Fluoxetine hydrochloride

1 INDICATIONS AND USAGE Fluoxetine delayed-release capsules are indicated for the treatment of: • Acute and maintenance treatment of Major Depressive Disorder [see Clinical Studies ( 14.1 )] . Fluoxetine delayed-release capsules are selective serotonin reuptake inhibitor indicated for: Acute and maintenance treatment of Major Depressive Disorder (MDD) (1)

2 DOSAGE AND ADMINISTRATION Indication Adult Pediatric MDD (2.1) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications ( 2.7) Dosing with fluoxetine weekly capsules - initiate 7 days after the last daily dose of fluoxetine 20 mg ( 2.1 ) 2.1 Major Depressive Disorder Initial Treatment Adult — Initiate fluoxetine delayed-release capsules 20 mg/day orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon).The maximum fluoxetine dose should not exceed 80 mg/day. In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases [see Clinical Studies ( 14.1 ) ]. Pediatric (children and adolescents) — Initiate fluoxetine delayed-release capsules, 10 or 20 mg/day. After 1 week at 10 mg/day, increase the dose to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement is observed. In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies ( 14.1 ) ]. All patients — As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. Periodically reassess to determine the need for maintenance treatment. Weekly Dosing — Initiate fluoxetine delayed-release capsules (once-weekly) 7 days after the last daily dose of fluoxetine 20 mg [see Clinical Pharmacology ( 12.3 ) ]. If satisfactory response is not maintained with fluoxetine delayed-release capsules once-weekly, consider reestablishing a daily dosing regimen [see Clinical Studies (14.1) ]. Switching Patients to a Tricyclic Antidepressant (TCA) — Dosage of a TCA 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 Warnings and Precautions (5.2) and Drug Interactions (7.7) ]. 2.7 Dosing in Specific Populations Treatment of Pregnant Women — When treating 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) ]. Geriatric — Consider a lower less frequent dosage for the elderly [see Use in Specific Populations (8.5) ] Hepatic Impairment — As with many other medications, use a lower or less frequent dosage in patients with hepatic impairment [see Clinical Pharmacology (12.4) and Use in Specific Populations (8.6) ]. Concomitant Illness — Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology (12.4) and Warnings and Precautions (5.12 ) ]. 2.8 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions ( 5.15 )] 2.9 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 …

5 WARNINGS AND PRECAUTIONS Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults : Monitor for clinical worsening and suicidal thinking and behavior (5.1) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including fluoxetine, both when taken alone, but especially when co-administered with other serotonergic agents. If such symptoms occur, discontinue fluoxetine and serotonergic agents and initiate supportive treatment. If concomitant use of fluoxetine 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 other 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 with untreated anatomically narrow angles treated with antidepressants. (5.8) Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing if symptomatic hyponatremia occurs (5.9) Anxiety and Insomnia: May ocur (5.10) QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with fluoxetine use. Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation ( 4.2 , 5.11 ) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery ( 5.13 ) Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks ( 5.14 ) Sexual Dysfunction: Fluoxetine may cause symptoms of sexual dysfunction. ( 5.16 ) 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults 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, 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…

4 CONTRAINDICATIONS Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine. Do not use fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue (4.1) Pimozide: Do not use. Risk of QT prolongation and drug interaction ( 4.2 , 5.11 , 7.7 , 7.8 ) Thioridazine: Do not use. Risk of QT interval prolongation and elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing fluoxetine. Do not use thioridazine within 5 weeks of discontinuing fluoxetine ( 4.2 , 5.11 , 7.7 , 7.8 ) 4.1 Monoamine Oxidase Inhibitors(MAOIs) The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.9) and Warnings and Precautions (5.2) ]. Starting fluoxetine 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 (2.10) and Warnings and Precautions (5.2) ]. 4.2 Other Contraindications The use of fluoxetine is contraindicated with the following: Pimozide [see Warnings and Precautions ( 5.11 ) and Drug Interactions (7.7 , 7.8 ) ]. Thioridazine [see Warnings and Precautions ( 5.11 ) and Drug Interactions ( 7.7 , 7.8 ) ] Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval.

7 DRUG INTERACTIONS As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility Monoamine Oxidase Inhibitors (MAOI) : ( 2.9 , 2.10 , 4.1 , 5.2 ) Drugs Metabolized by CYP2D6 : Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7 ) Tricyclic Antidepressants (TCAs) : Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued ( 5.2 , 7.7 ) 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 (7.7) Antipsychotics : Potential for elevation of haloperidol and clozapine levels (7.7) Anticonvulsants : Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.7) Serotonergic Drugs : ( 2.9 , 2.10 , 4.1 , 5.2 ) Drugs that Interfere with Hemostasis (e.g. NSAIDs, Aspirin, Warfarin) : May potentiate the risk of bleeding ( 7.4 ) Drugs Tightly Bound to Plasma Proteins : May cause a shift in plasma concentrations ( 7.6 , 7.7 ) Drugs that Prolong the QT Interval: Do not use fluoxetine with thioridazine or pimozide. Use with caution in combination with other drugs that prolong the QT interval ( 4.2 , 5.11 , 7.7 , 7.8 ) 7.1 Monoamine Oxidase Inhibitors (MAOI) [See Dosage and Administration ( 2.9 , 2.10 ) , Contraindications (4.1) , and Warnings and Precautions (5.2) ]. 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of fluoxetine and such 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 [See Dosage and Administration ( 2.9 , 2.10 ) , Contraindications (4.1) , and Warnings and Precautions (5.2) ]. 7.4 Drugs that Interfere with Hemostasis (e.g., 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) ]. 7.5 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. 7.6 Potential for Other Drugs to affect Fluoxetine 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) ]. 7.7 Potential for Fluoxetine to affect Other Drugs Pimozide — Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prolongation warrants restricting the concurrent use of pimozide and fluoxetine [see Contraindications ( 4.2 ), Warnings and Precautions ( 5.11 ), a…

8.1 Pregnancy Pregnancy Category C — 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. 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 ( 5.2 ) 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) ]. Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 - 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 [see Dosage and Administration (2.7) ]. Maternal Adverse Reactions — Use of fluoxetine in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.2 ) ]. Animal Data — In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 a…

8.3 Nursing Mothers Because fluoxetine is excreted in human milk, nursing while on fluoxetine 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 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 The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see Boxed Warning and Warnings and Precautions (5.1) ] Serotonin Syndrome [see Warnings and Precautions (5.2) ] Allergic Reactions and Rash [see Warnings and Precautions (5.3) ] Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see Warnings and Precautions (5.4) ] Seizures [see Warnings and Precautions (5.5 ) ] Altered Appetite and Weight [see Warnings and Precautions (5.6) ] Abnormal Bleeding [see Warnings and Precautions (5.7) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.8) ] Hyponatremia [see Warnings and Precautions (5.9) ] Anxiety and Insomnia [see Warnings and Precautions (5.10) ] QT Prolongation [see Warnings and Precautions (5.11) ] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13) ] Discontinuation Adverse Reactions [see Warnings and Precautions (5.15) ] Most common adverse reactions (≥5% and at least twice that for placebo) associated with: Major Depressive Disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation, and yawn (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 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 U.S. clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials. 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. Incidence in Major Depressive Disorder Placebo-Controlled Clinical Trials (excluding data from extensions of trials) — Table 3 enumerates the most common treatment-emergent adverse reactions associated with the use of fluoxetine (incidence of at least 5% for fluoxetine and at least twice that for placebo within at least 1 of the indications) for the treatment of Major Depressive Disorder, in U.S. controlled clinical trials. Table 5 enumerates treatment-emergent adverse reactions that occurred in 2% or more patients treated with fluoxetine and with incidence greater than placebo who participated in U.S. Major Depressiv Disorder controlled clinical trials. Table 4 provides combined data for the pool of studies that are provided separately by indication in Table 3. Table 3: Most Common Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder Placebo-Controlled Clinical Trials 1,2 Percentage of Patients Reporting Event Major Depressive Disorder Body System/ Adverse Reaction Fluoxetine (N=1728) Placebo (N=975) Body as a Whole Asthenia 9 5 Flu syndrome 3 4 Cardiovascular System Vasodilatation 3 2 Digestive System Nausea 21 9 Diarrhea 12 8 Anorexia 11 2 Dry mouth 10 7 Dyspepsia 7 5 Nervous System Insomnia 16 9 Anxiety 12 7 Nervousness 14 9 Somnolence 13 6 Tremor 10 3 Libido decreased 3 -- Abnormal dreams 1 1 Respiratory System Pharyngitis 3 3 Sinusitis 1 4 Yawn -- -- Skin and Appendages Sweating 8 3 Rash 4 3 Urogenital System Impotence 3 2 -- Abnormal ejaculation 3 -- -- 1 Incidence less than 1%. 2 Includes U.S. data for Major Depressive Disorder clinical trials. 3 Denominator used…