Fluoxetine HCL

Fluoxetine is indicated for the treatment of: Acute and maintenance treatment of Major Depressive Disorder [see Clinical Studies (14.1)] . Acute and maintenance treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2)] . Acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)] . Acute treatment of Panic Disorder, with or without agoraphobia [see Clinical Studies (14.4)] . Fluoxetine and Olanzapine in Combination is indicated for the treatment of: Acute treatment of depressive episodes associated with Bipolar I Disorder. Treatment resistant depression (Major Depressive Disorder in patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode). Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder or the treatment of treatment resistant depression. When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax ®.

2.1 Major Depressive Disorder Initial Treatment Adult — Initiate fluoxetine 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 mg/day to 80 mg/day. Studies comparing fluoxetine 20 mg/day, 40 mg/day, 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 10 mg/day 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. 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)]. 2.2 Obsessive Compulsive Disorder Initial Treatment Adult — Initiate fluoxetine 20 mg/day, orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon). A dose range of 20 mg/day to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20 mg, 40 mg, or 60 mg of fluoxetine or placebo [see CLINICAL STUDIES (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Pediatric (children and adolescents) — In adolescents and higher weight children, initiate treatment with a dose of 10 mg/day. After 2 weeks, increase the dose to 20mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed. A dose range of 20 mg/day to 60 mg/day is recommended. In lower weight children, initiate treatment with a dose of 10 mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed. A dose range of 20 mg/day 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 mg/day to 60 mg/day [see CLINICAL STUDIES (14.2)]. Periodically reassess to determine the need for treatment. 2.3 Bulimia Nervosa Initial Treatment — Administer fluoxetine 60 mg/day in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in …

Fluoxetine capsules, USP 10 mg** are white to off white powder filled in size “4” hard gelatin capsules with opaque light blue colored cap and opaque light orange colored body imprinted “SG” on cap and “113” on body with black ink. Fluoxetine capsules, USP 20 mg** are white to off white powder filled in size “2” hard gelatin capsules with opaque light blue colored cap and opaque light green colored body imprinted “SG” on cap and “114” on body with black ink. Fluoxetine capsules, USP 40 mg** are white to off white powder filled in size “0” hard gelatin capsules with opaque light blue colored cap and opaque white colored body imprinted “SG” on cap and “115” on body with black ink. **Fluoxetine base equivalent.

When using fluoxetine capsules and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. 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.

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)] Sexual Dysfunction [see WARNINGS AND FUNCTIONS (5.17)] When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. 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. 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, OCD, bulimia, and Panic 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, OCD, and bulimia in US controlled clinical trials and Panic Disorder in US plus non-US controlled 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 US Major Depressive Disorder, OCD, and bulimia controlled clinical trials and US plus non-US Panic 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, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials 1,2 Percentage of Patients Reporting Event Major Depressive Disorder OCD Bulimia Panic Disorder 1 Incidence less than 1%. 2Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. 3Denominator used was for males only (N=690 fluoxetine Major Depressive Disorder; N=410 placebo Major Depressive Disorder; N=116 fluoxetine OCD; N=43 placebo OCD; N=14 fluoxetine bulimia; N=1 placebo bulimia; N=162 fluoxetine panic; N=121 placebo panic). Body System/Adverse Reaction Fluoxetine (N=1,728) Placebo (N=975) Fluoxetine (N=266) Placebo (N=89) Fluoxetine (N=450) Placebo (N=267) Fluoxetine (N=425) Placebo (N=342) Body as a Whole Asthenia 9 5 15 11 21 9 7 7 Flu syndrome 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 …

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. 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 Other Serotonergic Drugs 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)]. 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 Thioridazine— Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued, because of the risk of QT Prolongation [see Contraindications (4.2), Warnings and Precautions (5.11), and Drug Interactions (7.8)]. 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 Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine. Thioridazine administration produces a dose-related prolongation of the QT interval, whic …

When using fluoxetine and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. Risk Summary 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). There are risks associated with untreated depression in pregnancy and risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including fluoxetine, during pregnancy (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 1.6 and 3.9 times, respectively, the maximum recommended human dose (MRHD) of 60 mg/day given to adolescents on a mg/m 2 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 time (during gestation and lactation) the MRHD given to adolescents on a mg/m 2 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. Fetal/Neonatal adverse reactions Neonates exposed to fluoxetine and other SSRI 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, th …

Fluoxetine capsules, USP are a selective serotonin reuptake inhibitor for oral administration. It is designated (±)-N-methyl-3-phenyl-3- [(α,α,α-trifluoro-p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C 17H 18F 3NO•HCl. Its molecular weight is 345.79. The structural formula is: [Chemical Structure] Fluoxetine hydrochloride, USP is a white to off-white crystalline powder with a solubility of 14 mg/mL in water. Each capsule contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The capsules also contain the following inactive ingredients: pregelatinized starch (maize [corn]), colloidal silicon dioxide, gelatin, sodium lauryl sulphate, FD&C Blue #1, FD&C Red #3, and titanium dioxide. In addition 20 mg capsules also contains D&C Yellow #10 and 10 mg capsules also contains FD&C Yellow #6. The capsules are printed with edible ink containing black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

The following have been reported with fluoxetine 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 pro-serotonergic 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.

16.1 How Supplied Fluoxetine Capsules, USP 10 mg** are white to off white powder filled in size “4” hard gelatin capsules with opaque light blue colored cap and opaque light orange colored body imprinted “SG” on cap and “113” on body with black ink. Bottles of 30 NDC 50228-113-30 Bottles of 100 NDC 50228-113-01 Bottles of 500 NDC 50228-113-05 Bottles of 1000 NDC 50228-113-10 Fluoxetine Capsules USP, 20 mg** are white to off white powder filled in size “2” hard gelatin capsules with opaque light blue colored cap and opaque light green colored body imprinted “SG” on cap and “114” on body with black ink. Bottles of 30 NDC 72189-656-30 Bottles of 100 NDC 50228-114-01 Bottles of 500 NDC 50228-114-05 Bottles of 1000 NDC 50228-114-10 Fluoxetine Capsules USP, 40 mg** are white to off white powder filled in size “0” hard gelatin capsules with opaque light blue colored cap and opaque white colored body imprinted “SG” on cap and “115” on body with black ink. Bottles of 30 NDC 50228-115-30 Bottles of 100 NDC 50228-115-01 Bottles of 500 NDC 50228-115-05 **Fluoxetine base equivalent.