Prozac 20

Dosage Forms And strengths

• 10 mg Pulvule is an opaque green cap and opaque green body, imprinted with DISTA 3104 on the cap and Prozac 10 mg on the body
• 20 mg Pulvule is an opaque green cap and opaque yellow body, imprinted with DISTA 3105 on the cap and Prozac 20 mg on the body
• 40 mg Pulvule is an opaque green cap and opaque orange body, imprinted with DISTA 3107 on the cap and Prozac 40 mg on the body
• 90 mg Prozac Weekly™ Capsule is an opaque green cap and clear body containing discretely visible white pellets through the clear body of the capsule, imprinted with Lilly on the cap and 3004 and 90 mg on the body

Storage And Handling

The following products are manufactured by Eli Lilly and Company for Dista Products Company: Pulvule are available in 10mg, 20mg and 40mg capsule strengths and packages as follows:

Store at Controlled Room Temperature, 15° to 30°C (59° to 86°F).

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA. Revised: Jan 2017.

PROZAC^® is indicated for the treatment of:

• Acute and maintenance treatment of Major Depressive Disorder.
• Acute and maintenance treatment of obsessions and compulsions in patients with Obsessive Compulsive Disorder (OCD).
• Acute and maintenance treatment of binge-eating and vomiting behaviors in patients with moderate to severe Bulimia Nervosa.
• Acute treatment of Panic Disorder, with or without agoraphobia.

PROZAC and Olanzapine in Combination is indicated for the treatment of:

• Acute treatment of depressive episodes associated with Bipolar I Disorder.
• Treatment resistant depression (Major Depressive Disorder in 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 depressive episodes associated with Bipolar I Disorder or the treatment of treatment resistant depression.

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

Major Depressive Disorder

Initial Treatment

Adult

Initiate PROZAC 20 mg/day orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon).The maximum fluoxetine dose should not exceed 80 mg/day.

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

Pediatric (children and adolescents)

Initiate PROZAC 10 or 20 mg/day. After 1 week at 10 mg/day, increase the dose to 20 mg/day. However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day. Consider a dose increase to 20 mg/day after several weeks if insufficient clinical improvement is observed. In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day.

All patients

As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer.

Periodically reassess to determine the need for maintenance treatment.

Weekly Dosing

Initiate PROZAC Weekly capsules 7 days after the last daily dose of PROZAC 20 mg.

If satisfactory response is not maintained with PROZAC Weekly, consider reestablishing a daily dosing regimen.

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.

Obsessive Compulsive Disorder

Initial Treatment

Adult

Initiate PROZAC 20 mg/day, orally in the morning. Consider a dose increase after several weeks if insufficient clinical improvement is observed. The full therapeutic effect may be delayed until 5 weeks of treatment or longer. Administer doses above 20 mg/day once daily in the morning or twice daily (i.e., morning and noon). A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD. The maximum fluoxetine dose should not exceed 80 mg/day.

In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo. In one of these studies, no dose-response relationship for effectiveness was demonstrated.

Pediatric (children and adolescents)

n adolescents and higher weight children, initiate treatment with a dose of 10 mg/day. After 2 weeks, increase the dose to 20 mg/day. Consider additional dose increases after several more weeks if insufficient clinical improvement is observed. A dose range of 20 to 60 mg/day is recommended.

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

In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day.

Periodically reassess to determine the need for treatment.

Bulimia Nervosa

Initial Treatment

Administer PROZAC 60 mg/day in the morning. For some patients it may be advisable to titrate up to this target dose over several days. Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo. Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting.

Periodically reassess to determine the need for maintenance treatment.

Panic Disorder

Initial Treatment

Initiate treatment with PROZAC 10 mg/day. After one week, increase the dose to 20 mg/day. Consider a dose increase after several weeks if no clinical improvement is observed. Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder. In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day. The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day.

Periodically reassess to determine the need for continued treatment.

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.

Adult

Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Make dosage adjustments, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg. Safety of co-administration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies. Periodically re-examine the need for continued pharmacotherapy.

Children and adolescents (10 -17 years of age)

Administer olanzapine and fluoxetine combination once daily in the evening, generally beginning with 2.5 mg of olanzapine and 20 mg of fluoxetine. Make dosage adjustments, if indicated, according to efficacy and tolerability. Safety of co-administration of doses above 12 mg of olanzapine with 50 mg of fluoxetine has not been evaluated in pediatric clinical studies. Periodically re-examine the need for continued pharmacotherapy.

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. Adjust dosage, if indicated, with the individual components according to efficacy and tolerability.

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

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

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.

Administer fluoxetine in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine. Adjust dosage, if indicated, according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 20 mg. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 18 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. Table 1 demonstrates the appropriate individual component doses of PROZAC and olanzapine versus Symbyax. Adjust dosage, if indicated, with the individual components according to efficacy and tolerability.

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 treatment resistant depression (Major Depressive Disorder in patients who do not respond to 2 antidepressants of adequate dose and duration in the current episode).

Dosing In Specific Populations

Treatment Of Pregnant Women

When treating pregnant women with PROZAC, 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.

Geriatric

Consider a lower or less frequent dosage for the elderly.

Hepatic Impairment

As with many other medications, use a lower or less frequent dosage in patients with hepatic impairment.

Concomitant Illness

Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments.

PROZAC And Olanzapine In Combination

Use a starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, non-smoking status), or those patients who may be pharmacodynamically sensitive to olanzapine. Titrate slowly and adjust dosage as needed in patients who exhibit a combination of factors that may slow metabolism. PROZAC and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 10 years of age.

Discontinuation Of Treatment

Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported.

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 PROZAC. Conversely, at least 5 weeks should be allowed after stopping PROZAC before starting an MAOI intended to treat psychiatric disorders.

Use Of PROZAC With Other MAOIs Such As Linezolid Or Methylene Blue

Do not start PROZAC 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.

In some cases, a patient already receiving PROZAC 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, PROZAC should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with PROZAC may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

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 PROZAC is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

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

Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with PROZAC or within 5 weeks of stopping treatment with PROZAC is contraindicated because of an increased risk of serotonin syndrome. The use of PROZAC within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting PROZAC 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.

Other Contraindications

The use of PROZAC is contraindicated with the following:

• Pimozide
• Thioridazine

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

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

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

Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults

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 18-24) 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

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.

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 PROZAC 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 PROZAC is approved in the pediatric population for Major Depressive Disorder and Obsessive Compulsive Disorder; and PROZAC in combination with olanzapine for the acute treatment of depressive episodes associated with Bipolar I Disorder.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including PROZAC, alone but particularly with concomitant use of other serotonergic drugs (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 and intravenous methylene blue).

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

The concomitant use of PROZAC with MAOIs intended to treat psychiatric disorders is contraindicated. PROZAC should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking PROZAC. PROZAC should be discontinued before initiating treatment with the MAOI.

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

Treatment with PROZAC and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Allergic Reactions And Rash

In US 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 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, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme. Other patients have had systemic syndromes suggestive of serum sickness.

Since the introduction of PROZAC, 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, PROZAC should be discontinued.

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 PROZAC and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder. PROZAC monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with PROZAC 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.

In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with PROZAC and no patients treated with placebo. No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia. In US PROZAC clinical trials, 0.7% of 10,782 patients reported mania/hypomania.

Seizures

In US 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 PROZAC and 0.2% of patients treated with placebo. No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia. In US PROZAC clinical trials, 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. PROZAC should be introduced with care in patients with a history of seizures.

Altered Appetite And Weight

Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with PROZAC.

In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with PROZAC and 2% of patients treated with placebo reported anorexia (decreased appetite). Weight loss was reported in 1.4% of patients treated with PROZAC and in 0.5% of patients treated with placebo. However, only rarely have patients discontinued treatment with PROZAC because of anorexia or weight loss.

In US placebo-controlled clinical trials for OCD, 17% of patients treated with PROZAC and 10% of patients treated with placebo reported anorexia (decreased appetite). One patient discontinued treatment with PROZAC because of anorexia.

In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with PROZAC 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite). Patients treated with PROZAC 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.

Abnormal Bleeding

SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants 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.

Angle-Closure Glaucoma

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including Prozac may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Hyponatremia

Hyponatremia has been reported during treatment with SNRIs and SSRIs, including PROZAC. 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 PROZAC 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. Discontinuation of PROZAC 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.

Anxiety And Insomnia

In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with

PROZAC and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with PROZAC and in 22% of patients treated with placebo. Anxiety was reported in 14% of patients treated with PROZAC and in 7% of patients treated with placebo.

In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with PROZAC 60 mg, and 13% of patients treated with placebo. Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with PROZAC 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 PROZAC in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder).

QT Prolongation

Post-marketing cases of QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with PROZAC. PROZAC 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). PROZAC is primarily metabolized by CYP2D6.

Pimozide and thioridazine are contraindicated for use with PROZAC. Avoid the concomitant use of drugs known to prolong the QT interval. These include specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol,); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

Consider ECG assessment and periodic ECG monitoring if initiating treatment with PROZAC in patients with risk factors for QT prolongation and ventricular arrhythmia. Consider discontinuing PROZAC and obtaining a cardiac evaluation if patients develop signs or symptoms consistent with ventricular arrhythmia.

Use In Patients With Concomitant Illness

Clinical experience with PROZAC in patients with concomitant systemic illness is limited. Caution is advisable in using PROZAC 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 PROZAC 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, PROZAC may alter glycemic control. Hypoglycemia has occurred during therapy with PROZAC, 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 PROZAC is instituted or discontinued.

Potential For Cognitive And Motor Impairment

As with any CNS-active drug, PROZAC 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.

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.

Discontinuation Adverse Reactions

During marketing of PROZAC, 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 PROZAC. 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.

PROZAC And Olanzapine In Combination

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

Patient Counseling Information

See the FDA-approved PATIENT INFORMATION.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking PROZAC as monotherapy or in combination with olanzapine. When using PROZAC and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

General Information

Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with PROZAC and to reread it each time the prescription is renewed.

Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with PROZAC and should counsel them in its appropriate use. Healthcare providers should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.

Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking PROZAC.

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

Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults

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 (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of PROZAC and other serotonergic agents including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort.

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

Allergic Reactions And Rash

Patients should be advised to notify their physician if they develop a rash or hives. Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing. Patients should be cautioned to seek medical care immediately if they experience these symptoms.

Abnormal Bleeding

Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding. Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking PROZAC.

Angle-Closure Glaucoma

Patients should be advised that taking Prozac can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

Hyponatremia

Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including PROZAC. 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.

QT Prolongation

Patients should be advised that QT interval prolongation and ventricular arrhythmia including Torsades de Pointes have been reported in patients treated with PROZAC. Signs and symptoms of ventricular arrhythmia include fast, slow, or irregular heart rate, dyspnea, syncope, or dizziness, which may indicate serious cardiac arrhythmia.

Potential For Cognitive And Motor Impairment

PROZAC may impair judgment, thinking, or motor skills. Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected.

Use Of Concomitant Medications

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax, Sarafem, or over-the-counter drugs, including herbal supplements or alcohol. Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on PROZAC.

Discontinuation Of Treatment

Patients should be advised to take PROZAC exactly as prescribed, and to continue taking PROZAC as prescribed even after their symptoms improve. Patients should be advised that they should not alter their dosing regimen, or stop taking PROZAC without consulting their physician. Patients should be advised to consult with their healthcare provider if their symptoms do not improve with PROZAC.

Use In Specific Populations

Pregnancy

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Prozac should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy. Because PROZAC is excreted in human milk, nursing while taking PROZAC is not recommended.

Pediatric Use Of PROZAC

PROZAC is approved for use in pediatric patients with MDD and OCD. Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients. Height and weight should be monitored periodically in pediatric patients receiving fluoxetine..

Pediatric Use of PROZAC and olanzapine in combination -Safety and efficacy of PROZAC and olanzapine in combination in patients 10 to 17 years of age have been established for the acute treatment of depressive episodes associated with Bipolar I Disorder.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

The dietary administration of fluoxetine to rats and mice for 2 years at doses of up to 10 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/m² basis], produced no evidence of carcinogenicity.

Mutagenicity

Fluoxetine and norfluoxetine have been shown to have no genotoxic effects based on the following assays: bacterial mutation assay, DNA repair assay in cultured rat hepatocytes, mouse lymphoma assay, and in vivo sister chromatid exchange assay in Chinese hamster bone marrow cells.

Impairment Of Fertility

Two fertility studies conducted in adult rats at doses of up to 7.5 and 12.5 mg/kg/day (approximately 0.9 and 1.5 times the MRHD on a mg/m² basis) indicated that fluoxetine had no adverse effects on fertility. However, adverse effects on fertility were seen when juvenile rats were treated with fluoxetine.

Use In Specific Population

When using PROZAC and olanzapine in combination, also refer to the Use in Specific Populations section of the package insert for Symbyax.

Pregnancy