Prescription Drug Name:
displayName: BOXED WARNING SECTION
FDA Article Code: 34066-1
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)].
HIGHLIGHTS OF PRESCRIBING INFORMATION
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5
FLUOXETINE capsules, USP for oral use
Initial U.S. Approval: 1987
SEE FULL PRESCRIBING INFORMATION FOR COMPLETE BOXED WARNING.
Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1).
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)
20 mg/day in am (initial dose)
10 to 20 mg/day (initial dose)
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)
Associated with Bipolar I
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
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)
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)
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 Symbyax (4)
Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including fluoxetine, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort). If such symptoms occur, discontinue fluoxetine and initiate supportive treatment. If concomitant use of fluoxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. (5.2) Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including fluoxetine, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort). If such symptoms occur, discontinue fluoxetine and initiate supportive treatment. If concomitant use of fluoxetine with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. (5.2)
Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena (5.3)
Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania (5.4)
Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.5)
Altered Appetite and Weight: Significant weight loss has occurred (5.6)
Abnormal Bleeding: May increase the risk of bleeding. Use with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding (5.7)
Angle-Closure Glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.8)
Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH). Consider discontinuing if symptomatic hyponatremia occurs (5.9)
Anxiety and Insomnia: May occur (5.10)
QT Prolongation: QT prolongation and ventricular arrhythmia including Torsades de Pointes have been reported with fluoxetine use. Use with caution in conditions that predispose to arrhythmias or increased fluoxetine exposure. Use cautiously in patients with risk factors for QT prolongation (4.2, 5.11)
Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery (5.13)
Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks (5.14)
Fluoxetine and Olanzapine in Combination: When using Fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax (5.16)
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 Vensun Pharmaceuticals, Inc. at 1-800-385-1540 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
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)
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)
FULL PRESCRIBING INFORMATION: CONTENTS*
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Major Depressive Disorder
2.2 Obsessive Compulsive Disorder
2.3 Bulimia Nervosa
2.4 Panic Disorder
2.5 Fluoxetine and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder
2.7 Dosing in Specific Populations
2.8 Discontinuation of Treatment
2.9 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
2.10 Use of Fluoxetine with Other MAOIs such as Linezolid or Methylene Blue
3 DOSAGE FORMS AND STRENGTHS
4.1 Monoamine Oxidase Inhibitors (MAOIs)
4.2 Other Contraindications
5 WARNINGS AND PRECAUTIONS
5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
5.2 Serotonin Syndrome
5.3 Allergic Reactions and Rash
5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania
5.6 Altered Appetite and Weight
5.7 Abnormal Bleeding
5.8 Angle-Closure Glaucoma
5.10 Anxiety and Insomnia
5.11 QT Prolongation
5.12 Use in Patients with Concomitant Illness
5.13 Potential for Cognitive and Motor Impairment
5.14 Long Elimination Half-Life
5.15 Discontinuation Adverse Reactions
5.16 Fluoxetine and Olanzapine in Combination
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Other Reactions
6.3 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Monoamine Oxidase Inhibitors (MAOI)
7.2 CNS Acting Drugs
7.3 Serotonergic Drugs
7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin)
7.5 Electroconvulsive Therapy (ECT)
7.6 Potential for Other Drugs to affect Fluoxetine
7.7 Potential for Fluoxetine to affect Other Drugs
7.8 Drugs that Prolong the QT Interval
8 USE IN SPECIFIC POPULATIONS
8.2 Labor and Delivery
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
9 DRUG ABUSE AND DEPENDENCE
10.1 Human Experience
10.2 Animal Experience
10.3 Management of Overdose
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.4 Specific Populations
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
14.1 Major Depressive Disorder
14.2 Obsessive Compulsive Disorder
14.3 Bulimia Nervosa
14.4 Panic Disorder
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Storage and Handling
17 PATIENT COUNSELING INFORMATION
17.1 General Information
17.2 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
17.3 Serotonin Syndrome
17.4 Allergic Reactions and Rash
17.5 Abnormal Bleeding
17.6 Angle-Closure Glaucoma
17.8 QT Prolongation
17.9 Potential for Cognitive and Motor Impairment
17.10 Use of Concomitant Medications
17.11 Discontinuation of Treatment
17.12 Use in Specific Populations
Sections or subsections omitted from the full prescribing information are not listed.
1 INDICATIONS AND USAGE
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9
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)].
When using Fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax®.
2 DOSAGE AND ADMINISTRATION
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7
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, 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 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)].
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 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.
Periodically reassess to determine the need for maintenance treatment.
Periodically reassess to determine the need for continued treatment.
For Symbyax (mg/day)
Use in Combination
1Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of fluoxetine and olanzapine.
3 mg olanzapine/25 mg fluoxetine
6 mg olanzapine/25 mg fluoxetine
12 mg olanzapine/25 mg fluoxetine
6 mg olanzapine/50 mg fluoxetine
12 mg olanzapine/50 mg fluoxetine
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 capsules 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)].
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)].
3 DOSAGE FORMS AND STRENGTHS
displayName: DOSAGE FORMS & STRENGTHS SECTION
FDA Article Code: 43678-2
• Fluoxetine capsules, USP 20 mg** are white to off white powder filled in size “2” hard gelatin capsules with opaque light blue colored cap and opaque light green colored body imprinted “SG” on cap and “114” on body with black ink.
• Fluoxetine capsules, USP 40 mg** are white to off white powder filled in size “0” hard gelatin capsules with opaque light blue colored cap and opaque white colored body imprinted “SG” on cap and “115” on body with black ink.
**Fluoxetine base equivalent.
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3
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)].
Thioridazine [see WARNINGS AND PRECAUTIONS (5.11) and DRUG INTERACTIONS (7.7, 7.8)]
5 WARNINGS AND PRECAUTIONS
displayName: WARNINGS AND PRECAUTIONS SECTION
FDA Article Code: 43685-7
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 2.
Age Range Drug-Placebo Difference in Number of Cases of Suicidality per
1000 Patients Treated
Increases Compared to Placebo
14 additional cases
5 additional cases
Decreases Compared to Placebo
1 fewer case
6 fewer cases
The concomitant use of fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluoxetine. Fluoxetine should be discontinued before initiating treatment with the MAOI [see CONTRAINDICATIONS (4.1) and DOSAGE AND ADMINISTRATION (2.9, 2.10)].
In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.
Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they may be serious, involving the lung, kidney, or liver. Death has been reported to occur in association with these systemic reactions.
Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.
Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom.
Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued.
In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see USE IN SPECIFIC POPULATIONS (8.4)].
In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In US fluoxetine clinical trials, 0.7% of 10,782 patients reported mania/hypomania [see USE IN SPECIFIC POPULATIONS (8.4)].
In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss [see USE IN SPECIFIC POPULATIONS (8.4)].
In US placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with fluoxetine because of anorexia [see USE IN SPECIFIC POPULATIONS (8.4)].
In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see DRUG INTERACTIONS (7.4)].
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.
In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo.
In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.
Among the most common adverse reactions associated with discontinuation (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 US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5].
Pimozide and thioridazine are contraindicated for use with fluoxetine. Avoid the concomitant use of drugs known to prolong the QT interval. 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) [see DRUG INTERACTIONS (7.7, 7.8) and CLINICAL PHARMACOLOGY (12.3)].
Consider ECG assessment and periodic ECG monitoring if initiating treatment with fluoxetine in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing fluoxetine and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.
Cardiovascular — Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.
Glycemic Control — In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.
6 ADVERSE REACTIONS
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4
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)]
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.
Percentage of Patients Reporting Event
Major Depressive Disorder OCD Bulimia Panic Disorder
1 Incidence less than 1%.
2Includes US data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials.
3Denominator used was for males only (N=690 fluoxetine Major Depressive Disorder; N=410 placebo Major Depressive Disorder; N=116 fluoxetine OCD; N=43 placebo OCD; N=14 fluoxetine bulimia; N=1 placebo bulimia; N=162 fluoxetine panic; N=121 placebo panic).
Body System/Adverse Reaction Fluoxetine(N=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
Vasodilatation 3 2 5 — 2 1 1 —
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
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
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
Impotence3 2 — — — 7 — 1 —
Abnormal ejaculation3 — — 7 — 7 — 2 1
Percentage of Patients Reporting Event
Major Depressive Disorder, OCD,
Bulimia, and Panic Disorder Combined
1 Incidence less than 1%.
2 Includes US data for Major Depressive Disorder, OCD, bulimia, and Panic Disorder clinical trials, plus non-US data for Panic Disorder clinical trials.
Body System/Adverse Reaction
Body as a Whole
Metabolic and Nutritional Disorders
Skin and Appendages
1 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
Major Depressive Disorder
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.
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, hypotension1.
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.
Investigations — Frequent: QT interval prolongation (QTcF ≥450 msec)3.
Nervous System — Frequent: emotional lability; Infrequent: akathisia, ataxia, balance disorder1, bruxism1, 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 bleeding2.
1MedDRA dictionary term from integrated database of placebo controlled trials of 15870 patients, of which 9673 patients received fluoxetine.
2Group 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.
3QT prolongation data are based on routine ECG measurements in clinical trials.
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 fibrillation1, cataract, cerebrovascular accident1, 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 pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, galactorrhea, gynecomastia, heart arrest1, 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, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including Torsades de Pointes–type arrhythmias), vaginal bleeding, and violent behaviors1.
1These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.
7 DRUG INTERACTIONS
displayName: DRUG INTERACTIONS SECTION
FDA Article Code: 34073-7
Thioridazine — Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued, because of the risk of QT Prolongation [see CONTRAINDICATIONS (4.2), WARNINGS AND PRECAUTIONS (5.11), and DRUG INTERACTIONS (7.8)].
In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher Cmax and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine.
Thioridazine administration produces a dose-related prolongation of the QT interval, 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. Coadministration 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 coadministered 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 coadministration 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.
8 USE IN SPECIFIC POPULATIONS
displayName: USE IN SPECIFIC POPULATIONS SECTION
FDA Article Code: 43684-0
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 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/m2 basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/m2basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m2 basis).
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/m2 basis. There was a decrease in bone mineralization and density at both doses, but the overall growth (body weight gain or femur length) was not affected.
Use of fluoxetine in combination with olanzapine in children and adolescents: Safety and efficacy of fluoxetine and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with Bipolar I Disorder. Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 10 years of age have not been established.
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.
9 DRUG ABUSE AND DEPENDENCE
displayName: DRUG ABUSE AND DEPENDENCE SECTION
FDA Article Code: 42227-9
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5
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 nodal rhythm, QT interval prolongation and ventricular arrhythmias, including Torsades de Pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope.
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)].
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 should be administered. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidotes for fluoxetine are known.
A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see DRUG INTERACTIONS (7.7)].
For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert.
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3
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.
12 CLINICAL PHARMACOLOGY
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1
Antagonism of muscarinic, histaminergic, and α1-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.
Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food.
Protein Binding — Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and α1-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important.
Enantiomers — Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state.
Metabolism — Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.
Variability in Metabolism — A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit.
Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions [see DRUG INTERACTIONS (7.7)].
Accumulation and Slow Elimination — The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used [see WARNINGS AND PRECAUTIONS (5.14)]. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks.
The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine.
Renal Disease — In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients.
Geriatric Pharmacokinetics — The disposition of single doses of fluoxetine in healthy elderly subjects (>65 years of age) did not differ significantly from that in younger normal subjects. However, given the long half-life and nonlinear disposition of the drug, a single-dose study is not adequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if they have systemic illness or are receiving multiple drugs for concomitant diseases. The effects of age upon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthy depressed patients (≥60 years of age) who received 20 mg fluoxetine for 6 weeks. Combined fluoxetine plus norfluoxetine plasma concentrations were 209.3 ± 85.7 ng/mL at the end of 6 weeks. No unusual age-associated pattern of adverse reactions was observed in those elderly patients.
Pediatric Pharmacokinetics (children and adolescents) — Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (10 children ages 6 to <13, 11 adolescents ages 13 to <18) diagnosed with Major Depressive Disorder or Obsessive Compulsive Disorder (OCD). Fluoxetine 20 mg/day was administered for up to 62 days. The average steady-state concentrations of fluoxetine in these children were 2-fold higher than in adolescents (171 and 86 ng/mL, respectively). The average norfluoxetine steady-state concentrations in these children were 1.5-fold higher than in adolescents (195 and 113 ng/mL, respectively). These differences can be almost entirely explained by differences in weight. No gender-associated difference in fluoxetine pharmacokinetics was observed. Similar ranges of fluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatric patients (ages 8 to <18) diagnosed with Major Depressive Disorder.
Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in children relative to adults; however, these concentrations were within the range of concentrations observed in the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively following multiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.
13 NONCLINICAL TOXICOLOGY
displayName: NONCLINICAL TOXICOLOGY SECTION
FDA Article Code: 43680-8
Mutagenicity — Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.
Impairment of Fertility — Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m2 basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine [see USE IN SPECIFIC POPULATIONS (8.4)].
14 CLINICAL STUDIES
displayName: CLINICAL STUDIES SECTION
FDA Article Code: 34092-7
Acute treatment of obsessions and compulsions in adults, and children and adolescents (7 to 17 years) with Obsessive Compulsive Disorder (OCD) in 3 short-term placebo-controlled trials [see CLINICAL STUDIES (14.2)].
Acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa in 3 short-term and 1 long-term, placebo-controlled trials [see CLINICAL STUDIES (14.3)].
Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients in 2 short-term, placebo-controlled trials [see CLINICAL STUDIES (14.4)].
Adult — The efficacy of fluoxetine was studied in 5- and 6-week placebo-controlled trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of Major Depressive Disorder. Fluoxetine was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D). Fluoxetine was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor.
Two 6-week controlled studies (N=671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with Major Depressive Disorder. In these studies, fluoxetine produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8. Fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between fluoxetine (12%) and placebo (9%).
A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on fluoxetine 20 mg/day. These patients (N=298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo. At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking fluoxetine compared with those on placebo.
Pediatric (children and adolescents) — The efficacy of fluoxetine 20 mg/day in children and adolescents (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) was studied in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of Major Depressive Disorder.
In both studies independently, fluoxetine produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo.
Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender.
Outcome Classification (%) on CGI Improvement Scale for
Completers in Pool of Two OCD Studies
Outcome Classification Placebo 20 mg 40 mg 60 mg
Worse 8% 0% 0% 0%
No change 64% 41% 33% 29%
Minimally improved 17% 23% 28% 24%
Much improved 8% 28% 27% 28%
Very much improved 3% 8% 12% 19%
Pediatric (children and adolescents) — In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD (DSM-IV), patients received fluoxetine 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks. The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. Fluoxetine produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS).
Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender.
In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo.
Study 1 (N=180 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively.
Study 2 (N=214 randomized) was a 12-week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.
16 HOW SUPPLIED/STORAGE AND HANDLING
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5
17 PATIENT COUNSELING INFORMATION
displayName: SPL UNCLASSIFIED SECTION
FDA Article Code: 42229-5
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine as monotherapy or in combination with olanzapine.
When using fluoxetine and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.
Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking fluoxetine.
When using fluoxetine and olanzapine in combination, also refer to the Medication Guide for Symbyax.
Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.
Nursing Mothers — Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy. Because fluoxetine is excreted in human milk, nursing while taking fluoxetine is not recommended [see USE IN SPECIFIC POPULATIONS (8.3)].
Pediatric Use of Fluoxetine — Fluoxetine is approved for use in pediatric patients with MDD and OCD [see BOX WARNING and WARNINGS AND PRECAUTIONS (5.1)]. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine. [see WARNINGS AND PRECAUTIONS (5.6) and USE IN SPECIFIC POPULATIONS (8.4)].
Pediatric Use of fluoxetine and olanzapine in combination – Safety and efficacy of fluoxetine and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with Bipolar I Disorder [see WARNINGS AND PRECAUTIONS (5.16) and USE IN SPECIFIC POPULATIONS (8.4)].
Symbyax® and Sarafem® are registered trademarks of Eli Lilly.
Vensun Pharmaceuticals, Inc.
Yardley, PA 19067
ScieGen Pharmaceuticals, Inc.
Hauppauge, NY 11788 USA
displayName: SPL MEDGUIDE SECTION
FDA Article Code: 42231-1
Read the Medication Guide that comes with fluoxetine capsules before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.
What is the most important information I should know about fluoxetine capsules?
Fluoxetine capsules and other antidepressant medicines may cause serious side effects, including:
1. Suicidal thoughts or actions:
Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
Watch for these changes and call your healthcare provider right away if you notice:
Pay particular attention to such changes when fluoxetine capsules is started or when the dose is changed.
Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:
acting on dangerous impulses
acting aggressive or violent
thoughts about suicide or dying
new or worse depression
new or worse anxiety or panic attacks
feeling agitated, restless, angry or irritable
an increase in activity or talking more than what is normal for you
other unusual changes in behavior or mood
2. Serotonin Syndrome. This condition can be life-threatening and may include:
coordination problems or muscle twitching (overactive reflexes)
racing heartbeat, high or low blood pressure
sweating or fever
nausea, vomiting, or diarrhea
swelling of the face, tongue, eyes or mouth
rash, itchy welts (hives) or blisters, alone or with fever or joint pain
5. Visual problems:
changes in vision
swelling or redness in or around the eye
severe trouble sleeping
unusually grand ideas
excessive happiness or irritability
talking more or faster than usual
9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:
weakness or feeling unsteady
confusion, problems concentrating or thinking or memory problems
shortness of breath
dizziness or fainting
headache, sweating, nausea, dizziness
electric shock-like sensations, shaking, confusion
Fluoxetine capsules are a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider.
Fluoxetine capsules are used to treat:
Obsessive Compulsive Disorder (OCD)
Depressive episodes associated with Bipolar I Disorder, taken with olanzapine (Zyprexa)
Talk to your healthcare provider if you do not think that your condition is getting better with fluoxetine capsules treatment.
Who should not take fluoxetine capsules?
Do not take fluoxetine capsules if you:
take a Monoamine Oxidase Inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
Do not start fluoxetine capsules if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.
uncontrolled muscle spasms
rapid changes in heart rate or blood pressure
loss of consciousness (pass out)
take the antipsychotic medicine pimozide (Orap®) because this can cause serious heart problems.
Before starting fluoxetine capsules, tell your healthcare provider if you:
Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, buspirone, SSRIs, SNRIs, MAOIs or antipsychotics
Tramadol and fentanyl
Over-the-counter supplements such as tryptophan or St. John’s Wort
Electroconvulsive therapy (ECT)
have kidney problems
have heart problems
have or had seizures or convulsions
have bipolar disorder or mania
have low sodium levels in your blood
have a history of a stroke
have high blood pressure
have or had bleeding problems
are pregnant or plan to become pregnant. It is not known if fluoxetine capsules will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy.
are breast-feeding or plan to breast-feed. Some fluoxetine capsules may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking fluoxetine capsules.
Your healthcare provider or pharmacist can tell you if it is safe to take fluoxetine capsules with your other medicines. Do not start or stop any medicine while taking fluoxetine capsules without talking to your healthcare provider first.
Fluoxetine capsules may be taken with or without food.
If you miss a dose of fluoxetine capsules, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of fluoxetine capsules at the same time.
If you take too much fluoxetine capsules, call your healthcare provider or poison control center right away, or get emergency treatment.
Fluoxetine capsules can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how fluoxetine capsules affects you. Do not drink alcohol while using fluoxetine capsules.
What are the possible side effects of fluoxetine capsules?
Fluoxetine capsules may cause serious side effects, including:
Problems with blood sugar control. People who have diabetes and take fluoxetine capsules may have problems with low blood sugar while taking fluoxetine capsules. High blood sugar can happen when fluoxetine capsules is stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine capsules.
Feeling anxious or trouble sleeping
loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth
feeling tired or fatigued
change in sleep habits
sinus infection or sore throat
tremor or shaking
feeling anxious or nervous
abnormal increase in muscle movement or agitation
urinating more often
heavy menstrual periods
possible slowed growth rate and weight change. Your child’s height and weight should be monitored during treatment with fluoxetine capsules.
CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088.
How should I store fluoxetine capsules?
Keep fluoxetine capsules away from light.
Keep fluoxetine capsules bottle closed tightly.
General information about fluoxetine capsules
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine capsules for a condition for which it was not prescribed. Do not give fluoxetine capsules to other people, even if they have the same condition. It may harm them.
This Medication Guide summarizes the most important information about fluoxetine capsules. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine capsules that is written for healthcare professionals.
For more information about fluoxetine capsules call Vensun Pharmaceuticals, Inc. at 1-800-385-1540.
What are the ingredients in fluoxetine capsules?
Active ingredient: fluoxetine hydrochloride, USP
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.
Symbyax® and Sarafem® are registered trademarks of Eli Lilly and Company.
Mellaril® is a registered trademark of Novartis AG Corporation.
Orap® is a registered trademark of Teva Pharmaceuticals USA.
Coumadin® is a registered trademark of Bristol Myers Squibb.
Jantoven® is a registered trademark of Upsher-Smith Laboratories Inc.
Zyprexa® is a registered trademark of Eli Lilly and Company.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Vensun Pharmaceuticals, Inc.
Yardley, PA 19067
ScieGen Pharmaceuticals, Inc.
Hauppauge, NY 11788 USA
PACKAGE LABEL – PRINCIPAL DISPLAY PANEL
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4