 13 9 Somnolence 13 6 Tremor 12 1 Dizziness 11 5 Libido decreased 4 1 Abnormal dreams 3 2 Thinking abnormal 2 3 2 Respiratory System Pharyngitis 6 5 Yawn 5 - Skin and Appendages Skin and Subcutaneous Tissue Disorders Sweating 8 3 Rash 5 3 Special Senses Abnormal vision 3 1 Urogenital System Urinary frequency 2 1 1 Included are reactions reported by at least 2% of patients taking fluoxetine, except the following adverse reactions, which had an incidence on placebo greater than fluoxetine (depression, OCD, and bulimia combined): back pain, cough increased, depression (includes suicidal thoughts), dysmenorrhea, flatulence, infection, myalgia, pain, pruritus, rhinitis, sinusitis. 2 Thinking abnormal is the COSTART term that captures concentration difficulties. Incidence less than 0.5%. Adverse reactions associated with discontinuation in two placebo-controlled PMDD clinical trials — In a continuous-dosing PMDD placebo-controlled trial, the most common adverse reaction (incidence at least 2% for fluoxetine tablet 20 mg and greater than placebo) associated with discontinuation was nausea (3% for fluoxetine tablet 20 mg, N = 104 and 1% for placebo, N = 108). In an intermittent-dosing placebo-controlled trial, no reactions associated with discontinuation reached an incidence of 2% for fluoxetine tablet 20 mg. In these clinical trials, more than one reaction may have been recorded as the cause of discontinuation. Adverse reactions associated with discontinuation in depression, OCD, and bulimia placebo-controlled US clinical trials (excluding data from extensions of trials) — In female patients age 18 to 45 years in US depression, OCD, and bulimia placebo-controlled clinical trials combined, which collected a single primary reaction associated with discontinuation (incidence at least 1% for fluoxetine and at least twice that for placebo), insomnia (1%, N = 561) was the only reaction reported. Female sexual dysfunction with SSRIs — Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a mood-related disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. For example, in women (age 18 to 45) receiving fluoxetine for indications other than PMDD, decreased libido was seen at an incidence of 4% for fluoxetine compared with 1% for placebo. There have been spontaneous reports in women (age 18 to 45) taking fluoxetine for indications other than PMDD of orgasmic dysfunction, including anorgasmia. There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects. 6.2 Other Reactions Following is a list of all treatment-emergent adverse reactions reported at anytime by females and males taking fluoxetine in all US clinical trials for conditions other than PMDD as of May 8, 1995 (10,782 patients) except (1) those listed in the body or footnotes of Tables 1 or 5 above or elsewhere in labeling; (2) those for which the COSTART terms were uninformative or misleading; (3) those adverse reactions for which a causal relationship to fluoxetine use was considered remote; (4) adverse reactions occurring in only 1 patient treated with fluoxetine and which did not have a substantial probability of being acutely life-threatening; and (5) adverse reactions that could only occur in males. Adverse reactions are classified within body system categories using the following definitions: frequent adverse reactions are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring in less than 1/1,000 patients. Body as a Whole — Frequent: chest pain and chills; Infrequent: face edema, intentional overdose, malaise, pelvic pain, suicide attempt; Rare: acute abdominal syndrome, hypothermia, intentional injury, photosensitivity reaction. Cardiovascular System — Frequent: hypertension; Infrequent: angina pectoris, arrhythmia, congestive heart failure, hypotension, migraine, myocardial infarct, postural hypotension, syncope, vascular headache; Rare: bradycardia, cerebral embolism, cerebral ischemia, extrasystoles, heart block, pallor, peripheral vascular disorder, phlebitis, shock, thrombophlebitis, thrombosis, vasospasm, ventricular arrhythmia, ventricular extrasystoles, ventricular fibrillation. Digestive System — Frequent: increased appetite; Infrequent: aphthous stomatitis, cholelithiasis, colitis, dysphagia, eructation, esophagitis, gastritis, gastroenteritis, glossitis, gum hemorrhage, hyperchlorhydria, increased salivation, liver function tests abnormal, melena, mouth ulceration, stomach ulcer, stomatitis, thirst; Rare: biliary pain, bloody diarrhea, cholecystitis, duodenal ulcer, enteritis, esophageal ulcer, fecal incontinence, hepatitis, intestinal obstruction, liver fatty deposit, pancreatitis, peptic ulcer, salivary gland enlargement, tongue edema. Endocrine System — Infrequent: hypothyroidism; Rare: diabetic acidosis, diabetes mellitus. Hemic and Lymphatic System — Infrequent: anemia, ecchymosis; Rare: blood dyscrasia, hypochromic anemia, leukopenia, lymphedema, lymphocytosis, petechia, purpura, thrombocythemia. Metabolic and Nutritional — Infrequent: dehydration, generalized edema, gout, hypercholesteremia, hyperlipemia, hypokalemia, peripheral edema; Rare: alcohol intolerance, alkaline phosphatase increased, BUN increased, creatine phosphokinase increased, hyperkalemia, hyperuricemia, hypocalcemia, iron deficiency anemia, SGPT increased. Musculoskeletal System — Infrequent: arthritis, bone pain, bursitis, leg cramps, tenosynovitis; Rare: arthrosis, chondrodystrophy, myasthenia, myopathy, myositis, osteomyelitis, osteoporosis, rheumatoid arthritis. Nervous System — Frequent: amnesia, emotional lability, paresthesia, and sleep disorder; Infrequent: abnormal gait, acute brain syndrome, akathisia, apathy, ataxia, buccoglossal syndrome, CNS depression, CNS stimulation, depersonalization, euphoria, hostility, hyperkinesia, hypertonia, hypesthesia, incoordination, libido increased, myoclonus, neuralgia, neuropathy, neurosis, paranoid reaction, personality disorder 1 , psychosis, vertigo; Rare: abnormal electroencephalogram, antisocial reaction, circumoral paresthesia, delusions, dysarthria, dystonia, extrapyramidal syndrome, foot drop, hyperesthesia, neuritis, paralysis, reflexes decreased, stupor. Respiratory System — Infrequent: asthma, epistaxis, hiccup, hyperventilation; Rare: apnea, atelectasis, cough decreased, emphysema, hemoptysis, hypoventilation, hypoxia, larynx edema, lung edema, pneumothorax, stridor. Skin and Appendages — Infrequent: acne, alopecia, contact dermatitis, eczema, maculopapular rash, skin discoloration, skin ulcer; Rare: furunculosis, herpes zoster, hirsutism, psoriasis, purpuric rash, seborrhea. Special Senses — Frequent: ear pain, taste perversion, tinnitus; Infrequent: conjunctivitis, dry eyes, mydriasis, photophobia; Rare: blepharitis, deafness, diplopia, exophthalmos, glaucoma, hyperacusis, iritis, parosmia, scleritis, strabismus, taste loss, visual field defect. Urogenital System — Infrequent: abortion 2 , albuminuria, amenorrhea 2 , anorgasmia, breast enlargement, breast pain, cystitis, dysuria, female lactation 2 , fibrocystic breast 2 , hematuria, leukorrhea 2 , menorrhagia 2 , metrorrhagia 2 , nocturia, polyuria, urinary incontinence, urinary retention, urinary urgency, vaginal hemorrhage 2 ; Rare: breast engorgement, glycosuria, hypomenorrhea 2 , kidney pain, oliguria, uterine hemorrhage 2 , uterine fibroids enlarged 2 . 1 Personality disorder is the COSTART term for designating non-aggressive objectionable behavior. 2 Adjusted for gender. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation 1 , cataract, cerebrovascular accident 1 , cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia 1 , epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest 1 , hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, pancreatitis 1 , pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia 1 , thrombocytopenic purpura, ventricular tachycardia (including torsades de pointes–type arrhythmias), vaginal bleeding, and violent behaviors 1 , drug reaction with eosinophilia and systemic symptoms (DRESS), and anosmia, hyposmia. 1 These terms represent serious adverse reactions, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

Monoamine Oxidase Inhibitors (MAOI): Fluoxetine is contraindicated for use with MAOI's, or within 14 days of discontinuing an MAOI due to risk of drug interaction. At least 5 weeks should be allowed after stopping fluoxetine before starting treatment with an MAOI ( 4 , 7.1 ) Pimozide: Fluoxetine is contraindicated for use with pimozide due to risk of drug interaction or QTc prolongation ( 4 , 7.9 ) Thioridazine: Fluoxetine is contraindicated for use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing fluoxetine tablet. ( 4 , 7.9 ) Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway ( 7.9 ) Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine hydrochloride or when fluoxetine hydrochloride has been recently discontinued ( 7.9 ) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs ( 7.2 ) Benzodiazepines: Diazepam – increased t ½ , alprazolam - further psychomotor performance decrement due to increased levels ( 7.9 ) Antipsychotics: Potential for elevation of haloperidol and clozapine levels ( 7.9 ) Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity ( 7.9 ) Serotonergic Drugs: Potential for Serotonin Syndrome ( 5.2 , 7.3 ) Triptans: There have been rare post marketing reports of Serotonin Syndrome with use of an SSRI and a triptan ( 5.2 , 7.4 ) Tryptophan: Concomitant use with tryptophan is not recommended ( 5.2 , 7.5 ) Drugs that Interfere with Hemostasis (for example, NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding ( 7.6 ) Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations ( 7.8 , 7.9 ) The potential for interaction by a variety of mechanisms (for example, pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. 7.1 Monoamine Oxidase Inhibitors (MAOI) Concomitant use of fluoxetine tablets in patients taking MAOIs is contraindicated. There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Therefore, fluoxetine, including fluoxetine tablet , should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Contraindications ( 4 )]. Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should be allowed after stopping fluoxetine before starting an MAOI [see Dosage and Administration ( 2.4 and 2.5 ), Contraindications ( 4.1 ), Warnings and Precautions ( 5.2 ), and Clinical Pharmacology ( 12.3 )]. 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of fluoxetine, including fluoxetine tablet, and other CNS acting drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology ( 12.3 )] . 7.3 Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including fluoxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when fluoxetine hydrochloride is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, amphetamines, or St. John's Wort [see Warnings and Precautions ( 5.2 )] . The concomitant use of fluoxetine hydrochloride with SNRIs, SSRIs, or tryptophan is not recommended [see Dosage and Administration ( 2.4 and 2.5 ), Contraindications ( 4.1 ), Warnings and Precautions ( 5.2 ), and Drug Interactions ( 7.4 ), ( 7.5 )] . 7.4 Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of fluoxetine hydrochloride 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 ) and Drug Interactions ( 7.3 )] . 7.5 Tryptophan Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress. The concomitant use with tryptophan is not recommended [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.3 )] . 7.6 Drugs that Interfere with Hemostasis (for example, NSAIDS, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see Warnings and Precautions ( 5.7 )] . 7.7 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. 7.8 Potential for Other Drugs to affect Fluoxetine hydrochloride Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs [see Clinical Pharmacology ( 12.3 )] . 7.9 Potential for Fluoxetine hydrochloride to affect Other Drugs Pimozide — Concomitant use of fluoxetine hydrochloride in patients taking pimozide is contraindicated. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and fluoxetine [see Contraindications ( 4 )] . Thioridazine — Concomitant use of fluoxetine hydrochloride in patients taking thioridazine is contraindicated. Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications ( 4 )] . In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine. 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. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Drugs Metabolized by CYP2D6 — Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (for example, tricyclic antidepressants (TCAs)), antipsychotics (for example, phenothiazines and most atypicals), and antiarrhythmics (for example, propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (for example, flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications ( 4 )] . Tricyclic Antidepressants (TCAs) — In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see Clinical Pharmacology ( 12.3 )] . Benzodiazapines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology ( 12.3 )] . Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Antipsychotics — Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine [see Contraindications ( 4 )] . Anticonvulsants — Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Lithium — There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly. Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (for example, warfarin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect [see Clinical Pharmacology ( 12.3 )] . Drugs Metabolized by CYP3A4 — In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].