Fluoxetine Hydrochloride (fluoxetine hydrochloride 20 mg) Dailymed

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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 adult and pediatric patients aged 7 to 17 years. (1.2)
• Acute and maintenance treatment of bulimia nervosa in adult patients. (1.3)
• Acute treatment of panic disorder, with or without agoraphobia, in adult patients. (1.4)

Fluoxetine and olanzapine in combination for:

• Acute treatment of depressive episodes associated with bipolar I disorder in adults. (1.5)

1.1 Major Depressive Disorder

Fluoxetine capsules are indicated for the acute and maintenance treatment of major depressive disorder in adult patients and in pediatric patients aged 8 to18 years [see Clinical Studies (14.1)].

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

1.2 Obsessive Compulsive Disorder

Fluoxetine capsules are indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with obsessive compulsive disorder (OCD) [see Clinical Studies (14.2)].

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

1.3 Bulimia Nervosa

Fluoxetine capsules are indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe bulimia nervosa [see Clinical Studies (14.3)].

The physician who elects to use fluoxetine capsules for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.3)].

1.4 Panic Disorder

Fluoxetine capsules are indicated for the acute treatment of panic disorder, with or without agoraphobia, in adult patients [see Clinical Studies (14.4)].

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

1.5 Fluoxetine and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder

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

  Fluoxetine and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with bipolar I disorder in adult patients.

  Fluoxetine capsule monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

2 Dosage And Administration

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Indication	Adult	Pediatric
MDD (2.1)	20 mg/day in am (initial dose)	10 to 20 mg/day (initial dose)
OCD (2.2)	20 mg/day in am (initial dose)	10 mg/day (initial dose)
Bulimia Nervosa (2.3)	60 mg/day in am	-
Panic Disorder (2.4)	10 mg/day (initial dose)	-
Depressive Episodes Associated with Bipolar I Disorder (2.5)	Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose)	-

• Consider tapering the dose of fluoxetine for pregnant women during the third trimester. (2.7)
• A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly and for patients with concurrent disease or on multiple concomitant medications. (2.7)

Fluoxetine and olanzapine in combination:

• Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability. (2.5)
• Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder. (2.5)
• Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated. (2.5)

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 to 80 mg/day. Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in major depressive disorder in most cases. 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 to 20 mg/day [see Clinical Studies (14.1) ]. Treatment should be initiated with a dose of 10 or 20 mg/day. After one 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 capsules 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 Drug Interactions (7.9) ].
Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI)
At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with fluoxetine capsules. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping fluoxetine capsules before starting an MAOI [see  Contraindications (4) and Drug Interactions (7.1) ].

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 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 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 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 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 capsules, 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 capsules 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking fluoxetine capsules 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 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 two 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 capsules, 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.

2.5 Fluoxetine and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder

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

  Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 mg to 50 mg and oral olanzapine 5 mg to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 mg to 12 mg and fluoxetine 25 mg to 50 mg.

  Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax ^® (fixed-dose combination of olanzapine and fluoxetine). Symbyax ^® is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day. The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine vs. Symbyax ^® . Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

TABLE 1: Approximate Dose Correspondence Between Symbyax^® * and the Combination of Fluoxetine and Olanzapine

For Symbyax ® (mg/day)	Use in Combination
Olanzapine(mg/day)	Fluoxetine(mg/day)
3 mg olanzapine/25 mg fluoxetine	2.5	20
6 mg olanzapine/25 mg fluoxetine	5	20
12 mg olanzapine/25 mg fluoxetine	10 + 2.5	20
6 mg olanzapine/50 mg fluoxetine	5	40 + 10
12 mg olanzapine/50 mg fluoxetine	10 + 2.5	40 + 10

*Symbyax ^® (olanzapine/fluoxetine hydrochloride) is a fixed-dose combination of fluoxetine and olanzapine.
  While there is no body of evidence to answer the question of how long a patient treated with fluoxetine and olanzapine in combination should remain on it, it is generally accepted that bipolar I disorder, including the depressive episodes associated with bipolar I disorder, is a chronic illness requiring chronic treatment. The physician should periodically reexamine the need for continued pharmacotherapy.

  Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

  Fluoxetine capsule monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

2.7 Dosing in Specific Populations

Treatment of Pregnant Women during the Third Trimester
When treating pregnant women with fluoxetine capsules during the third trimester, the physician should carefully consider the potential risks and potential benefits of treatment. Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. The physician may consider tapering fluoxetine capsules in the third trimester [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 (5.10) ].
Fluoxetine and Olanzapine in Combination
The starting dose of oral olanzapine 2.5 mg to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modifications may be necessary in patients who exhibit a combination of factors that may slow metabolism. When indicated, dose escalation should be performed with caution in these patients. Fluoxetine and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 18 years of age [see Warnings and Precautions (5.14) and Drug Interactions (7.9) ].

2.8 Discontinuation of Treatment

Symptoms associated with discontinuation of fluoxetine, SNRIs and SSRIs, have been reported [see Warnings and Precautions (5.13) ].

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

• Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior. (5.1)
• Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions: Have been reported with fluoxetine. Discontinue fluoxetine and initiate supportive treatment. (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)
• Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH). (5.8)
• Anxiety and Insomnia: May occur. (5.9)
• Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking and motor skills. Use caution when operating machinery. (5.11)
• Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks. (5.12)
• 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^®. (5.14)

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 nine antidepressant drugs in over 4,400 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 vs. 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 1,000 patients treated) are provided in Table 2.

TABLE 2: Suicidality per 1,000 Patients Treated

Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 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 number was not sufficient to reach any conclusion about drug effect on suicide.

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

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

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania and mania, have been reported in adult and 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 symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these 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 as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see Warnings and Precautions (5.13)].

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for fluoxetine should be written for the smallest quantity of capsules consistent with good patient management, 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. Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 18 years of age have not been established.

5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions

The development of a potentially life threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including fluoxetine treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

  The concomitant use of fluoxetine with MAOIs intended to treat depression is contraindicated [see Contraindications (4) and Drug Interactions (7.1) ].

    If concomitant treatment of fluoxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions (7.4) ].

  The concomitant use of fluoxetine with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions (7.3) ].

  Treatment with fluoxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur and supportive symptomatic treatment should be initiated.

5.3 Allergic Reactions and Rash

In U.S. fluoxetine clinical trials as of May 8, 1995, 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 were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash. Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria and mild transaminase elevation. Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.

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

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

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

Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely. These reactions have occurred with dyspnea as the only preceding symptom.

Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known. Furthermore, a specific underlying immunologic basis for these reactions has not been identified. Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued.

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 alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described for clinical worsening and suicide risk represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression. It should be noted that fluoxetine and olanzapine in combination is approved for the acute treatment of depressive episodes associated with bipolar I disorder [see Warnings and Precautions section of the package insert for Symbyax]. Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with bipolar I disorder.

In U.S. placebo-controlled clinical trials for major depressive disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder treated with other marketed drugs effective in the treatment of major depressive disorder [see Use in Specific Populations (8.4) ].

In U.S. placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo. No patients reported mania/hypomania in U.S. placebo-controlled clinical trials for bulimia. In all U.S. fluoxetine clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported 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 having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo. No patients reported convulsions in U.S. placebo-controlled clinical trials for either OCD or bulimia. In all U.S. fluoxetine clinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions. The percentage appears 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 undesirable result of treatment with fluoxetine.

In U.S. placebo-controlled clinical trials for major depressive disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss [see Use in Specific Populations (8.4) ].

In 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 discontinued treatment 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 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial. Weight change should be monitored during therapy.

5.7 Abnormal Bleeding

SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, non-steroidal anti-inflammatory drugs, warfarin and other anticoagulants may add to this risk. Case reports and epidemiological studies (case control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis and petechiae to life threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin or other drugs that affect coagulation [see Drug Interactions (7.6) ].

5.8 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.

5.9 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 with fluoxetine and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo.

In U.S. placebo-controlled clinical trials for bulimia nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.

Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in U.S. placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia) and nervousness (1% in major depressive disorder) [see Table 5].

5.10 Use in Patients with Concomitant Illness

Clinical experience with fluoxetine in patients with concomitant systemic illness is limited. Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.
Cardiovascular
Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing. However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed. The mean heart rate was reduced by approximately 3 beats/min.
Glycemic Control
In patients with diabetes, fluoxetine may alter glycemic control. Hypoglycemia has occurred during therapy with fluoxetine and hyperglycemia has developed following discontinuation of the drug. As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.

5.11 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 they are reasonably certain that the drug treatment does not affect them adversely.

5.12 Long Elimination Half-Life

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

5.13 Discontinuation of Treatment

During marketing of fluoxetine, SNRIs and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia and hypomania. While these reactions are generally self limiting, there have been reports of serious discontinuation symptoms. Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon 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. Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug.

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^®.

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


Most common adverse reactions (≥ 5% and at least twice that for placebo) associated with:

Major depressive disorder, obsessive compulsive disorder, bulimia and panic disorder: abnormal dreams, abnormal ejaculation, anorexia, anxiety, asthenia, diarrhea, dry mouth, dyspepsia, flu syndrome, impotence, insomnia, libido decreased, nausea, nervousness, pharyngitis, rash, sinusitis, somnolence, sweating, tremor, vasodilatation and yawn. (6.1)

Fluoxetine and olanzapine in combination – Also refer to the Adverse Reactions section of the package insert for Symbyax^®. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3769 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

6.1 Clinical Trials Experience

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

Multiple doses of fluoxetine had been administered to 10,782 patients with various diagnoses in U.S. clinical trials as of May 8, 1995. 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 uled. 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 one 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* †

	Percentage of Patients Reporting Event
	Major Depressive Disorder	OCD	Bulimia	Panic Disorder
Body System/Adverse Reaction	Fluoxetine (N=1,728)	Placebo(N=975)	Fluoxetine(N=266)	Placebo(N=89)	Fluoxetine(N=450)	Placebo(N=267)	Fluoxetine(N=425)	Placebo(N=342)
Body as a Whole
Asthenia	9	5	15	11	21	9	7	7
Flu syndrome	3	4	10	7	8	3	5	5
Cardiovascular System
Vasodilatation	3	2	5	--	2	1	1	--
Digestive System
Nausea	21	9	26	13	29	11	12	7
Diarrhea	12	8	18	13	8	6	9	4
Anorexia	11	2	17	10	8	4	4	1
Dry mouth	10	7	12	3	9	6	4	4
Dyspepsia	7	5	10	4	10	6	6	2
Nervous System
Insomnia	16	9	28	22	33	13	10	7
Anxiety	12	7	14	7	15	9	6	2
Nervousness	14	9	14	15	11	5	8	6
Somnolence	13	6	17	7	13	5	5	2
Tremor	10	3	9	1	13	1	3	1
Libido decreased	3	--	11	2	5	1	1	2
Abnormal dreams	1	1	5	2	5	3	1	1
Respiratory System
Pharyngitis	3	3	11	9	10	5	3	3
Sinusitis	1	4	5	2	6	4	2	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

*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 = 43 placebo OCD; N = 4 fluoxetine bulimia; N = 1 placebo bulimia; N = 162 fluoxetine panic; N = 121 placebo panic).

TABLE 4: Treatment-Emergent Adverse Reactions: Incidence in Major Depressive Disorder, OCD, Bulimia and Panic Disorder Placebo-Controlled Clinical Trials* †

	Percentage of Patients Reporting Event
	Major Depressive Disorder, OCD, Bulimia and Panic Disorder Combined
Body System/Adverse Reaction	Fluoxetine(N = 2,869)	Placebo(N = 1,673)
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

*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.Associated with Discontinuation in Major Depressive Disorder, OCD, Bulimia and Panic Disorder Placebo-Controlled Clinical Trials (excluding data from extensions of trials)
Table 5 uls 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*

Major Depressive Disorder, OCD, Bulimia and Panic Disorder Combined (N = 1,533)	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%)	--	--

*Includes U.S. major depressive disorder, OCD, bulimia and panic disorder clinical trials, plus non-U.S. panic disorder clinical trials.Other Adverse Reactions in Pediatric Patients (children and adolescents)
Treatment-emergent adverse reactions were collected in 322 pediatric patients (180 fluoxetine-treated, 142 placebo-treated). The overall profile of adverse reactions was generally similar to that seen in adult studies, as shown in Tables 4 and 5. However, the following adverse reactions (excluding those which appear in the body or footnotes of Tables 4 and 5 and those for which the COSTART terms were uninformative or misleading) were reported at an incidence of at least 2% for fluoxetine and greater than placebo: thirst, hyperkinesia, agitation, personality disorder, epistaxis, urinary frequency and menorrhagia.

The most common adverse reaction (incidence at least 1% for fluoxetine and greater than placebo) associated with discontinuation in three 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.

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 ul of treatment-emergent adverse reactions reported by patients treated with fluoxetine in clinical trials. This uling is not intended to include reactions (1) already uled in previous tables or elsewhere in labeling, (2) for which a drug cause was remote, (3) which were so general as to be uninformative, (4) which were not considered to have significant clinical implications, or (5) which occurred at a rate equal to or less than placebo.

Reactions are classified by body system using the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare reactions are those occurring in fewer than 1/1000 patients.

Body as a Whole: Frequent: chills; Infrequent: suicide attempt; Rare: acute abdominal syndrome, photosensitivity reaction.

Cardiovascular System: Frequent: palpitation; Infrequent: arrhythmia.

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, buccoglossal syndrome, euphoria, hypertonia, libido increased, myoclonus, paranoid reaction; Rare: delusions.

Respiratory System: Rare: larynx edema.

Skin and Appendages: Rare: purpuric rash.

Special Senses: Frequent: taste perversion; Infrequent: mydriasis.

6.3 Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of fluoxetine. Because these reactions are reported voluntarily from a population of uncertain size, it is difficult to reliably estimate their frequency or evaluate a causal relationship to drug exposure.

Voluntary reports of adverse reactions temporally associated with fluoxetine that have been received since market introduction and that may have no causal relationship with the drug include the following: aplastic anemia, atrial fibrillation1, cataract, cerebrovascular accident1, cholestatic jaundice, dyskinesia (including, for example, a case of buccal-lingual-masticatory syndrome with involuntary tongue protrusion reported to develop in a 77 year old female after 5 weeks of fluoxetine therapy and which completely resolved over the next few months following drug discontinuation), eosinophilic pneumonia1, epidermal necrolysis, erythema multiforme, erythema nodosum, exfoliative dermatitis, gynecomastia, heart arrest1, hepatic failure/necrosis, hyperprolactinemia, hypoglycemia, immune-related hemolytic anemia, kidney failure, movement disorders developing in patients with risk factors including drugs associated with such reactions and worsening of preexisting movement disorders, optic neuritis, pancreatitis1, pancytopenia, pulmonary embolism, pulmonary hypertension, QT prolongation, Stevens-Johnson Syndrome, thrombocytopenia1, thrombocytopenic purpura, ventricular tachycardia (including Torsades de pointes type arrhythmias), and vaginal bleeding, and violent behaviors1.
1
These terms represent serious adverse events, but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.