Data from FDA - Curated by EPG Health - Last updated 05 July 2018

Indication(s)

1 INDICATIONS AND USAGE Fluoxetine capsules USP are 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 capsules USP and Olanzapine in Combination is indicated for the treatment of: 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. 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 are 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) Fluoxetine capsules USP and olanzapine in combination for treatment of: Acute Depressive Episodes Associated with Bipolar I Disorder ( 1)

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Advisory information

contraindications
4 CONTRAINDICATIONS When using fluoxetine 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 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 ( 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 Symbyax ( 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.
Adverse reactions
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)] When using fluoxetine 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) Fluoxetine and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for Symbyax ( 6) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice. Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in 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 Incidence less than 1%. Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. Percentage of Patients Reporting Event Major Depressive Disorder 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) 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 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 Denominator 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). 2 – – – 7 – 1 – Abnormal ejaculation – – 7 – 7 – 2 1 Table 4. Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials Incidence less than 1%. Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials. Percentage of Patients Reporting Event Major Depressive Disorder, 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 Associated with discontinuation in Major Depressive Disorder, OCD, bulimia, and Panic Disorder placebo-controlled clinical trials (excluding data from extensions of trials) – Table 5 lists the adverse reactions associated with discontinuation of fluoxetine treatment (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials. Table 5: Most Common Adverse Reactions Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Placebo-Controlled Clinical Trials Includes US Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US Panic Disorder clinical trials. Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined (N=1533) Major Depressive Disorder (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%) – – Other adverse reactions in pediatric patients (children and adolescents) – Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency, and menorrhagia. 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 – Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences. Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance, cited in product labeling, are likely to underestimate their actual incidence. In patients enrolled in US Major Depressive Disorder, OCD, and bulimia placebo-controlled clinical trials, decreased libido was the only sexual side effect reported by at least 2% of patients taking fluoxetine (4% fluoxetine, <1% placebo). There have been spontaneous reports in women taking fluoxetine of orgasmic dysfunction, including anorgasmia. 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 side effects. 6.2 Other Reactions Following is a list of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This listing is not intended to include reactions (1) already listed in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo. 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 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients. Body as a Whole – Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction. Cardiovascular System – Frequent: palpitation; Infrequent: arrhythmia hypotension 1. Digestive System – Infrequent: dysphagia, gastritis, gastroenteritis, melena, stomach ulcer; Rare: bloody diarrhea, duodenal ulcer, esophageal ulcer, gastrointestinal hemorrhage, hematemesis, hepatitis, peptic ulcer, stomach ulcer hemorrhage. Hemic and Lymphatic System – Infrequent: ecchymosis; Rare: petechia, purpura. Nervous System – Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder 1, bruxism 1, buccoglossal syndrome, depersonalization, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions. Respiratory System – Rare: larynx edema. Skin and Appendages – Infrequent: alopecia; Rare: purpuric rash. Special Senses – Frequent: taste perversion; Infrequent: mydriasis. Urogenital System – Frequent: micturition disorder; Infrequent: dysuria, gynecological bleeding 2. MedDRA dictionary term from integrated database of placebo controlled trials of 15870 patients, of which 9,673 patients received fluoxetine. Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterine bleeding, genital hemorrhage, menometrorrhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal hemorrhage, uterine hemorrhage, vaginal hemorrhage. Adjusted for gender. 6.3 Postmarketing Experience 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: aplastic anemia, atrial fibrillation 1, cataract, cerebrovascular accident 1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia 1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest 1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, memory impairment, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of pre-existing movement disorders, optic neuritis, pancreatitis 1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia 1, thrombocytopenic purpura, ventricular tachycardia (including Torsades de Pointes–type arrhythmias), vaginal bleeding, and violent behaviors 1. These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

Usage information

Dosing and administration
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) 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 and olanzapine in combination: Dosage adjustments, should be made with the individual components according to efficacy and tolerability ( 2.5) Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder ( 2.5) Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in adults ( 2.5) 2.1 Major Depressive Disorder Initial Treatment Adult – Initiate fluoxetine capsules 20 mg/day orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon).The maximum fluoxetine dose should not exceed 80 mg/day. In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. [see Clinical Studies ( 14.1)] . Pediatric (children and adolescents) – Initiate fluoxetine capsules 10 or 20 mg/day. After 1 week at 10 mg/day, increase the dose to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement is observed. In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see Clinical Studies ( 14.1)] . All patients – As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer. Periodically reassess to determine the need for maintenance treatment. 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 capsules 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 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)] . 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 20 mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed. A dose range of 20 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 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. 2.3 Bulimia Nervosa Initial Treatment – Administer fluoxetine capsules 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 patients with bulimia. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo [see Clinical Studies ( 14.3)] . Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting. Periodically reassess to determine the need for maintenance treatment. 2.4 Panic Disorder Initial Treatment – Initiate treatment with fluoxetine capsules 10 mg/day. After one week, increase the dose to 20 mg/day. Consider a dose increase after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see Clinical Studies ( 14.4)] . The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day. Periodically reassess to determine the need for continued treatment. 2.5 Fluoxetine and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax. Adult – Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Make dosage adjustments, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. Periodically re-examine the need for continued pharmacotherapy. Information for pediatric patients (10-17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine). Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax. Adjust dosage, if indicated, with the individual components according to efficacy and tolerability. Table 1: Approximate Dose Correspondence Between Symbyax Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of fluoxetine and olanzapine. and the Combination of Fluoxetine and Olanzapine For Use in Combination Symbyax (mg/day) Olanzapine (mg/day) Fluoxetine (mg/day) 3 mg olanzapine/25 mg fluoxetine 2.5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder. 2.7 Dosing in Specific Populations Treatment of Pregnant Women – When treating pregnant women with fluoxetine, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding [see Use in Specific Populations ( 8.1)]. Geriatric – Consider a lower or less frequent dosage for the elderly [see Use in Specific Populations ( 8.5)] . Hepatic Impairment – As with many other medications, use a lower or less frequent dosage in patients with hepatic impairment [see Clinical Pharmacology ( 12.4) and Use in Specific Populations ( 8.6)] . Concomitant Illness – Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see Clinical Pharmacology ( 12.4) and Warnings and Precautions ( 5.12)] . Fluoxetine and Olanzapine in Combination – Use a starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Titrate slowly and adjust dosage as needed in patients who exhibit a combination of factors that may slow metabolism. Fluoxetine and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 10 years of age [see Warnings and Precautions ( 5.16) and Drug Interactions ( 7.7)]. 2.8 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see Warnings and Precautions ( 5.15) ]. 2.9 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy 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)]. 2.10 Use of Fluoxetine with Other MAOIs such as Linezolid or Methylene Blue Do not start fluoxetine capsules 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)]. In some cases, a patient already receiving fluoxetine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, fluoxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with fluoxetine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions ( 5.2)]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluoxetine is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions ( 5.2)].
Use in special populations
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 1 Disorder have not been established ( 8.4). Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis ( 8.6) Information for pediatric patients (10-17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 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 = 1359) 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 with the established benefits of treating depression with an antidepressant. The decision can only be made on a case by case basis [see Dosage and Administration ( 2.7)]. Animal Data – In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m 2 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 on a mg/m 2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m 2 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 (0.6 times the MRHD on a mg/m 2 basis). 8.2 Labor and Delivery The effect of fluoxetine on labor and delivery in humans is unknown. However, because fluoxetine crosses the placenta and because of the possibility that fluoxetine may have adverse effects on the newborn, fluoxetine should be used during labor and delivery only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding. 8.4 Pediatric Use Use of fluoxetine in children –The efficacy of fluoxetine for the treatment of Major Depressive Disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 [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 Major Depressive Disorder and <7 years of age in OCD have not been established. Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with Major Depressive Disorder 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 Major Depressive Disorder 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)] . 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 Box Warning and Warnings and Precautions ( 5.1)] . Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need. Animal Data Significant toxicity on muscle tissue, neurobehavior, reproductive organs, and bone development, has been observed following exposure of juvenile rats to fluoxetine from weaning through maturity. Oral administration of fluoxetine to rats from weaning postnatal day 21 through adulthood day 90 at 3, 10, or 30 mg/kg/day was associated with testicular degeneration and necrosis, epididymal vacuolation and hypospermia (at 30 mg/kg/day corresponding to plasma exposures [AUC] approximately 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day), increased serum levels of creatine kinase (at AUC as low as 1 to 2 times the average AUC in pediatric patients at the MRHD of 20 mg/day), skeletal muscle degeneration and necrosis, decreased femur length/growth and body weight gain (at AUC 5 to 10 times the average AUC in pediatric patients at the MRHD of 20 mg/day) The high dose of 30 mg/kg/day exceeded a maximum tolerated dose. When animals were evaluated after a drug-free period (up to 11 weeks after cessation of dosing), fluoxetine was associated with neurobehavioral abnormalities (decreased reactivity at AUC as low as approximately 0.1 to 0.2 times the average AUC in pediatric patients at the MRHD and learning deficit at the high dose), and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose). In addition, the testicular and epididymal microscopic lesions and decreased sperm concentrations found in high dose group were also observed, indicating that the drug effects on reproductive organs are irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. 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 0.1 to 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, are approximately 0.3 to 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 mg/m 2 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. Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 10 years of age have not been established. Information for pediatric patients (10-17 years) is approved for Eli Lilly and Company’s Fluoxetine Capsules. However due to Eli Lilly and Company’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 8.5 Geriatric Use 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)] . For pharmacokinetic information in geriatric patients, [see Clinical Pharmacology ( 12.4)] . No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions ( 5.9)] . Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients. 8.6 Hepatic Impairment 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 ( 2.7) and Clinical Pharmacology ( 12.4)] .
Pregnancy and lactation
8.3 Nursing Mothers Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended. In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother’s plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.

Interactions

7 DRUG INTERACTIONS As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. Monoamine Oxidase Inhibitors (MAOI): ( 2.9, 2.10, 4.1, 5.2) Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway ( 7.7) Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued ( 5.2, 7.7) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs ( 7.2) Benzodiazepines: Diazepam – increased t½ , 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 prolongation warrants restricting the concurrent use of pimozide and fluoxetine [see Contraindications ( 4.2), Warnings and Precautions ( 5.11), and Drug Interactions ( 7.8)] . 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 C max 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, which is associated with serious ventricular arrhythmias, such as Torsades de Pointes-type arrhythmias, and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism. Drugs Metabolized by CYP2D6 – Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Co-administration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. Thus, his/her dosing requirements resemble those of poor metabolizers. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs). Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications ( 4.2)] . Tricyclic Antidepressants (TCAs) – In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is co-administered or has been recently discontinued [see Warnings and Precautions ( 5.2) and Clinical Pharmacology ( 12.3)] . Benzodiazepines – The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology ( 12.3)] . Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels. Antipsychotics – Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics. Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine. Anticonvulsants – Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment. Lithium – There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored when these drugs are administered concomitantly [see Warnings and Precautions ( 5.2)] . Drugs Tightly Bound to Plasma Proteins – Because fluoxetine is tightly bound to plasma proteins, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. [see Clinical Pharmacology ( 12.3)] . Drugs Metabolized by CYP3A4 – In an in vivo interaction study involving co-administration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. 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 – Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended. When using fluoxetine and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax. 7.8 Drugs that Prolong the QT Interval 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 (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., 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 ( 4.2), Warnings and Precautions ( 5.11), Drug Interactions ( 7.7), and Clinical Pharmacology ( 12.3)].

More information

Category Value
Authorisation number ANDA075049
Agency product number I9W7N6B1KJ
Orphan designation No
Product NDC 70518-0170
Date Last Revised 07-06-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 310385
Marketing authorisation holder REMEDYREPACK INC.
Warnings WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions ( 5.1)] . In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions ( 5.1)] . Fluoxetine is not approved for use in children less than 7 years of age [see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.4)] . When using fluoxetine and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants ( 5.1). Monitor for worsening and emergence of suicidal thoughts and behaviors ( 5.1). When using fluoxetine and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax.