Fluoxetine

1 INDICATIONS AND USAGE 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 )].

2 DOSAGE AND ADMINISTRATION 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 Preca…

5 WARNINGS AND PRECAUTIONS Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1 ) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including fluoxetine hydrochloride, both when taken alone, but especially when co-administered with other serotonergic agents. If such symptoms occur, discontinue fluoxetine tablet and serotonergic agents and initiate supportive treatment. If concomitant use of fluoxetine hydrochloride 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 ) Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena ( 5.3 ) Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania ( 5.4 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold ( 5.5 ) Altered Appetite and Weight: Significant weight loss has occurred ( 5.6 ) Abnormal Bleeding : May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding ( 5.7 ) Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients who have untreated anatomically narrow angles and who are treated with antidepressants ( 5.8 ) Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH) ( 5.9 ) Anxiety and Insomnia: May occur ( 5.10 ) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery ( 5.12 ) Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks ( 5.13 ) Sexual dysfunction: Fluoxetine tablets use may cause symptoms of sexual dysfunction ( 5.15 ) 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 4,400 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, wi…

4 CONTRAINDICATIONS 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 )]

7 DRUG INTERACTIONS 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, suc…

8.1 Pregnancy Pregnancy Category C — It should be noted that the diagnosis of PMDD does exist during pregnancy. Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. . Treatment of Pregnant Women during the First Trimester — There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1,359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. Non-teratogenic 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 ( 5.7 ) and Clinical Considerations] . Neonates exposed to fluoxetine 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 )] . Maternal Adverse Reactions — Use of fluoxetine tablets in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.7 )] . 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 epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) 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 with fluoxetine the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis . Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at dose…

8.3 Nursing Mothers Because fluoxetine is excreted in human milk, nursing while on fluoxetine tablet is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.

6 ADVERSE REACTIONS 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 reaction…