Prozac, Page 1

Prozac® (fluoxetine) is a selective serotonin reuptake inhibitor indicated for the treatment of major depressive disorder, OCD, bulimia nervosa, panic disorder and — in combination with olanzapine — for the treatment of treatment resistant depression and of depressive episodes associated with bipolar disorder.

PROZAC- fluoxetine hydrochloride capsule
Dista Products Company

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of PROZAC or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. PROZAC is approved for use in pediatric patients with MDD and Obsessive Compulsive Disorder (OCD) [see Warnings and Precautions (5.1) and Use in Specific Populations (8.4)].

When using PROZAC 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

PROZAC® 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

PROZAC 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 PROZAC 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 PROZAC 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

PROZAC 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 PROZAC 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

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

The effectiveness of PROZAC 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 PROZAC for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see Dosage and Administration (2.4)].

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

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

PROZAC and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder in adult patients.

PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

1.6 PROZAC and Olanzapine in Combination: Treatment Resistant Depression

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

PROZAC and olanzapine in combination is indicated for the acute treatment of treatment resistant depression (Major Depressive Disorder in adult patients, who do not respond to 2 separate trials of different antidepressants of adequate dose and duration in the current episode).

PROZAC monotherapy is not indicated for the treatment of treatment resistant depression.

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 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 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 PROZAC 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)].

Weekly Dosing — Systematic evaluation of PROZAC® Weekly™ in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 25 weeks with once-weekly dosing following 13 weeks of open-label treatment with PROZAC 20 mg once daily. However, therapeutic equivalence of PROZAC Weekly given on a once-weekly basis with PROZAC 20 mg given daily for delaying time to relapse has not been established [see Clinical Studies (14.1)].

Weekly dosing with PROZAC Weekly capsules is recommended to be initiated 7 days after the last daily dose of PROZAC 20 mg [see Clinical Pharmacology (12.3)].

If satisfactory response is not maintained with PROZAC Weekly, consider reestablishing a daily dosing regimen [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 PROZAC. In addition, at least 5 weeks, perhaps longer, should be allowed after stopping PROZAC 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, 40, or 60 mg of fluoxetine or placebo [see Clinical Studies (14.2)]. In one of these studies, no dose-response relationship for effectiveness was demonstrated. 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 PROZAC, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient. Although the efficacy of PROZAC 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 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 PROZAC 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking PROZAC 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 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 PROZAC, 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 PROZAC and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder

When using PROZAC 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 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg.

Safety 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 PROZAC and olanzapine versus Symbyax. Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

Table 1: Approximate Dose Correspondence Between Symbyax1 and the Combination of PROZAC and Olanzapine

1 Symbyax (olanzapine/fluoxetine HCL) is a fixed-dose combination of PROZAC and olanzapine.

For
Symbyax
(mg/day)
Use in Combination
Olanzapine
(mg/day)
PROZAC
(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

While there is no body of evidence to answer the question of how long a patient treated with PROZAC 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 re-examine 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.

PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

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