FLUOXETINE- fluoxetine tablet, film coated 
Appco Pharma LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use FLUOXETINE TABLETS safely and effectively. See full prescribing information for FLUOXETINE TABLETS.

FLUOXETINE tablets, for oral use

Initial U.S. Approval: 1987

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 ®.

INDICATIONS AND USAGE

Fluoxetine is a selective serotonin reuptake inhibitor indicated for:

  • Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult and pediatric patients aged 8 to 18 years (1.1)
  • Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in adults and pediatric patients aged 7 to 17 years (1.2)
  • Acute and maintenance treatment of Bulimia Nervosa in adult patients (1.3)
  • Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients (1.4)

DOSAGE AND ADMINISTRATION

IndicationAdultPediatric
MDD (2.1)
20 mg/day in am (initial dose)
10 mg/day 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)
  • 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)

DOSAGE FORMS AND STRENGTHS

Tablets: 10 mg, 20 mg (3)

CONTRAINDICATIONS

  • 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)

WARNINGS AND PRECAUTIONS

  • Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1)
  • Serotonin Syndrome:Serotonin syndrome has been reported with SSRIs and SNRIs, including with fluoxetine, both when taken alone, but especially when coadministered 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 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 (4.2,5.11,7.7,7.8,10.1)
  • 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)

ADVERSE REACTIONS

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 Appco Pharma LLC, at 1-855-672-7726 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

  • Monoamine Oxidase Inhibitors (MAOIs):(2.9,2.10,4.1,5.2)
  • Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7)
  • Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued (5.2,7.7)
  • CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2)
  • Benzodiazepines: Diazepam—increased t ½, 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)

USE IN SPECIFIC POPULATIONS

  • 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.
  • Hepatic Impairment: Lower or less frequent dosing may be appropriate in patients with cirrhosis (8.6)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 1/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder

1.2 Obsessive Compulsive Disorder

1.3 Bulimia Nervosa

1.4 Panic Disorder

2 DOSAGE AND ADMINISTRATION

2.1 Major Depressive Disorder

2.2 Obsessive Compulsive Disorder

2.3 Bulimia Nervosa

2.4 Panic 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 CONTRAINDICATIONS

4.1 Monoamine Oxidase Inhibitors (MAOIs)

4.2 Other Contraindications

5 WARNINGS AND PRECAUTIONS

5.1 Clinical Worsening and Suicide Risk

5.2 Serotonin Syndrome

5.3 Allergic Reactions and Rash

5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania

5.5 Seizures

5.6 Altered Appetite and Weight

5.7 Abnormal Bleeding

5.8 Angle-closure Glaucoma

5.9 Hyponatremia

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 (MAOIs)

7.2 CNS Acting Drugs

7.3 Serotonergic Drugs

7.4 Drugs that Interfere with Hemostasis (eg, 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

8.1 Pregnancy

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

9.3 Dependence

10 OVERDOSAGE

10.1 Human Experience

10.2 Animal Experience

10.3 Management of Overdose

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

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 Clinical Worsening and Suicide Risk

17.3 Serotonin Syndrome

17.4 Allergic Reactions and Rash

17.5 Abnormal Bleeding

17.6 Angle-closure Glaucoma

17.7 Hyponatremia

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.

FULL PRESCRIBING INFORMATION

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 ®.

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder

Fluoxetine is indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to 18 years [see Clinical Studies (14.1)].

The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods should periodically be re-evaluated [see Dosage and Administration (2.1)].

1.2 Obsessive Compulsive Disorder

Fluoxetine is indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD) [see Clinical Studies (14.2)].

The effectiveness of fluoxetine in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.2)].

1.3 Bulimia Nervosa

Fluoxetine is indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa [see Clinical Studies (14.3)].
The physician who elects to use fluoxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)].

1.4 Panic Disorder

Fluoxetine is indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [see Clinical Studies (14.4)].

The effectiveness of fluoxetine in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials. Therefore, the physician who elects to use fluoxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.4)].

2 DOSAGE AND ADMINISTRATION

2.1 Major Depressive Disorder

Initial Treatment

Adult

In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 mg/day to 80 mg/day. Studies comparing fluoxetine 20 mg/day, 40 mg/day, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.

A dose increase may be considered after several weeks if insufficient clinical improvement is observed. Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day.

Pediatric (Children and Adolescents)

In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 mg/day to 20 mg/day [see Clinical Studies (14.1)]. Treatment should be initiated with a dose of 10 mg/day or 20 mg/day. After 1 week at 10 mg/day, the dose should be increased 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. A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed.

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.

Maintenance/Continuation/Extended Treatment

It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Daily Dosing

Systematic evaluation of fluoxetine in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day [see Clinical Studies (14.1)].

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

In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20 mg, 40 mg, or 60 mg of fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose. Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer.

Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon). A dose range of 20 mg/day to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day.

Pediatric (Children and Adolescents)

In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 mg/day to 60 mg/day [see Clinical Studies (14.2)].

In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day. After 2 weeks, the dose should be increased to 20 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 mg/day to 60 mg/day is recommended

In lower weight children, treatment should be initiated with a dose of 10 mg/day. Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed. A dose range of 20 mg/day to 30 mg/day is recommended. Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg.

Maintenance/Continuation Treatment

While there are no systematic studies that answer the question of how long to continue fluoxetine, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of fluoxetine after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit. However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment.

2.3 Bulimia Nervosa

Initial Treatment

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 mg 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. Consequently, the recommended dose is 60 mg/day, administered 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.

Maintenance/Continuation Treatment

Systematic evaluation of continuing fluoxetine 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking fluoxetine 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment [see Clinical Studies (14.3)]. Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

2.4 Panic Disorder

Initial Treatment

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 mg/day to 60 mg/day [see Clinical Studies (14.4)]. Treatment should be initiated with a dose of 10 mg/day. After one week, the dose should be increased to 20 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day.

A dose increase may be considered 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.

Maintenance/Continuation Treatment

While there are no systematic studies that answer the question of how long to continue fluoxetine, Panic Disorder is a chronic condition and it is reasonable to consider continuation for a responding patient. Nevertheless, patients should be periodically reassessed to determine the need for continued treatment.

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)].

Geriatrics

A lower or less frequent dosage should be considered for the elderly [see Use in Specific Populations (8.5)].

Hepatic Impairment

As with many other medications, a lower or less frequent dosage should be used 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)].

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 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 5 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

Fluoxetine Tablets, USP are available containing fluoxetine hydrochloride, USP equivalent to 10 mg or 20 mg of fluoxetine.

  • The 10 mg 1 tablets are white to off white colored, capsule shaped, film coated, scored tablets, debossed with “A” and “C” separated by break line on one side and “402” on other side.
  • The 20 mg 1 tablets are white to off white colored, capsule shaped, film coated, scored tablets, debossed with “A” and “C” separated by break line on one side and “403” on other side.

1
Fluoxetine base equivalent.

4 CONTRAINDICATIONS

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

4.1 Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with fluoxetine or within 5 weeks of stopping treatment with fluoxetine is contraindicated because of an increased risk of serotonin syndrome. The use of fluoxetine within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [see Dosage and Administration (2.9) and Warnings and Precautions (5.2)].

Starting fluoxetine in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [see Dosage and Administration (2.10) and Warnings and Precautions (5.2)].

4.2 Other Contraindications

The use of fluoxetine is contraindicated with the following:

  • Pimozide [see Warnings and Precautions (5.11) and Drug Interactions (7.7,7.8)]
  • Thioridazine [see Warnings and Precautions (5.11) and Drug Interactions (7.7,7.8)]

Pimozide and thioridazine prolong the QT interval. Fluoxetine can increase the levels of pimozide and thioridazine through inhibition of CYP2D6. Fluoxetine can also prolong the QT interval.

5 WARNINGS AND PRECAUTIONS

When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax ®.

5.1 Clinical Worsening and Suicide Risk

Patients with Major Depressive Disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with Major Depressive Disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

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.

Table 2: Suicidality per 1000 Patients Treated
Age Range
Drug-Placebo Difference in Number of Cases of Suicidality per
1000 Patients Treated

Increases Compared to Placebo
<18
14 additional cases
18 to 24
5 additional cases
Decreases Compared to Placebo
25 to 64
1 fewer case
≥65
6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the numberwas not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, ie, beyond several months.However, there is substantial evidence from placebo-controlled maintenance trials in adults withdepression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriatelyand observed closely for clinical worsening, suicidality, and unusual changes in behavior, especiallyduring the initial few months of a course of drug therapy, or at times of dose changes, either increasesor decreases.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness,impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adultand pediatric patients being treated with antidepressants for Major Depressive Disorder as well as for other indications,both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptomsand either the worsening of depression and/or the emergence of suicidal impulses has not beenestablished, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuingthe medication, in patients whose depression is persistently worse, or who are experiencing emergentsuicidality or symptoms that might be precursors to worsening depression or suicidality, especially ifthese symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly asis feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.15)].

Families and caregivers of patients being treated with antidepressants for MDD or other indications,both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for theemergence of agitation, irritability, unusual changes in behavior, and the other symptoms describedabove, as well as the emergence of suicidality, and to report such symptoms immediately to health careproviders. Such monitoring should include daily observation by families and caregivers. Prescriptionsfor fluoxetine should be written for the smallest quantity of tablets consistent with good patientmanagement, in order to reduce the risk of overdose.

It should be noted that fluoxetine is approved in the pediatric population only for Major Depressive Disorder and Obsessive Compulsive Disorder.

5.2 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIsand SSRIs, including with fluoxetine, alone but particularly with concomitant use of other serotonergicdrugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone,amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin (in particular,MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid andintravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (eg, agitation, hallucinations,delirium, coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis,flushing, hyperthermia), neuromuscular symptoms (eg, tremor, rigidity, myoclonus, hyperreflexia,incoordination), seizures, and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Patientsshould be monitored for the emergence of serotonin syndrome.

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 linezolidor intravenous methylene blue. All reports with methylene blue that provided information on the routeof administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reportsinvolved the administration of methylene blue by other routes (such as oral tablets or local tissueinjection) or at lower doses. There may be circumstances when it is necessary to initiate treatmentwith an MAOI such as linezolid or intravenous methylene blue in a patient taking fluoxetine. Fluoxetineshould be discontinued before initiating treatment with the MAOI [see Contraindications (4.1) andDosage and Administration (2.9,2.10)].

If concomitant use of fluoxetine with other serotonergic drugs, ie, triptans, tricyclic antidepressants,fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, and St. John’s Wort, is clinicallywarranted, patients should be made aware of a potential increased risk for serotonin syndrome,particularly during treatment initiation and dose increases.

Treatment with fluoxetine and any concomitant serotonergic agents should be discontinuedimmediately if the above events occur and supportive symptomatic treatment should be initiated

5.3 Allergic Reactions and Rash

In U.S. fluoxetine clinical trials, 7% of 10,782 patients developed various types of rashes and/or urticaria.Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third werewithdrawn from treatment because of the rash and/or systemic signs or symptoms associated with therash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema,carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminaseelevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctivetreatment with antihistamines or steroids, and all patients experiencing these reactions were reportedto recover completely

In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemicillness. In neither patient was there an unequivocal diagnosis, but one was considered to havea leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was consideredvariously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromessuggestive of serum sickness.

Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis and includinglupus-like syndrome, have developed in patients with rash. Although these reactions are rare, they maybe serious, involving the lung, kidney, or liver. Death has been reported to occur in association withthese systemic reactions.

Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone andin combination, have been reported.

Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, havebeen 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 differentetiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basisfor these reactions has not been identified. Upon the appearance of rash or of other possibly allergicphenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued.

5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania

A major depressive episode may be the initial presentation of Bipolar Disorder. It is generally believed(though not established in controlled trials) that treating such an episode with an antidepressant alonemay increase the likelihood of precipitation of a mixed/manic episode in patients at risk for BipolarDisorder. Whether any of the symptoms described for clinical worsening and suicide risk representsuch a conversion is unknown. However, prior to initiating treatment with an antidepressant, patientswith depressive symptoms should be adequately screened to determine if they are at risk for BipolarDisorder; such screening should include a detailed psychiatric history, including a family history ofsuicide, Bipolar Disorder, and depression.

In U.S. placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patientstreated with fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania hasalso been reported in a small proportion of patients with Major Affective Disorder treated with othermarketed drugs effective in the treatment of Major Depressive Disorder [see Use in Specific Populations (8.4)].

In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patientstreated with fluoxetine and no patients treated with placebo. No patients reported mania/hypomania inU.S. placebo-controlled clinical trials for bulimia. In U.S. fluoxetine clinical trials, 0.7% of 10,782 patientsreported mania/hypomania [see Use in Specific Populations (8.4)].

5.5 Seizures

In U.S. placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly havingbeen seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treatedwith placebo. No patients reported convulsions in U.S. placebo-controlled clinical trials for either OCD orbulimia. In U.S. fluoxetine clinical trials, 0.2% of 10,782 patients reported convulsions. The percentageappears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder.Fluoxetine should be introduced with care in patients with a history of seizures.

5.6 Altered Appetite and Weight

Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirableresult of treatment with fluoxetine.

In U.S. placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with fluoxetine and 2% ofpatients 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 rarelyhave patients discontinued treatment with fluoxetine because of anorexia or weight loss [see Use inSpecific Populations (8.4)].

In U.S. 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 discontinuedtreatment with fluoxetine because of anorexia [see Use in Specific Populations (8.4)].

In U.S. placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treatedwith fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treatedwith placebo in the 16-week double-blind trial. Weight change should be monitored during therapy.

5.7 Abnormal Bleeding

SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant useof aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to thisrisk. Case reports and epidemiological studies (case-control and cohort design) have demonstratedan association between use of drugs that interfere with serotonin reuptake and the occurrence ofgastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged fromecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients shouldbe 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)].

5.8 Angle-closure Glaucoma

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including fluoxetine tablets maytrigger an angle-closure attack in a patient with anatomically narrow angles who does not have apotent iridectomy.

5.9 Hyponatremia

Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when fluoxetine was discontinued. Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs. Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see Use in Specific Populations (8.5)]. Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

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.

5.10 Anxiety and Insomnia

In U.S. placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with fluoxetine and 7%to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In U.S. placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated withfluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treatedwith fluoxetine and in 7% of patients treated with placebo.

In U.S. placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patientstreated with fluoxetine 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness werereported, 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 twicethat for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reactionassociated with discontinuation) in U.S. placebo-controlled fluoxetine clinical trials were anxiety (2% inOCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [ see Table 5].

5.11 QT Prolongation

Postmarketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with fluoxetine. Fluoxetine should be used with caution in patients with congenital long QT syndrome; a previous history of QT prolongation; a family history of long QT syndrome or sudden cardiac death; and other conditions that predispose to QT prolongation and ventricular arrhythmia. Such conditions include concomitant use of drugs that prolong the QT interval; hypokalemia or hypomagnesemia; recent myocardial infarction, uncompensated heart failure, bradyarrhythmias, and other significant arrhythmias; and conditions that predispose to increased fluoxetine exposure (overdose, hepatic impairment, use of CYP2D6 inhibitors, CYP2D6 poor metabolizer status, or use of other highly protein-bound drugs). Fluoxetine is primarily metabolized by CYP2D6 [see Contraindications (4.2), Drug Interactions (7.7,7.8), Overdose (10.1), and Clinical Pharmacology (12.3)].

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 (eg, ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (eg, erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class IA antiarrhythmic medications (eg, quinidine, procainamide); Class III antiarrhythmics (eg, amiodarone, sotalol); and others (eg, 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

5.12 Use in Patients with Concomitant Illness

Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution isadvisable in using fluoxetine in patients with diseases or conditions that could affect metabolism orhemodynamic responses.

Cardiovascular

Fluoxetine has not been evaluated or used to any appreciable extent in patients witha recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses weresystematically excluded from clinical studies during the product’s premarket testing. However, theelectrocardiograms of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; noconduction abnormalities that resulted in heart block were observed. The mean heart rate was reducedby approximately 3 beats/min.

Glycemic Control

In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia hasoccurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuationof the drug. As is true with many other types of medication when taken concurrently by patientswith diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy withfluoxetine is instituted or discontinued.

5.13 Potential for Cognitive and Motor Impairment

As with any CNS-active drug, fluoxetine has the potential to impair judgment, thinking, or motor skills.Patients should be cautioned about operating hazardous machinery, including automobiles, until theyare reasonably certain that the drug treatment does not affect them adversely.

5.14 Long Elimination Half-Life

Because of the long elimination half-lives of the parent drug and its major active metabolite, changesin dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration tofinal dose and withdrawal from treatment. This is of potential consequence when drug discontinuationis required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine followingthe discontinuation of fluoxetine [see Clinical Pharmacology (12.3) ].

5.15 Discontinuation Adverse Reactions

During marketing of fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adversereactions occurring upon discontinuation of these drugs, particularly when abrupt, including thefollowing: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (eg, paresthesiassuch as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability,insomnia, and hypomania. While these reactions are generally self-limiting, there have been reportsof serious discontinuation symptoms. Patients should be monitored for these symptoms whendiscontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessationis recommended whenever possible. If intolerable symptoms occur following a decrease in the dose orupon discontinuation of treatment, then resuming the previously prescribed dose may be considered.Subsequently, the physician may continue decreasing the dose but at a more gradual rate. Plasmafluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which mayminimize the risk of discontinuation symptoms with this drug.

5.16 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 ®.

6 ADVERSE REACTIONS

When using fluoxetine and olanzapine in combination, also refer to the Adverse Reactions section of the package insert for Symbyax ®.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect or predict the rates observed in practice.

Multiple doses of fluoxetine have been administered to 10,782 patients with various diagnoses in U.S. clinical trials. In addition, there have been 425 patients administered fluoxetine in panic clinical trials.Adverse reactions were recorded by clinical investigators using descriptive terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse reactions without first grouping similar types of reactions into a limited (i.e., reduced) number of standardized reaction categories.

In the tables and tabulations that follow, COSTART Dictionary terminology has been used to classify reported adverse reactions. 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. It is important to emphasize that reactions reported during therapy were not necessarily caused by it.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

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 U.S. controlled clinical trials and Panic Disorder in U.S. plus non-U.S. 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 U.S. Major Depressive Disorder, OCD, and bulimia controlled clinical trials and U.S. plus non-U.S. 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 U.S. data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non- U.S. data for Panic Disorder clinical trials.
Denominator used was for males only (N = 690 fluoxetine Major Depressive Disorder; N = 410 placebo Major Depressive Disorder; N = 116 fluoxetine OCD; N = 4 3 placebo OCD; N = 14 fluoxetine bulimia; N = 1 placebo bulimia; N = 162 fluoxetine panic; N = 121 placebo panic).
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
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 U.S. data for Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non- U.S. data for Panic Disorder clinical trials.
Percentage of Patients Reporting Event
Major Depressive Disorder, OCD, Bulimia, and Panic Disorder Combined
Body System/Adverse ReactionFluoxetine
(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-U.S. 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 U.S. Major Depressive Disorder, OCD, Bulimia, and Panic Disorder clinical trials, plus non- U.S. 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 Table 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Table 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 U.S. 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 arethose occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to1/1000 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.

1MedDRA dictionary term from integrated database of placebo controlled trials of 15,870 patients, ofwhich 9673 received fluoxetine

2Group term that includes individual MedDRA terms: cervix hemorrhage uterine, dysfunctional uterinebleeding, 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 postapproval use of fluoxetine. Becausethese reactions are reported voluntarily from a population of uncertain size, it is difficult to reliablyestimate their frequency or evaluate a causal relationship to drug exposure.

Voluntary reports of adverse reactions temporally associated with fluoxetine that have been receivedsince 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 tongueprotrusion reported to develop in a 77-year-old female after 5 weeks of fluoxetine therapy and whichcompletely 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-relatedhemolytic anemia, kidney failure, memory impairment, movement disorders developing inpatients with risk factors including drugs associated with such reactions and worsening of preexistingmovement disorders, optic neuritis, pancreatitis 1, pancytopenia, pulmonary embolism, pulmonaryhypertension, QT prolongation, Stevens-Johnson syndrome, thrombocytopenia 1, thrombocytopenicpurpura, ventricular tachycardia (including Torsades de Pointes-type arrhythmias), vaginal bleeding,and violent behaviors 1.

1These terms represent serious adverse events, but do not meet the definition for adverse drugreactions. They are included here because of their seriousness.

7 DRUG INTERACTIONS

As with all drugs, the potential for interaction by a variety of mechanisms (eg, pharmacodynamic,pharmacokinetic drug inhibition or enhancement, etc) is a possibility.

7.1 Monoamine Oxidase Inhibitors (MAOIs)

[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 theconcomitantly administered drugs, using conservative titration schedules, and monitoring of clinicalstatus [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 (eg, NSAIDS, Aspirin, Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of thecase-control and cohort design that have demonstrated an association between use of psychotropicdrugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding havealso shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Alteredanticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministeredwith warfarin. Patients receiving warfarin therapy should be carefully monitored whenfluoxetine 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. 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 (eg, 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 ®.

7.8 Drugs That Prolong the QT Interval

Do not use fluoxetine in combination with thioridazine or pimozide. Use fluoxetine with caution incombination with other drugs that cause QT prolongation. These include: specific antipsychotics(eg, ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (eg,erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class IA antiarrhythmic medications (eg,quinidine, procainamide); Class III antiarrhythmics (eg, amiodarone, sotalol); and others (eg,pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate,probucol or tacrolimus). Fluoxetine is primarily metabolized by CYP2D6. Concomitant treatment withCYP2D6 inhibitors can increase the concentration of fluoxetine. Concomitant use of other highly protein-bounddrugs can increase the concentration of fluoxetine [see Contraindications (4.2), Warnings andPrecautions (5.11), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS

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 mg/kg/day 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 fluoxetinecrosses the placenta and because of the possibility that fluoxetine may have adverse effects on thenewborn, fluoxetine should be used during labor and delivery only if the potential benefit justifiesthe 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 infantwere 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 offluoxetine 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 Boxed 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 mg/kg/day, 10 mg/kg/day, 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 the 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 mg/kg/day, 10 mg/kg/day, 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, were 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 a 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.

8.5 Geriatric Use

U.S. fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 yearsof age. The efficacy in geriatric patients has been established [see Clinical Studies (14.1)]. Forpharmacokinetic information in geriatric patients, [see Clinical Pharmacology (12.4)]. No overalldifferences in safety or effectiveness were observed between these subjects and younger subjects,and other reported clinical experience has not identified differences in responses between theelderly 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 significanthyponatremia in elderly patients, who may be at greater risk for this adverse reaction [seeWarnings and Precautions (5.9)].

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. Cautionis advised when using fluoxetine in patients with diseases or conditions that could affect itsmetabolism [see Dosage and Administration (2.7) and Clinical Pharmacology (12.4)].

9 DRUG ABUSE AND DEPENDENCE

9.3 Dependence

Fluoxetine has not been systematically studied, in animals or humans, for its potential for abuse,tolerance, or physical dependence. While the premarketing clinical experience with fluoxetinedid not reveal any tendency for a withdrawal syndrome or any drug seeking behavior, theseobservations were not systematic and it is not possible to predict on the basis of this limitedexperience the extent to which a CNS active drug will be misused, diverted, and/or abused oncemarketed. Consequently, physicians should carefully evaluate patients for history of drug abuseand follow such patients closely, observing them for signs of misuse or abuse of fluoxetine (eg,development of tolerance, incrementation of dose, drug-seeking behavior).

10 OVERDOSAGE

10.1 Human Experience

Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa1999). Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs,reported from this population, there were 195 deaths.

Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fataloutcome, 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 commonsigns and symptoms associated with nonfatal overdosage were seizures, somnolence, nausea,tachycardia, and vomiting. The largest known ingestion of fluoxetine hydrochloride in adult patientswas 8 g in a patient who took fluoxetine alone and who subsequently recovered. However, in anadult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated withlethal outcome, but causality has not been established.

Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involvingfluoxetine alone or in combination with other drugs. Six patients died, 127 patients completelyrecovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One ofthe 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 fluoxetinedaily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drugingestion or other methods of suicide complicated all 6 overdoses in children that resulted infatalities. 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, andventricular arrhythmias, including Torsades de Pointes-type arrhythmias), hypotension, mania,neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope.

10.2 Animal Experience

Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose. However, animal experiments can provide useful insights into possible treatment strategies.

The oral median lethal dose in rats and mice was found to be 452 mg/kg and 248 mg/kg, respectively. Acute high oral doses produced hyperirritability and convulsions in several animal species.

Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures. Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam. In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically.


In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals. Tachycardia and an increase in blood pressure were observed. Consequently, the value of the ECG in predicting cardiac toxicity is unknown. Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see Overdosage (10.3)].

10.3 Management of Overdose

For current information on the management of fluoxetine overdose, contact a certified poison control center (1-800-222-1222 or www.poison.org). Treatment should consist of those general measures employed in the management of overdosage with any drug. Consider the possibility of multi-drug overdose.

Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs.Use general supportive and symptomatic measures. Induction of emesis is not recommended.

Activated charcoal 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. Nospecific antidotes for fluoxetine are known.

A specific caution involves patients who are taking or have recently taken fluoxetine and mightingest excessive quantities of a TCA. In such a case, accumulation of the parent tricyclic and/or anactive metabolite may increase the possibility of clinically significant sequelae and extend the timeneeded 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.

11 DESCRIPTION

Fluoxetine is a selective serotonin reuptake inhibitor for oral administration. It is also marketed for the treatment of premenstrual dysphoric disorder (Sarafem ®, fluoxetine hydrochloride). It is designated (±)- N-methyl-3-phenyl-3-[(α,α,α-trifluoro- p-tolyl)oxy]propylamine hydrochloride and has the empirical formula of C 17H 18F 3NO•HCl. Its molecular weight is 345.79. The structural formula is:

Checmical Structure

Fluoxetine hydrochloride is a white or almost white powder.

Each tablet contains fluoxetine hydrochloride equivalent to 10 mg or 20 mg of fluoxetine. In addition, each tablet also contains the following inactive ingredients: hypromellose, magnesium stearate, maize starch, mannitol, microcrystalline cellulose, polyethylene glycol, polysorbate, povidone and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibitionof CNS neuronal uptake of serotonin.

12.2 Pharmacodynamics

Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptakeof serotonin into human platelets. Studies in animals also suggest that fluoxetine is a muchmore potent uptake inhibitor of serotonin than of norepinephrine.

Antagonism of muscarinic,histaminergic, and α 1-adrenergic receptors has been hypothesized to be associated with variousanticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds tothese and other membrane receptors from brain tissue much less potently in vitro than do thetricyclic drugs.

12.3 Pharmacokinetics

Systemic Bioavailability

In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 ng/mL to 55 ng/mL are observed after 6 to 8 hours.

The tablet and capsule dosage forms of fluoxetine are bioequivalent. 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 ng/mL to 1000 ng/mL, approximately 94.5% offluoxetine is bound in vitro to human serum proteins, including albumin and α 1-glycoprotein. Theinteraction 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-fluoxetineenantiomers. In animal models, both enantiomers are specific and potent serotonin uptakeinhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer iseliminated 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 ofother unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed bydemethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitorof serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine issignificantly less potent than the parent drug in the inhibition of serotonin uptake. The primary routeof 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 drugmetabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as “poormetabolizers” of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involvinglabeled 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 inthese poor metabolizers appears normal. When compared with normal metabolizers, the total sumat steady-state of the plasma concentrations of the 4 active enantiomers was not significantlygreater among poor metabolizers. Thus, the net pharmacodynamic activities were essentiallythe same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolismof fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather thanincreasing without limit.

Because fluoxetine’s metabolism, like that of a number of other compounds including TCAs andother selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized bythis 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-lifeof 1 to 3 days after acute administration and 4 to 6 days after chronic administration) andits active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronicadministration), leads to significant accumulation of these active species in chronic use anddelayed 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 of91 ng/mL to 302 ng/mL and norfluoxetine in the range of 72 ng/mL to 258 ng/mL have been observed. Plasmaconcentrations of fluoxetine were higher than those predicted by single-dose studies, becausefluoxetine’s metabolism is not proportional to dose. Norfluoxetine, however, appears to have linearpharmacokinetics. Its mean terminal half-life after a single dose was 8.6 days and after multipledosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4to 5 weeks.

The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosingis stopped, active drug substance will persist in the body for weeks (primarily depending onindividual patient characteristics, previous dosing regimen, and length of previous therapy atdiscontinuation). This is of potential consequence when drug discontinuation is required orwhen drugs are prescribed that might interact with fluoxetine and norfluoxetine following thediscontinuation of fluoxetine.

12.4 Specific Populations

Liver disease

As might be predicted from its primary site of metabolism, liver impairment canaffect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a studyof cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen insubjects without liver disease; norfluoxetine elimination was also delayed, with a mean durationof 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. Thissuggests that the use of fluoxetine in patients with liver disease must be approached with caution.If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should beused [see Dosage and Administration (2.7) and Use in Specific Populations (8.6)].

Renal Disease

In depressed patients on dialysis (N = 12), fluoxetine administered as 20 mgonce daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrationscomparable with those seen in patients with normal renal function. While the possibility existsthat renally excreted metabolites of fluoxetine may accumulate to higher levels in patients withsevere renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renallyimpaired patients.

Geriatric Pharmacokinetics

The disposition of single doses of fluoxetine in healthy elderlysubjects (> 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 notadequate to rule out the possibility of altered pharmacokinetics in the elderly, particularly if theyhave systemic illness or are receiving multiple drugs for concomitant diseases. The effects of ageupon the metabolism of fluoxetine have been investigated in 260 elderly but otherwise healthydepressed patients (≥ 60 years of age) who received 20 mg fluoxetine for 6 weeks. Combinedfluoxetine plus norfluoxetine plasma concentrations were 209.3 ng/mL ± 85.7 ng/mL at the end of 6weeks. No unusual age-associated pattern of adverse reactions was observed in those elderlypatients.

Pediatric Pharmacokinetics (Children and Adolescents)

Fluoxetine pharmacokinetics wereevaluated 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 higherthan in adolescents (171 ng/mL and 86 ng/mL, respectively). The average norfluoxetine steady-stateconcentrations in these children were 1.5-fold higher than in adolescents (195 ng/mL 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 offluoxetine and norfluoxetine plasma concentrations were observed in another study in 94 pediatricpatients (ages 8 to < 18) diagnosed with Major Depressive Disorder..

Higher average steady-state fluoxetine and norfluoxetine concentrations were observed in childrenrelative to adults; however, these concentrations were within the range of concentrations observedin the adult population. As in adults, fluoxetine and norfluoxetine accumulated extensively followingmultiple oral dosing; steady-state concentrations were achieved within 3 to 4 weeks of daily dosing.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

The dietary administration of fluoxetine to rats and mice for 2 years at doses ofup to 10 mg/kg/day and 12 mg/kg/day, respectively [approximately 1.2 and 0.7 times, respectively, the maximum recommended human dose (MRHD)of 80 mg on a mg/m 2 basis], produced no evidence of carcinogenicity.

Mutagenicity

Fluoxetine and norfluoxetine have been shown to have no genotoxic effects basedon 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 bonemarrow cells.

Impairment of fertility

Two fertility studies conducted in adult rats at doses of up to 7.5 mg/kg/day and12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m 2 basis) indicated thatfluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen whenjuvenile rats were treated with fluoxetine [see Use in Specific Populations (8.4)].

13.2 Animal Toxicology and/or Pharmacology

Phospholipids are increased in some tissues of mice, rats, and dogs given fluoxetine chronically.This effect is reversible after cessation of fluoxetine treatment. Phospholipid accumulationin animals has been observed with many cationic amphiphilic drugs, including fenfluramine,imipramine, and ranitidine. The significance of this effect in humans is unknown.

14 CLINICAL STUDIES

When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax ®.

14.1 Major Depressive Disorder

Daily Dosing

Adult

The efficacy of fluoxetine was studied in 5- and 6-week placebo-controlled trials withdepressed adult and geriatric outpatients (≥18 years of age) whose diagnoses correspondedmost closely to the DSM-III (currently DSM-IV) category of Major Depressive Disorder. Fluoxetine was shown to besignificantly 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 subscoresfor depressed mood, sleep disturbance, and the anxiety subfactor.

Two 6-week controlled studies (N = 671, randomized) comparing fluoxetine 20 mg and placebohave shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients ( ≥60 yearsof age) with Major Depressive Disorder. In these studies, fluoxetine produced a significantly higher rate of response andremission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpointHAM-D score of ≤ 8. Fluoxetine was well tolerated and the rate of treatment discontinuations dueto adverse reactions did not differ between fluoxetine (12%) and placebo (9%).

A study was conducted involving depressed outpatients who had responded (modified HAMD-17score of ≤ 7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder byDSM-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 (definedas 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 andadolescents (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 whosediagnoses 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 changeon the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpointthan did placebo.
Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness onthe basis of age or gender.

14.2 Obsessive Compulsive Disorder

Adult

The effectiveness of fluoxetine for the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in two 13-week, multicenter, parallel-group studies (studies 1 and 2) of adult outpatients who received fixed fluoxetine doses of 20 mg/day, 40 mg/day, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo. Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26. In Study 1, patients receiving fluoxetine experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. In Study 2, patients receiving fluoxetine experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients. While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups. The following provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined:

Table 6: Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies
Fluoxetine
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%

Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

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 mg/day 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.

14.3 Bulimia Nervosa

The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel-group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8-week studies received either 20 mg/day or 60 mg/day of fluoxetine or placebo in the morning. Patients in the 16-week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these 3 studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg versus placebo was present as early as week 1 and persisted throughout each study. The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these 3 studies, the treatment effect, as measured by differences between fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies. Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging.

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.

14.4 Panic Disorder

The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia.

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 mg/day 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 mg/day 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

16.1 How Supplied

Fluoxetine Tablets, US, are available containing fluoxetine hydrochloride, USP equivalent to 10 mg or 20 mg of fluoxetine.

The 10 mg tablets are white to off white colored, capsule shaped, film coated, scored tablets, debossed with “A” and “C” separated by break line on one side and “402” on other side. They are available as follows:

NDC 55801-402-01
bottles of 30 tablets

NDC 55801-402-02
bottles of 1000 tablets

The 20 mg tablets are white to off white colored, capsule shaped, film coated, scored tablets, debossed with “A” and “C” separated by break line on one side and “403” on other side. They are available as follows:

NDC 55801-403-01
bottles of 30 tablets

NDC 55801-403-02
bottles of 1000 tablets

16.2 Storage and Handling

Store at 20° to 25°C (68°F to 77°F) [See USP Controlled Room Temperature].

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure

PHARMACIST: Dispense a Medication Guide with each prescription.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).
Patients should be advised of the following issues and asked to alert their prescriber if these occur whiletaking fluoxetine as monotherapy. When using fluoxetine and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax ® .

17.1 General Information

Healthcare providers should instruct their patients to read the Medication Guide before starting therapywith fluoxetine tablets and to reread it each time the prescription is renewed.

Healthcare providers should inform patients, their families, and their caregivers about the benefits andrisks 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 MedicationGuide and should assist them in understanding its contents. Patients should be given the opportunity todiscuss 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 theseoccur while taking fluoxetine tablets.

When using fluoxetine and olanzapine in combination, also refer to the Medication Guide for Symbyax ®.

17.2 Clinical Worsening and Suicide Risk

Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety,agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotorrestlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, andsuicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up ordown. Families and caregivers of patients should be advised to look for the emergence of such symptomson a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’sprescriber or health professional, especially if they are severe, abrupt in onset, or were not part of thepatient’s presenting symptoms. Symptoms such as these may be associated with an increased risk forsuicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in themedication [see Boxed Warning and Warnings and Precautions (5.1)].

17.3 Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of fluoxetine and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamines, and St. John’s Wort [see Contraindications (4.1), Warnings and Precautions (5.2), and Drug Interactions (7.3)].


Patients should be advised of the signs and symptoms associated with serotonin syndrome that may include mental status changes (eg, agitation, hallucinations, delirium, and coma), autonomic instability (eg, tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (eg, tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea). Patients should be cautioned to seek medical care immediately if they experience these symptoms.

17.4 Allergic Reactions and Rash

Patients should be advised to notify their physician if they develop a rash or hives [see Warnings andPrecautions (5.3)]. Patients should also be advised of the signs and symptoms associated with a severeallergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients shouldbe cautioned to seek medical care immediately if they experience these symptoms.

17.5 Abnormal Bleeding

Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, orother drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotoninreuptake and these agents have been associated with an increased risk of bleeding [see Warnings andPrecautions (5.7) and Drug Interactions (7.4)]. Patients should be advised to call their doctor if theyexperience any increased or unusual bruising or bleeding while taking fluoxetine.

17.6 Angle-closure Glaucoma

Patients should be advised that taking fluoxetine tablets can cause mild pupillary dilation, which in susceptibleindividuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost alwaysopen-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively withiridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to beexamined to determine whether they are susceptible to angle closure, and have a prophylactic procedure(eg, iridectomy), if they are susceptible [see Warning and Precautions (5.8)].

17.7 Hyponatremia

Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIsand SSRIs, including fluoxetine. Signs and symptoms of hyponatremia include headache, difficultyconcentrating, 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 [see Warnings and Precautions (5.9)].

17.8 QT Prolongation

Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsadesde Pointes have been reported in patients treated with fluoxetine. Signs and symptoms of ventriculararrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicateserious cardiac arrhythmia [see Warnings and Precautions (5.11)].

17.9 Potential for Cognitive and Motor Impairment

Fluoxetine may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a caror operating hazardous machinery until they are reasonably certain that their performance is not affected [see Warnings and Precautions (5.13)].

17.10 Use of Concomitant Medications

Patients should be advised to inform their physician if they are taking, or plan to take, any prescriptionmedication, including Symbyax ®, Sarafem ®, or over-the-counter drugs, including herbalsupplements or alcohol. Patients should also be advised to inform their physicians if they plan todiscontinue any medications they are taking while on fluoxetine.

17.11 Discontinuation of Treatment

Patients should be advised to take fluoxetine exactly as prescribed, and to continue taking fluoxetine asprescribed even after their symptoms improve. Patients should be advised that they should not alter theirdosing regimen, or stop taking fluoxetine without consulting their physician [see Warnings and Precautions (5.15)]. Patients should be advised to consult with their healthcare provider if their symptoms do notimprove with fluoxetine.

17.12 Use in Specific Populations

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend tobecome pregnant during therapy. Fluoxetine should be used during pregnancy only if the potential benefitjustifies the potential risk to the fetus [see Use in Specific Populations (8.1)].

Nursing Mothers

Patients should be advised to notify their physician if they intend to breast-feed aninfant during therapy. Because fluoxetine is excreted in human milk, nursing while taking fluoxetine is notrecommended [see Use in Specific Populations (8.3)].

Pediatric Use of Fluoxetine

Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Boxed Warningand Warnings and Precautions (5.1)]. Limited evidence is available concerning the longer-term effects offluoxetine on the development and maturation of children and adolescent patients. Height and weightshould be monitored periodically in pediatric patients receiving fluoxetine [see Warnings and Precautions (5.6) and Use in Specific Populations (8.4)].

Medication GuideFluoxetine Tablets, USP (floo ox' e teen)

Read the Medication Guide that comes with fluoxetine tablets 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 tablets?

Fluoxetine tablets and other antidepressant medicines may cause serious side effects, including:

  1. Suicidal thoughts or actions:
    • Fluoxetine tablets and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.
    • 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:
      • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
      • Pay particular attention to such changes when fluoxetine tablets is started or when the dose is changed.

Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

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:

  • attempts to commit suicide
  • 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
  • trouble sleeping
  • an increase in activity or talking more than what is normal for you
  • other unusual changes in behavior or mood

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Fluoxetine may be associated with these serious side effects:

2. Serotonin Syndrome. This condition can be lifethreatening and may include:

  • agitation, hallucinations, coma, or other changes in mental status
  • coordination problems or muscle twitching (overactive reflexes)
  • racing heartbeat, high or low blood pressure
  • sweating or fever
  • nausea, vomiting, or diarrhea
  • muscle rigidity
  • dizziness
  • flushing
  • tremor
  • seizures

3. Severe allergic reactions:

  • trouble breathing
  • swelling of the face, tongue, eyes, or mouth
  • rash, itchy welts (hives) or blisters, alone or with fever or joint pain

4. Abnormal bleeding: Fluoxetine and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin (Coumadin ®, Jantoven ®), a nonsteroidal anti-inflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

5. Visual problems:

  • eye pain
  • changes in vision
  • swelling or redness in or around the eye

Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are.

6. Seizures or convulsions
7. Manic episodes:

  • greatly increased energy
  • severe trouble sleeping
  • racing thoughts,
  • reckless behavior,
  • unusually grand ideas
  • excessive happiness or irritability,
  • talking more or faster than usual

8. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.
9. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

  • headache
  • weakness or feeling unsteady
  • confusion, problems concentrating, or thinking or memory problems

10. Changes in the electrical activity of your heart (QT prolongation and ventricular arrhythmia including Torsades de Pointes). This condition can be life threatening. The symptoms may include:

  • fast, slow, or irregular heartbeat
  • shortness of breath
  • dizziness or fainting

Do not stop fluoxetine tablets without first talking to your healthcare provider. Stopping fluoxetine too quickly may cause serious symptoms including:

  • anxiety, irritability, high or low mood, feeling restless, or changes in sleep habits
  • headache, sweating, nausea, dizziness
  • electric shock-like sensations, shaking, confusion

What are fluoxetine tablets?
Fluoxetine tablets 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 is used to treat:

  • Major Depressive Disorder (MDD)
  • Obsessive Compulsive Disorder (OCD)
  • Bulimia Nervosa*
  • Panic Disorder*

*Not approved for use in children.
Talk to your healthcare provider if you do not think that your condition is getting better with fluoxetine treatment.

Who should not take fluoxetine tablets?
Do not take fluoxetine tablets if you:

  • are allergic to fluoxetine hydrochloride or any of the ingredients in fluoxetine tablets. See the end of this Medication Guide for a complete list of ingredients in fluoxetine tablets.
  • 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 take an MAOI within 5 weeks of stopping fluoxetine unless directed to do so by your physician.
    • Do not start fluoxetine if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

People who take fluoxetine tablets close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:

  • high fever
  • uncontrolled muscle spasms
  • stiff muscles
  • rapid changes in heart rate or blood pressure
  • confusion
  • loss of consciousness (pass out)
  • take Mellaril ® (thioridazine). Do not take Mellaril ® within 5 weeks of stopping fluoxetine tablets because this can cause serious heart rhythm problems or sudden death.
  • take the antipsychotic medicine pimozide (Orap ®) because this can cause serious heart problems.

What should I tell my healthcare provider before taking fluoxetine tablets? Ask if you are not sure.

Before starting fluoxetine tablets, tell your healthcare provider if you:

  • Are taking certain drugs or treatments such as:
    • Triptans used to treat migraine headache
    • Medicines used to treat mood, anxiety, psychotic, or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, MAOIs, or antipsychotics
    • Amphetamines
    • Tramadol and fentanyl
    • Over-the-counter supplements such as tryptophan or St.John’s Wort
    • Electroconvulsive therapy (ECT)
    • have liver problems
    • 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 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 may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking fluoxetine.

Tell your healthcare provider about all the medicines that you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Fluoxetine tablets and some medicines may interact with each other, may not work as well, or may cause serious side effects.
Your healthcare provider or pharmacist can tell you if it is safe to take fluoxetine tablets with your other medicines. Do not start or stop any medicine while taking fluoxetine tablets without talking to your healthcare provider first.

If you take fluoxetine tablets, you should not take any other medicines that contain fluoxetine hydrochloride including:
  • Symbyax ®
  • Sarafem ®
  • Prozac Weekly ®

How should I take fluoxetine tablets?

  • Take fluoxetine tablets exactly as prescribed. Your healthcare provider may need to change the dose of fluoxetine tablets until it is the right dose for you.
  • Fluoxetine tablets may be taken with or without food.
  • If you miss a dose of fluoxetine tablets, 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 tablets at the same time.
  • If you take too many fluoxetine tablets, call your healthcare provider or poison control center right away, or get emergency treatment.

What should I avoid while taking fluoxetine tablets?
Fluoxetine tablets 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 tablets affects you. Do not drink alcohol while using fluoxetine tablets.

What are the possible side effects of fluoxetine tablets?
Fluoxetine tablets may cause serious side effects, including:

  • See “What is the most important information I should know about fluoxetine tablets?”
  • Problems with blood sugar control. People who have diabetes and take fluoxetine tablets may have problems with low blood sugar while taking fluoxetine tablets. High blood sugar can happen when fluoxetine tablets are stopped. Your healthcare provider may need to change the dose of your diabetes medicines when you start or stop taking fluoxetine tablets.
  • Feeling anxious or trouble sleeping

Common possible side effects in people who take fluoxetine tablets include:

  • unusual dreams
  • sexual problems
  • loss of appetite, diarrhea, indigestion, nausea or vomiting, weakness, or dry mouth
  • flu symptoms
  • feeling tired or fatigued
  • change in sleep habits
  • yawning
  • sinus infection or sore throat
  • tremor or shaking
  • sweating
  • feeling anxious or nervous
  • hot flashes
  • rash

Other side effects in children and adolescents include:

  • increased thirst
  • abnormal increase in muscle movement or agitation
  • nose bleed
  • 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 tablets.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of fluoxetine tablets. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1- 800-FDA-1088.

How should I store fluoxetine tablets?

  • Store fluoxetine tablets at 20° to 25°C (68° to 77°F).
  • Keep fluoxetine tablets away from light.
  • Keep fluoxetine tablets bottle closed tightly.

Keep fluoxetine tablets and all medicines out of the reach of children.

General information about fluoxetine tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use fluoxetine tablets for a condition for which it was not prescribed. Do not give fluoxetine tablets to other people, even if they have the same condition. It may harm them.

This Medication Guide summarizes the most important information about fluoxetine tablets. If you would like more information, talk with your healthcare provider. You may ask your healthcare provider or pharmacist for information about fluoxetine tablets that is written for healthcare professionals.

For more information about fluoxetine tablets, call Appco Pharma LLC at 1-855-672-7726.

What are the ingredients in fluoxetine tablets?

Active ingredient:
fluoxetine hydrochloride

Inactive ingredients: hypromellose, magnesium stearate, maize starch, mannitol, microcrystalline cellulose, polyethylene glycol, polysorbate, povidone and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

The brands listed are trademarks of their respective owners.

Manufactured by:
Appco Pharma LLC,
Piscataway, NJ 08854.

Revision: 01/2019

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

Container-10mg30c



Container-10mg1000



Container-20mg30c



Container-20mg1000c


FLUOXETINE 
fluoxetine tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:55801-402
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
FLUOXETINE HYDROCHLORIDE (UNII: I9W7N6B1KJ) (FLUOXETINE - UNII:01K63SUP8D) FLUOXETINE10 mg
Inactive Ingredients
Ingredient NameStrength
HYPROMELLOSE 2910 (3 MPA.S) (UNII: 0VUT3PMY82)  
HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
MANNITOL (UNII: 3OWL53L36A)  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)  
POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
POVIDONE K30 (UNII: U725QWY32X)  
STARCH, CORN (UNII: O8232NY3SJ)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
Product Characteristics
Colorwhite (White to off white) Score2 pieces
ShapeCAPSULESize9mm
FlavorImprint Code AC;402
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:55801-402-0130 in 1 BOTTLE; Type 0: Not a Combination Product03/01/201812/09/2019
2NDC:55801-402-021000 in 1 BOTTLE; Type 0: Not a Combination Product03/01/201812/09/2019
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA21169603/01/201812/09/2019
FLUOXETINE 
fluoxetine tablet, film coated
Product Information
Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC:55801-403
Route of AdministrationORAL
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
FLUOXETINE HYDROCHLORIDE (UNII: I9W7N6B1KJ) (FLUOXETINE - UNII:01K63SUP8D) FLUOXETINE20 mg
Inactive Ingredients
Ingredient NameStrength
HYPROMELLOSE 2910 (3 MPA.S) (UNII: 0VUT3PMY82)  
HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6)  
MAGNESIUM STEARATE (UNII: 70097M6I30)  
MANNITOL (UNII: 3OWL53L36A)  
MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)  
POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)  
POLYSORBATE 80 (UNII: 6OZP39ZG8H)  
POVIDONE K30 (UNII: U725QWY32X)  
STARCH, CORN (UNII: O8232NY3SJ)  
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)  
Product Characteristics
Colorwhite (White to off white) Score2 pieces
ShapeCAPSULESize12mm
FlavorImprint Code AC;403
Contains    
Packaging
#Item CodePackage DescriptionMarketing Start DateMarketing End Date
1NDC:55801-403-0130 in 1 BOTTLE; Type 0: Not a Combination Product03/01/201812/09/2019
2NDC:55801-403-021000 in 1 BOTTLE; Type 0: Not a Combination Product03/01/201812/09/2019
Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
ANDAANDA21169603/01/201812/09/2019
Labeler - Appco Pharma LLC (078510186)
Registrant - Appco Pharma LLC (078510186)
Establishment
NameAddressID/FEIBusiness Operations
Appco Pharma LLC078510186manufacture(55801-402, 55801-403)

Revised: 12/2019
 
Appco Pharma LLC