Prozac

Warnings and Precautions ( 5.2 , 5.7 ) 08/2023

1 INDICATIONS AND USAGE PROZAC ® 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 )]. PROZAC 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). PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder or the treatment of treatment resistant depression. When using PROZAC and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax ® . PROZAC ® is a selective serotonin reuptake inhibitor indicated for: Acute and maintenance treatment of Major Depressive Disorder (MDD) ( 1 ) Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) ( 1 ) Acute and maintenance treatment of Bulimia Nervosa ( 1 ) Acute treatment of Panic Disorder, with or without agoraphobia ( 1 ) PROZAC and olanzapine in combination for treatment of: Acute Depressive Episodes Associated with Bipolar I Disorder ( 1 ) Treatment Resistant Depression ( 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) OCD ( 2.2 ) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa ( 2.3 ) 60 mg/day in am Panic Disorder ( 2.4 ) 10 mg/day (initial dose) Depressive Episodes Associated with Bipolar I Disorder ( 2.5 ) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) Oral in combination with olanzapine: 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) Treatment Resistant Depression ( 2.6 ) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (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 ) PROZAC and olanzapine in combination: Dosage adjustments should be made with the individual components according to efficacy and tolerability ( 2.5 , 2.6 ) Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder or treatment resistant depression ( 2.5 , 2.6 ) Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults ( 2.5 , 2.6 ) Safety of the coadministration of doses above 12 mg olanzapine with 50 mg fluoxetine has not been evaluated in children and adolescents ages 10 to 17 ( 2.5 ) 2.1 Major Depressive Disorder Initial Treatment Adult — Initiate PROZAC 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 PROZAC 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. 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 PROZAC 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 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 …

3 DOSAGE FORMS AND STRENGTHS 10 mg Pulvule is an opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body 20 mg Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body 40 mg Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body Pulvules: 10 mg, 20 mg, 40 mg ( 3 )

4 CONTRAINDICATIONS When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax. Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with PROZAC or within 5 weeks of stopping treatment with PROZAC. Do not use PROZAC within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start PROZAC 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 PROZAC. Do not use thioridazine within 5 weeks of discontinuing PROZAC ( 4.2 , 5.11 , 7.7 , 7.8 ) When using PROZAC and olanzapine in combination, also refer to the Contraindications section of the package insert for Symbyax ( 4 ) 4.1 Monoamine Oxidase Inhibitors (MAOIs) The use of MAOIs intended to treat psychiatric disorders with PROZAC or within 5 weeks of stopping treatment with PROZAC is contraindicated because of an increased risk of serotonin syndrome. The use of PROZAC 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 PROZAC 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 PROZAC 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. PROZAC can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. PROZAC can also prolong the QT interval.

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 )] 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 )] Sexual Dysfunction [see Warnings and Precautions ( 5.17 )] When using PROZAC and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax. Most common adverse reactions (≥5% and at least twice that for placebo) associated with: Major Depressive Disorder, Obsessive Compulsive Disorder, Bulimia, and Panic 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 ) PROZAC and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for Symbyax ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) 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 PROZAC have been administered to 10,782 patients with various diagnoses in US clinical trials. In addition, there have been 425 patients administered PROZAC 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 PROZAC (incidence of at least 5% for PROZAC 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 PROZAC 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 1 Incidence less than 1%. 2 Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinica …

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 (MAOIs): ( 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 PROZAC or when PROZAC 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 t1⁄2, 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 ) Olanzapine: When used in combination with PROZAC, also refer to the Drug Interactions section of the package insert for Symbyax ( 7.7 ) Drugs that Prolong the QT Interval: Do not use Prozac 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 PROZAC 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 PROZAC 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 PROZAC 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 PROZAC 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 PROZAC to affect Other Drugs Pimozide — Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong t …

8 USE IN SPECIFIC POPULATIONS When using PROZAC and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. 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 : Safety and effectiveness of PROZAC in patients <8 years of age with Major Depressive Disorder and <7 years of age with OCD have not been established. Safety and effectiveness of PROZAC and olanzapine in combination in patients <10 years of age for depressive episodes associated with Bipolar I Disorder have not been established ( 8.4 ) Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis ( 8.6 ) 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 Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions ( 5.7 ) and Clinical Considerations ] . 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 PROZAC, 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. Maternal Adverse Reactions Use of PROZAC in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions ( 5.7 )] . Fetal/Neonatal adverse reaction …

12.1 Mechanism of Action Although the exact mechanism of PROZAC is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin.

11 DESCRIPTION PROZAC ® (fluoxetine capsules, USP) is 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 17 H 18 F 3 NO•HCl. Its molecular weight is 345.79. The structural formula is: Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water. Each Pulvule ® contains fluoxetine hydrochloride equivalent to 10 mg (32.3 μmol), 20 mg (64.7 μmol), or 40 mg (129.3 μmol) of fluoxetine. The Pulvules also contain starch, gelatin, silicone, titanium dioxide, iron oxide, and other inactive ingredients. The 10 and 20 mg Pulvules also contain FD&C Blue No. 1, and the 40 mg Pulvule also contains FD&C Blue No. 1 and FD&C Yellow No. 6. Figure

10 OVERDOSAGE 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 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied The following products are manufactured by Eli Lilly and Company for Dista Products Company: Pulvule are available in 10 mg, 20 mg and 40 mg capsule strengths and packages as follows: 1 Fluoxetine base equivalent. 2 Protect from light. Pulvule Strength 10 mg 1 20 mg 1 40 mg 1 Pulvule No. 2 PU3104 PU3105 PU3107 Cap Color Opaque green Opaque green Opaque green Body Color Opaque green Opaque yellow Opaque orange Identification DISTA 3104 DISTA 3105 DISTA 3107 Prozac 10 mg Prozac 20 mg Prozac 40 mg NDC Codes: Bottles of 30 0777-3105-30 0777-3107-30 Bottles 100 0777-3104-02 0777-3105-02 16.2 Storage and Handling Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F).

16.1 How Supplied The following products are manufactured by Eli Lilly and Company for Dista Products Company: Pulvule are available in 10 mg, 20 mg and 40 mg capsule strengths and packages as follows: 1 Fluoxetine base equivalent. 2 Protect from light. Pulvule Strength 10 mg 1 20 mg 1 40 mg 1 Pulvule No. 2 PU3104 PU3105 PU3107 Cap Color Opaque green Opaque green Opaque green Body Color Opaque green Opaque yellow Opaque orange Identification DISTA 3104 DISTA 3105 DISTA 3107 Prozac 10 mg Prozac 20 mg Prozac 40 mg NDC Codes: Bottles of 30 0777-3105-30 0777-3107-30 Bottles 100 0777-3104-02 0777-3105-02