FLUOXETINE- fluoxetine hydrochloride_tablet

Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and alpha 1 in vitro Systemic bioavailability The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. The exposure (C max Protein binding in vitro 1 Enantiomers R S S Metabolism S R S R Variability in metabolism S- S R Because fluoxetine's metabolism, like that of a number of other compounds including TCAs and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see Drug Interactions ( 7. 6 Accumulation and slow elimination [see Warnings and Precautions ( 5. 14 The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine. Liver Disease [see Dosage and Administration ( 2. 6 Renal Disease Geriatric pharmacokinetics Pediatric pharmacokinetics (children and adolescents) Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.

Fluoxetine tablets are indicated for the treatment of: Major Depressive Disorder (MDD). The efficacy of fluoxetine in MDD was established in one 5-week trial, three 6-week trials, and one maintenance study in adults. The efficacy of fluoxetine was also established in two 8- to 9-week trials in pediatric patients 8 to 18 years of age [see Clinical Studies ( 14. 1 Obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD). The efficacy of fluoxetine in OCD was demonstrated in two 13-week trials in adults and one 13-week trial in pediatric patients 7 to 17 years of age [see Clinical Studies ( 14. 2 Binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa. The efficacy of fluoxetine in Bulimia Nervosa was demonstrated in two 8-week trials and one 16-week trial in adults [see Clinical Studies ( 14. 3 Panic Disorder, with or without agoraphobia. The efficacy of fluoxetine in Panic Disorder was demonstrated in two 12-week trials in adults [see Clinical Studies ( 14. 4 Fluoxetine tablets are a selective serotonin reuptake inhibitor indicated (SSRI) the treatment of: Major Depressive Disorder (MDD) ( 1 Adults: Efficacy was established in one 5-week trial, three 6-week trials, and one maintenance study ( 14. 1 Pediatrics: Efficacy was established in two 8-to 9-week trials of patients aged 8 to 18 years ( 14. 1 Obsessive Compulsive Disorder (OCD) ( 1 Adults: Efficacy was established in two 13-week trials ( 14. 2 Pediatrics: Efficacy was established in one 13-week trial in patients aged 7 to 17 years ( 14. 2 Bulimia Nervosa ( 1 Adults: Efficacy was established in two 8-week trials and one 16-week trial ( 14. 3 Panic Disorder, with or without agoraphobia ( 1 Adults: Efficacy was established in two 12-week trials ( 14.

This product is only available in a 60 mg dosage form. A 30 mg dose may be achieved with one-half of the scored tablet. Use of this product requires initial titration with another fluoxetine product according to the dosing guidelines indicated below. Use another fluoxetine product for initial doses of 10 to 20 mg/day or for doses other than 30 mg or 60 mg: Indication Adult Pediatric MDD ( 2. 1 20 mg/day in morning (initial dose) 10 to 20 mg/day (initial dose)* OCD ( 2. 2 20 mg/day in morning (initial dose) 10 mg/day (initial dose) 10 to 60 mg/day (target dose) Bulimia Nervosa ( 2. 3 60 mg/day in morning - Panic Disorder ( 2. 4 10 mg/day (initial dose) - No additional benefits seen at higher doses above 20 mg/day in MDD ( 2. 1 Use a lower or less frequent dosage in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications ( 2. 6 Initial Treatment Adult 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 MDD in most cases [see Clinical Studies ( 14. 1 Pediatric (children and adolescents) [see Clinical Studies ( 14. 1 All patients Periodically reassess to determine the need for maintenance treatment. Switching Patients to a Tricyclic Antidepressant (TCA) [see Warnings and Precautions ( 5. 6 Initial Treatment Adults In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo [see Clinical Studies ( 14. 2 Pediatric (children and adolescents) In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg. In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies ( 14. 2 Periodically reassess to determine the need for treatment. Initial Treatment [see Clinical Studies ( 14. 3 Periodically reassess to determine the need for maintenance treatment. 4 Periodically reassess to determine the need for continued treatment. Geriatrics see Use in Specific Populations ( 8. 5 Hepatic Impairmentem dash see Clinical Pharmacology ( 12. 6 At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluoxetine. Conversely, at least 5 weeks should be allowed after stopping fluoxetine before starting an MAOI intended to treat psychiatric disorders [see Contraindications ( 4. 1 Do not start fluoxetine 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 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5.

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 Increased Risk of 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): 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 Nivagen Pharmaceuticals, Inc. at 1-877-977-0687 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 had been administered to 10,782 patients with various diagnoses in US 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, an adverse reaction of the type listed. An adverse reaction was included if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Incidence in MDD, OCD, Bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) Table 2 Table 3 Table 2. Most Common Adverse Reactions: Incidence in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials Percentage of Patients Reporting Event MDD OCD Bulimia Panic Disorder Body System/ Adverse Reaction Fluoxetine (N = 1728) Placebo (N = 975) Fluoxetine (N = 266) Placebo (N = 89) Fluoxetine (N = 450) Placebo (N = 267) Fluoxetine (N = 425) Placebo (N = 342) Bodyas a Whole Asthenia 9 5 15 11 21 9 7 7 FluSyndrome 3 4 10 7 8 3 5 5 Cardiovascular System Vasodilatation 3 2 5 -- 2 1 1 -- Digestive System Nausea 21 9 26 13 29 11 12 7 Diarrhea 12 8 18 13 8 6 9 4 Anorexia 11 2 17 10 8 4 4 1 Dry Mouth 10 7 12 3 9 6 4 4 Dyspepsia 7 5 10 4 10 6 6 2 Nervous System Insomnia 16 9 28 22 33 13 10 7 Anxiety 12 7 14 7 15 9 6 2 Nervousness 14 9 14 15 11 5 8 6 Somnolence 13 6 17 7 13 5 5 2 Tremor 10 3 9 1 13 1 3 1 Libido Decreased 3 -- 11 2 5 1 1 2 Abnormal Dreams 1 1 5 2 5 3 1 1 Respiratory System Pharyngitis 3 3 11 9 10 5 3 3 Sinusitis 1 4 5 2 6 4 2 3 Yawn -- -- 7 -- 11 -- 1 -- Skin and Appendages Sweating 8 3 7 -- 8 3 2 2 Rash 4 3 6 3 4 4 2 2 Urogenital System Impotence a 2 -- -- -- 7 -- 1 -- AbnormalEjaculation a -- -- 7 -- 7 -- 2 1 Note: Includes US data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials a Table 3 Adverse Reactions: Incidence in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials Percentage of Patients Reporting Event MDD,OCD,Bulimia,and Panic Disorder Combined Body System/Adverse Reaction Fluoxetine(N=2869) Placebo (N=1673) Body as a Whole Headache 21 19 Asthenia 11 6 Flu syndrome 5 4 Fever 2 1 Cardiovascular System Vasodilatation 2 1 Digestive System Nausea 22 9 Diarrhea 11 7 Anorexia 10 3 Dry mouth 9 6 Dyspepsia 8 4 Constipation 5 4 Flatulence 3 2 Vomiting 3 2 Metabolic and Nutritional Disorders Weight loss 2 1 Nervous System Insomnia 19 10 Nervousness 13 8 Anxiety 12 6 Somnolence 12 5 Dizziness 9 6 Tremor 9 2 Libido Decreased 4 1 Thinking Abnormal 2 1 Respiratory System Yawn 3 - Skin and Appendages Sweating 7 3 Rash 4 3 Pruritus 3 2 Special Senses Abnormal Vision 2 1 Note: Includes US data for MDD, OCD, Bulimia,and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. Associated with discontinuation in MDD, OCD, Bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials)em dashTable 4 Table 4. Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials MDD, OCD, Bulimia, and Panic Disorder Combined (N=1533) MDD (N = 392) OCD (N = 266) Bulimia (N = 450) Panic Disorder (N = 425) Anxiety (1%) -- Anxiety (2%) -- Anxiety (2%) - - - Insomnia (2%) - - Nervousness (1%) - - Nervousness (1%) - - Rash (1%) - - Note: Includes US data for MDD, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. Other adverse reactions in pediatric patients (children and adolescents) The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in 3 pediatric placebo-controlled trials (N = 418 randomized; 228 fluoxetine-treated; 190 placebo-treated) was mania/hypomania (1. 8% for fluoxetine-treated, 0% for placebo-treated). In these clinical trials, only a primary reaction associated with discontinuation was collected. Male and female sexual dysfunction with SSRIs There are no adequate and well-controlled studies examining sexual dysfunction with fluoxetine treatment. Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment. Priapism has been reported with all SSRIs. 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 adverse effects. Other adverse reactions observed during the premarketing evaluation of fluoxetineem dash Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1,000 patients; rare reactions are those occurring in fewer than 1/1,000 patients. Body as a Whole- Frequent Infrequen Rare Cardiovascular System- Frequent Infrequent 1 Digestive System- Infrequent Rare Hemic and Lymphatic System- Infrequent Rare Nervous System- Frequent Infrequent 1 1 Rare Respiratory System- Rare Skin and Appendages- Infrequent Rare Special Senses- Frequent Infrequent Urogenital System- Frequent Infrequent 2 1 2 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: anosmia,aplastic anemia, atrial fibrillation 1 1 1 1 1 1 1 1.

Monoamine Oxidase Inhibitors (MAOIs): 4. 1 Pimozide 4. 7 Thioridazine 4. 7 Known hypersensitivity to fluoxetine products ( 4. 3 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. 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. 2 The use of fluoxetine is contraindicated with the following: Pimozide [see Warnings and Precautions ( 5. 7 Thioridazine [see Warnings and Precautions ( 5. 7 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. Known hypersensitivity to fluoxetine: Do not use this product in patients with known hypersensitivity to fluoxetine due to risk of anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria [see Warnings and Precautions ( 5.

Pregnancy: SSRI use, particularly later in pregnancy, may increase risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, tremor, irritability) in the neonate ( 8. 1 Pediatric Use: 8. 4 Risk Summary 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 Available data from published epidemiologic studies and postmarketing reports over several decades have not established an increased risk of major birth defects or miscarriage. Some studies have reported an increased incidence of cardiovascular malformations; however, these studies results do not establish a causal relationship [see Data] (see Data) (see Clinical Considerations). In rats and rabbits treated with fluoxetine during the period of organogenesis, there was no evidence of developmental effects at doses up to 1. 9 times, respectively, the maximum recommended human dose (MRHD) of 60 mg on a mg/m2 given to adolescents on a mg/m2 basis. However, in other reproductive studies in rats, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths early after birth occurred at doses that are 1. 5 times (during gestation) and 0. 97 times (during gestation and lactation) the MRHD given to adolescents on a mg/m2 basis. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. 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 Fetal/Neonatal Adverse Reactions Neonates exposed to Fluoxetine Tablets and other SSRIs or 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, tremors, jitteriness, irritability, and constant crying. These findings 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 Data Human Data It has been shown that SSRIs (including fluoxetine) can cross the placenta. Published epidemiological studies of pregnant women exposed to fluoxetine have not established an increased risk of major birth defects, miscarriage, and other adverse developmental outcomes. Several publications reported an increased incidence of cardiovascular malformations in children with in utero exposure to fluoxetine. However, these studies results do not establish a causal relationship. Methodologic limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders and confirmatory studies. However, these studies cannot definitely establish or exclude any drug-associated risk during pregnancy. Exposure to SSRIs, particularly later in pregnancy, may have an increased risk for PPHN. PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Animal data em dash In embryofetal development studies in rats and rabbits, there was no evidence of malformations or developmental variations following administration of fluoxetine at doses up to 12. 5 and 15 mg/kg/day, respectively (1. 9 times, respectively, the MRHD of 60 mg given to adolescents on a mg/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1. 5 times the MRHD given to adolescents on a mg/m2 basis) during gestation or 7. 5mg/kg/day (0. 97 times the MRHD given to adolescents on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0. 65 times the MRHD given to adolescents on a mg/m2 basis). Risk Summary Data from published literature report the presence of fluoxetine and norfluoxetine in human milk (see Data) (see Clinical Considerations) Clinical Considerations Infants exposed to Fluoxetine Tablets should be monitored for agitation, irritability, poor feeding, and poor weight gain. Data A study of 19 nursing mothers on fluoxetine with daily doses of 10 to 60 mg showed that fluoxetine was detectable in 30% of nursing infant sera (range: 1 to 84 ng/mL) whereas norfluoxetine was found in 85% (range: <1 to 265 ng/mL). Use of fluoxetine in children [see Clinical Studies ( 14. 1 The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13- week placebo- controlled clinical trial with 103 pediatric outpatients ages 7 to <18 [see Clinical Studies ( 14. 2 The safety and effectiveness in pediatric patients <8 years of age in MDD and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to <=18) with MDD or OCD [see Clinical Pharmacology ( 12. 3 The acute adverse reaction profiles observed in the 3 studies (N = 418 randomized;228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. The longer-term adverse reaction profile observed in the 19-week MDD study (N= 219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see Adverse Reactions ( 6. 1 The acute adverse reaction profiles observed in the 3 studies (N = 418 randomized;228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine. 1 Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2. 6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients. Mania/hypomania led to the discontinuation of 4 (1. 8%) fluoxetine-treated patients from the acute phases of the 3 studies combined. Consequently, regular monitoring for the occurrence of mania/hypomania is recommended. As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients. After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1. 1 cm less in height and 1. 1 kg less in weight than subjects treated with placebo. In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels. The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration. In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients. Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine [see Warnings and Precautions ( 5. 6 Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Boxed Warning 5. 1 Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. Juvenile Animal Toxicity data These fluoxetine toxicities in juvenile rats have not been observed in adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving 3, 10, or 30 mg/kg/day doses in this study are approximately 0. 2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the MRHD of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0. 8, 1 to 8, and 3 to 20 times, respectively, the pediatric exposure at the MRHD. A specific effect on bone development was reported in juvenile mice administered fluoxetine by the intraperitoneal route to 4-week-old mice for 4 weeks at doses 0. 5 and 2 times the oral MRHD of 20 mg/day on a mg/m2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected. US fluoxetine clinical trials included 687 patients >=65 years of age and 93 patients >=75 years of age. The efficacy in geriatric patients has been established [ see Clinical Studies ( 14. 1 see Clinical Pharmacology ( 12. 3 see Warnings and Precautions ( 5. 9 In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of fluoxetine should be used in patients with cirrhosis. Caution is advised when using fluoxetine in patients with diseases or conditions that could affect its metabolism [ see Dosage and Administration ( 2.

RECENT MAJOR CHANGES
Warnings and Precautions ( 5.2 5.7
DRUG INTERACTIONS
As with all drugs, the potential for interaction by a variety of mechanisms (e. , pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc. ) is a possibility. Drugs Metabolized by CYP2D6: 7. 6 Tricyclic Antidepressants (TCAs): 7. 6 Benzodiazepines: Diazepamem dashincreased t1/2 7. 6 Antipsychotics: 7. 6 Anticonvulsants: 7. 6 Serotonergic Drugs: 2. 2 Drugs that Prolong the QT Interval: 4. 7 [See Dosage and Administration ( 2. 2 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 The concomitant use of serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John''s Wort) with fluoxetine increases the risk of serotonin syndrome. Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of fluoxetine and/or concomitant serotonergic drugs [ see Warnings and Precautions ( 5. 2 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 Drugs Tightly Bound to Plasma Proteins [see Clinical Pharmacology ( 12. 3 Pimozide [see Contraindications ( 4. 7 Thioridazine [see Contraindications ( 4. 7 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 Thioridazine administration produces a dose-related prolongation of the QT interval, which is associated with serious ventricular arrhythmias, such as Torsade de Pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Drugs Metabolized by CYP2D6 [see Contraindications ( 4. 2 Tricyclic Antidepressants (TCAs) [see Warnings and Precautions ( 5. 3 Benzodiazepines [see Clinical Pharmacology ( 12. 3 Antipsychotics Anticonvulsants Lithium see Warnings and Precautions ( 5. 2 Drugs tightly bound to plasma proteins [see Clinical Pharmacology ( 12. 3 Drugs metabolized by CYP3A4 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. Olanzapine Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution in combination with other drugs that cause QT prolongation. These include: specific antipsychotics (eg, ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (eg, erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class IA antiarrhythmic medications (eg, quinidine, procainamide); Class III antiarrhythmics (eg, amiodarone, sotalol); and others (eg, pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment with CYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bound drugs can increase the concentration of fluoxetine [see Contraindications ( 4.

OVERDOSAGE
The following have been reported with fluoxetine tablet overdosage: Seizures, which may be delayed, and altered mental status including coma. Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, torsade de pointes, and cardiac arrest. Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol. Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk). Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a fluoxetine overdose. Consider contacting a Poison Center (1-800-221-2222) or a medical toxicologist for additional overdosage management recommendations.
NONCLINICAL TOXICOLOGY
Carcinogenicity 2 Mutagenicity Impairment of Fertility 2 see Use in Specific Populations ( 8. 4 Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically. This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulation in animals has been observed with many cationic amphiphilic drugs, including fenfluramine, imipramine, and ranitidine. The significance of this effect in humans is unknown.
CLINICAL STUDIES
Efficacy for fluoxetine was established for the: Acute and maintenance treatment of MDD in adults, and children and adolescents (8 to 18 years) in 7 short-term and 2 long-term, placebo-controlled trials [see Clinical Studies ( 14. 1 Acute treatment of obsessions and compulsions in adults, and children and adolescents (7 to 17 years) with OCD in 3 short-term, placebo-controlled trials [see Clinical Studies ( 14. 2 Acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa in 3 short-term and 1 long-term, placebo-controlled trials [see Clinical Studies ( 14. 3 Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients in 2 short-term, placebo-controlled trials [see Clinical Studies ( 14. 4 Daily Dosing Adultem dash Two 6- week controlled studies (N = 671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (>=60 years of age) with MDD. In these studies, fluoxetine produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of <= 8. Fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between fluoxetine (12%) and placebo (9%). A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of <=7 during each of the last 3 weeks of open-label treatment and absence of MDD by DSM-III-R criteria) by the end of an initial 12- week, open-treatment phase on fluoxetine 20 mg/day. These patients (N = 298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of MDD for 2 weeks or a modified HAMD-17 score of >=14 for 3 weeks) was observed for patients taking fluoxetine compared with those on placebo. Pediatric (children and adolescents)em dash Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender. Adult Table 5 Table 5. Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Fluoxetine Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex. Pediatric (children and adolescents) Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender. The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8- week and one 16- week, multicenter, parallel-group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8 week studies received either 20 mg/day or 60 mg/day of fluoxetine or placebo in the morning. Patients in the 16 week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as week 1 and persisted throughout each study. The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the HAM-D. In each of these 3 studies, the treatment effect, as measured by differences between fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging. In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8 week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo. The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia. Study 1 (N = 180 randomized) was a 12-week, flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively. Study 2 (N = 214 randomized) was a 12-week, flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 mg/day to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.
MEDICATION GUIDE
FLUOXETINE (floo-OX-e-teen) TABLETS USP Read the Medication Guide that comes with fluoxetine before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about fluoxetine? Fluoxetine and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: Fluoxetine and other antidepressant medicines may increase suicidal thoughts or actions first few months of treatment or when the dose is changed Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice: New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe. Pay particular attention to such changes when fluoxetine is started or when the dose is changed. Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: attempts to commit suicide acting on dangerous impulses acting aggressive or violent thoughts about suicide or dying new or worse depression new or worse anxiety or panic attacks feeling agitated, restless, angry or irritable trouble sleeping an increase in activity or talking more than what is normal for you other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluoxetine may be associated with these serious side effects: 2. Serotonin Syndrome. This condition can be life-threatening and may include: agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) racing heartbeat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity dizziness flushing tremor seizures 3. Severe allergic reactions: trouble breathing swelling of the face, tongue, eyes or mouth rash, itchy welts (hives) or blisters, alone or with fever or joint pain 4. Abnormal bleeding: registered registered 5. Visual problems eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. 6. Seizures or convulsions 7. Manic episodes: greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual 8. Changes in appetite or weight. 9. Low salt (sodium) levels in the blood. headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 10. Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsades de Pointes). This condition can be life threatening. The symptoms may include: fast, slow, or irregular heartbeat shortness of breath dizziness or fainting Do not stop fluoxetine without first talking to your healthcare provider. Stopping fluoxetine too quickly may cause serious symptoms including: anxiety, irritability, high or low mood, feeling restless, or changes in sleep habits headache, nausea, dizziness electric shock-like sensations, shaking, confusion 11. Sexual problems (dysfunction). fluoxetine, may cause sexual problems. Symptoms in males may include: Delayed ejaculation or inability to have an ejaculation Decreased sex drive Problems getting or keeping an erection Symptoms in females may include: Decreased sex drive Delayed orgasm or inability to have an orgasm Talk to your healthcare provider if you develop any changes in your sexual function or if you have any questions or concerns about sexual problems during treatment with fluoxetine. There may be treatments your healthcare provider can suggest. What is fluoxetine? Fluoxetine is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. Fluoxetine is used to treat: Major Depressive Disorder (MDD) Obsessive Compulsive Disorder (OCD) Bulimia Nervosa* Panic Disorder* Depressive episodes associated with Bipolar I Disorder, taken with olanzapine (Zyprexa)* Treatment Resistant Depression (depression that has not gotten better with at least 2 other treatments), taken with olanzapine (Zyprexa)* *Not approved for use in children. Talk to your healthcare provider if you do not think that your condition is getting better with fluoxetine treatment. Who should not take fluoxetine? Do not take fluoxetine if you: are allergic to fluoxetine hydrochloride or any of the ingredients in fluoxetine. See the end of this Medication Guide for a complete list of ingredients in fluoxetine. take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. - Do not take an MAOI within 5 weeks of stopping fluoxetine unless directed to do so by your physician - Do not start fluoxetine if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take fluoxetine close in time to an MAOI may have serious or even life- threatening side effects. Get medical help right away if you have any of these symptoms: - high fever - uncontrolled muscle spasms - stiff muscles - rapid changes in heart rate or blood pressure - confusion - loss of consciousness (pass out) take Mellaril registered ). Do not take Mellaril registered within 5 weeks of stopping fluoxetine because this can cause serious heart rhythm problems or sudden death. take the antipsychotic medicine pimozide (Orap registered because this can cause serious heart problems. What should I tell my healthcare provider before taking fluoxetine? Ask if you are not sure. Before starting fluoxetine, tell your healthcare provider if you: are taking certain drugs or treatments such as: - Triptans used to treat migraine headache - Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, MAOIs, or antipsychotics - Tramadol, fentanyl , meperidine, methadone, or other opoids - Amphetamines - Over-the-counter supplements such as tryptophan or St. John''s Wort - Electroconvulsive therapy (ECT) have liver problems have kidney problems have heart problems have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have a history of a stroke have high blood pressure have or had bleeding problems are pregnant or plan to become pregnant. Taking Fluoxetine Tablets late in pregnancy may lead to an increased risk of certain problems in your newborn. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy. are breast-feeding or plan to breast-feed. fluoxetine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking fluoxetine Tablets. Tell your healthcare provider about all the medicines that you take, Your healthcare provider or pharmacist can tell you if it is safe to take fluoxetine with your other medicines. Do not start or stop any medicine while taking fluoxetine without talking to your healthcare provider first. If you take fluoxetine, you should not take any other medicines that contain fluoxetine hydrochloride including: Symbyax registered Sarafem registered Prozac registered Prozac registered trademark How should I take fluoxetine? Take fluoxetine exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine until it is the right dose for you. Each tablet can be broken in half (along the functional score). Fluoxetine may be taken with or without food If you miss a dose of fluoxetine, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of fluoxetine at the same time. If you take too much fluoxetine, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking fluoxetine? Fluoxetine can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how fluoxetine affects you. Do not drink alcohol while using fluoxetine. What are the possible side effects of fluoxetine? Fluoxetine may cause serious side effects, including: See "What is the most important information I should know about fluoxetine?" Problems with blood sugar control. Feeling anxious or trouble sleeping Common possible side effects in people who take fluoxetine include: unusual dreams sexual problems loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth flu symptoms feeling tired or fatigued change in sleep habits yawning sinus infection or sore throat tremor or shaking sweating feeling anxious or nervous hot flashes rash Other side effects in children and adolescents include: increased thirst abnormal increase in muscle movement or agitation nose bleed urinating more often heavy menstrual periods possible slowed growth rate and weight change. Your child''s height and weight should be monitored during treatment with fluoxetine. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of fluoxetine. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. How should I store fluoxetine? Store fluoxetine at room temperature between 68 °F and 77 °F (20 °C to 25 °C). Keep fluoxetine away from light. Keep fluoxetine bottle closed tightly. Keep fluoxetine and all medicines out of the reach of children. General information about fluoxetine Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine for a condition for which it was not prescribed. Do not give fluoxetine to other people, even if they have the same condition. It may harm them. This Medication Guide summarizes the most important information about fluoxetine. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine that is written for healthcare professionals. For more information about fluoxetine call 1-877-977-0687. What are the ingredients in fluoxetine tablets, 60 mg? Active ingredient: Fluoxetine hydrochloride USP Inactive ingredients: Corn starch, hypromellose, mannitol, microcrystalline cellulose, magnesium stearate, polyethylene glycol and titanium dioxide. This Medication Guide has been approved by the US Food and Drug Administration. Symbyax and Prozac are registered trademarks of Eli Lilly and Company. Prozac Weekly is a registered trademark of Eli Lilly and Company. Sarafem is a registered trademark of Warner Chilcott. Mellaril is a registered trademark of Novartis AG Corporation. Orap is a registered trademark of Teva Pharmaceuticals USA. Coumadin is a registered trademark of Bristol Myers Squibb. Jantoven is a registered trademark of Upsher-Smith Laboratories Inc. Manufactured by: Inventia Healthcare Limited F1-F1/1-F75/1, Additional Ambernath M.I.D.C., Ambernath (East)-421506, Dist. Thane, Maharashtra, India Marketed by: Nivagen Pharmaceuticals, Inc. Sacramento, CA 95827 Toll Free Number: 1-877-977-0687 Product of India Revised: 3/2024

NIVAGEN PHARMACEUTICALS, INC.

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