Fluoxetine

Boxed Warning: Warnings: Suicidal Thoughts and Behaviors 07/2013 Indications and Usage: Fluoxetine Capsules, USP and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder (1.5) 07/2013 Dosage and Administration: Fluoxetine Capsules and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder (2.5) 07/2013 Dosing in Specific Populations (2.7) 07/2013 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders (2.9) 01/2013 Use of Fluoxetine Capsules with Other MAOIs such as Linezolid or Methylene Blue (2.10) 01/2013 Contraindications: Monoamine Oxidase Inhibitors (MAOIs) (4.1) 01/2013 Other Contraindications (4.2) 07/2013 Warnings and Precautions: Clinical Worsening and Suicide Risk (5.1) 07/2013 Serotonin Syndrome (5.2) 01/2013 QT Prolongation (5.10) 07/2013

1 INDICATIONS AND USAGE Fluoxetine capsules, USP are a selective serotonin reuptake inhibitor indicated for: • Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult and pediatric patients aged 8 to 18 years (1.1) • Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in adult and pediatric patients aged 7 to 17 years (1.2) • Acute and maintenance treatment of Bulimia Nervosa in adult patients (1.3) • Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients (1.4) Fluoxetine capsules, USP and olanzapine in combination for: • Acute treatment of Depressive Episodes Associated with Bipolar I Disorder (1.5) 1.1 Major Depressive Disorder Fluoxetine capsules, USP are indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to 18 years [see Clinical Studies (14.1) ]. The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods, should periodically be re-evaluated [see Dosage and Administration (2.1) ] . 1.2 Obsessive Compulsive Disorder Fluoxetine capsules, USP are indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2) ]. The effectiveness of fluoxetine capsules, USP in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine capsules, USP for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.2 )]. 1.3 Bulimia Nervosa Fluoxetine capsules, USP are indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3) ]. The physician who elects to use fluoxetine capsules, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3 )] . 1.4 Panic Disorder Fluoxetine capsules, USP are indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [see Clinical Studies (14.4) ] . The effectiveness of fluoxetine capsules, USP in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine capsules, USP for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.4) ]. 1.5 Fluoxetine Capsules, USP and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using fluoxetine capsules, USP and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax ® . Fluoxetine capsules, USP and olanzapine in combination are indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder. Fluoxetine capsules, USP monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

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 ) Fluoxetine capsules 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 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 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 mg/day 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 co …

3 DOSAGE FORMS AND STRENGTHS Fluoxetine Capsules USP, 10 mg* are opaque green cap/opaque green body, size ‘3’ hard gelatin capsule filled with white to off-white granular powder and imprinted with ‘E’ on opaque green cap and ‘88’ on opaque green body with black ink. Fluoxetine Capsules USP, 20 mg* are opaque green cap/opaque off white body, size ‘3’ hard gelatin capsule filled with white to off-white granular powder and imprinted with ‘E’ on opaque green cap and ‘91’ on opaque off white body with black ink. Fluoxetine Capsules USP, 40 mg* are opaque green cap/opaque orange body, size ‘2’ hard gelatin capsule filled with white to off-white granular powder and imprinted with ‘E’ on opaque green cap and ‘92’ on opaque orange body with black ink. *Fluoxetine base equivalent. • Capsules: 10 mg, 20 mg, and 40 mg (3)

4. CONTRAINDICATIONS When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for olanzapine and fluoxetine hydrochloride capsules . Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine. Do not use fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue (4.1) Pimozide: Do not use. Risk of QT prolongation and drug interaction (4.2, 5.11,7.7, 7.8) Thioridazine: Do not use. Risk of QT interval prolongation and elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing fluoxetine Do not use thioridazine within 5 weeks of discontinuing fluoxetine (4.2, 5.11,7.7, 7.8). When using fluoxetine and olanzapine in combination, also refer to the Contraindications section of the package insert for olanzapine and fluoxetine hydrochloride capsules (4) 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.

6. Adverse Reactions The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)] Serotonin Syndrome [see WARNINGS AND PRECAUTIONS (5.2)] Allergic Reactions and Rash [see WARNINGS AND PRECAUTIONS (5.3)] Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania [see WARNINGS AND PRECAUTIONS (5.4)] Seizures [see WARNINGS AND PRECAUTIONS (5.5)] Altered Appetite and Weight [see WARNINGS AND PRECAUTIONS (5.6)] Abnormal Bleeding [see WARNINGS AND PRECAUTIONS (5.7)] Angle-Closure Glaucoma [see WARNINGS AND PRECAUTIONS (5.8)] Hyponatremia [see WARNINGS AND PRECAUTIONS (5.9)] Anxiety and Insomnia [see WARNINGS AND PRECAUTIONS (5.10)] QT Prolongation [see WARNINGS AND PRECAUTIONS (5.11)] Potential for Cognitive and Motor Impairment [see WARNINGS AND PRECAUTIONS (5.13)] Discontinuation Adverse Reactions [see WARNINGS AND PRECAUTIONS (5.15)] 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 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 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 …

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 fluoxetine or when fluoxetine has been recently discontinued ( 5.2 , 7.7 ) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs ( 7.2 ) Benzodiazepines: Diazepam – increased t 1/2 , 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 fluoxetine, also refer to the Drug Interactions section of the package insert for Symbyax ( 7.7 ) Drugs that Prolong the QT Interval: Do not use fluoxetine with thioridazine or pimozide. Use with caution in combination with other drugs that prolong the QT interval ( 4.2 , 5.11 , 7.7 , 7.8 ) 7.1 Monoamine Oxidase Inhibitors (MAOI) [See Dosage and Administration (2.9, 2.10), Contraindications ( 4.1 ), and Warnings and Precautions ( 5.2 )]. 7.2 CNS Acting Drugs Caution is advised if the concomitant administration of fluoxetine and such drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [ see Clinical Pharmacology ( 12.3 ) ] . 7.3 Serotonergic Drugs [See Dosage and Administration (2.9, 2.10), Contraindications ( 4.1 ), and Warnings and Precautions ( 5.2 )]. 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [ see Warnings and Precautions ( 5.7 ) ] . 7.5 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment. 7.6 Potential for Other Drugs to affect Fluoxetine Drugs Tightly Bound to Plasma Proteins — Because fluoxetine is tightly bound to plasma proteins, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs [ see Clinical Pharmacology ( 12.3 ) ] . 7.7 Potential for Fluoxetine to affect Other Drugs Pimozide — Concomitant use in patients taking pimozide is contraindicated. Pimozide can prolong the QT interval. Fluoxetine can increase the level of pimozide through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT prol …

8 USE IN SPECIFIC POPULATIONS When using fluoxetine and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax. Pregnancy: Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risks to the fetus ( 8.1 ) Nursing Mothers: Breast feeding is not recommended ( 8.3 ) Pediatric Use: Safety and effectiveness of fluoxetine 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 fluoxetine 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 Category C — Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. All pregnancies have a background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. Treatment of Pregnant Women during the First Trimester — There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N = 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1,359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established. Nonteratogenic Effects — Neonates exposed to fluoxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2) ]. Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiological studies suggest a positive statistical association between SSRI use (including fluoxetine) in pregnancy and PPHN. Other studies do not show a significant statistical association. Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with fluoxetine, the physician should carefully consider both the potential risks of taking an SSRI, along wi …

12.2. Pharmacodynamics 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 α 1 -adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.

11 DESCRIPTION Fluoxetine capsules, USP are a selective serotonin reuptake inhibitor for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem ® , fluoxetine hydrochloride). 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, 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. Chemical Structure

10. OVERDOSAGE 10.1. Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths. Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established. Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams which was nonlethal. Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricul ararrhythmias, including Torsades de Pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope. 10.2. Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies. The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species. Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically. In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see Overdosage (10.3)] . 10.3. Management of Overdose For current information on the management of fluoxetine overdose, contact a certified poison control center (1-800-222-1222 or www.poison.org). Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multi-drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use general supportive and symptomatic measures. Induction of emesis is not recommended. Activated charcoal shou …

16 HOW SUPPLIED/STORAGE AND HANDLING 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. NDC 42543-725-30: Bottles of 30 capsules NDC 42543-725-01: Bottles of 100 capsules NDC 42543-725-05: Bottles of 500 capsules NDC 42543-725-10: Bottles of 1000 capsules 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. NDC 42543-726-30: Bottles of 30 capsules NDC 42543-726-01: Bottles of 100 capsules NDC 42543-726-05: Bottles of 500 capsules NDC 42543-726-10: Bottles of 1000 capsules 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. NDC 42543-727-30: Bottles of 30 capsules NDC 42543-727-01: Bottles of 100 capsules NDC 42543-727-05: Bottles of 500 capsules **Fluoxetine base equivalent. 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

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. NDC 42543-725-30: Bottles of 30 capsules NDC 42543-725-01: Bottles of 100 capsules NDC 42543-725-05: Bottles of 500 capsules NDC 42543-725-10: Bottles of 1000 capsules 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. NDC 42543-726-30: Bottles of 30 capsules NDC 42543-726-01: Bottles of 100 capsules NDC 42543-726-05: Bottles of 500 capsules NDC 42543-726-10: Bottles of 1000 capsules 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. NDC 42543-727-30: Bottles of 30 capsules NDC 42543-727-01: Bottles of 100 capsules NDC 42543-727-05: Bottles of 500 capsules **Fluoxetine base equivalent.