Olanzapine and Fluoxetine

Par Pharmaceutical, Inc
Par Pharmaceutical, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Olanzapine and Fluoxetine Capsules USP safely and effectively. See full prescribing information for Olanzapine and Fluoxetine Capsules USP. Olanzapine and Fluoxetine Capsules USP for oral use.Initial U.S. Approval: 2003 BOXED WARNINGWARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS AND INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSISSee full prescribing information for complete boxed warning. •Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for Major Depressive Disorder (MDD) and other psychiatric disorders. Olanzapine and Fluoxetine Hydrochloride is not approved for use in children and adolescents (5.1, 8.4, 17.2). •Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine and Fluoxetine Hydrochloride is not approved for the treatment of patients with dementia-related psychosis (5.2, 5.19, 17.3). RECENT MAJOR CHANGES Dosage and Administration:Specific Populations (2.3)                                                                                             01/2013Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI)Intended to Treat Psychiatric Disorders (2.4)                                                               01/2013Use of Olanzapine and Fluoxetine Capsules with other MAOIs such as Linezolid or Methylene Blue (2.5)                                                                        01/2013 Contraindications: Monoamine Oxidase Inhibitors (MAOIs) (4.1)                                                           01/2013Other Contraindications (4.2)                                                                                      01/2013 Warnings and Precautions: Serotonin Syndrome (5.7)                                                                                           01/2013INDICATIONS AND USAGEOlanzapine and fluoxetine capsules combines olanzapine, an atypical antipsychotic and fluoxetine, a selective serotonin reuptake inhibitor, indicated for acute treatment of: •Depressive Episodes Associated with Bipolar I Disorder in adults (1.1) DOSAGE AND ADMINISTRATION •Once daily in the evening, generally beginning with 6 mg/25 mg (2.1) •The starting dose of Olanzapine and Fluoxetine Capsules 3 mg/25 mg – 6 mg/25 mg should be used in patients predisposed to hypotensive reactions, hepatic impairment, or with potential for slowed metabolism. Escalate dose cautiously (2.3) •Consider tapering the dose of fluoxetine for pregnant women during the third trimester (2.3) •Discontinue gradually (2.4) •The safety of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical trials (2.1) DOSAGE FORMS AND STRENGTHS •Capsules: 3 mg/25 mg, 6 mg/25 mg, 6 mg/50 mg, 12 mg/25 mg, and 12 mg/50 mg (mg equivalent olanzapine/mg equivalent fluoxetine) (3) CONTRAINDICATIONS •Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with Olanzapine and Fluoxetine Capsules or within 5 weeks of stopping treatment with Olanzapine and Fluoxetine Capsules. Do not use Olanzapine and Fluoxetine Capsules withing 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start Olanzapine and Fluoxetine Capsules in a patient who is being treated with linezolid or intravenous methylene blue. (4.1) • Do not use with pimozide due to risk of drug interaction or QTc prolongation (4, 7.7) •Do not use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing olanzapine and fluoxetine hydrochloride (4, 7.7) WARNINGS AND PRECAUTIONS • Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior (5.1) • Elderly Patients with Dementia-Related Psychosis: Increased risk of death and increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack) (5.2) • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.3) • Hyperglycemia: In some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients taking olanzapine. Patients taking olanzapine and fluoxetine hydrochloride should be monitored for symptoms of hyperglycemia and undergo fasting blood glucose testing at the beginning of, and periodically during, treatment. (5.4) • Hyperlipidemia: Undesirable alterations in lipids have been observed. Appropriate clinical monitoring is recommended, including fasting blood lipid testing at the beginning of, and periodically during, treatment (5.5) • Weight gain: Potential consequences of weight gain should be considered. Patients should receive regular monitoring of weight (5.6) • Serotonin Syndrome: Serotonin Syndrome has been reported with SSRIs and SNRIs, including Olanzapine and fluoxetine capsules, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St. John’s Wort). If such symptoms occur, discontinue Olanzapine and fluoxetine capsules and initiate supportive treatment. If concomitant use of Olanzapine and fluoxetine capsules with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk of serotonin syndrome, particularly during treatment initiation and dose increases (5.7). • Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena (5.8) • Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for activation of mania/hypomania (5.9) • Tardive Dyskinesia: Discontinue if clinically appropriate (5.10) • Orthostatic Hypotension: Orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, may occur especially during initial dose titration. Use caution in patients with cardiovascular disease or cerebrovascular disease, and those conditions that could affect hemodynamic responses (5.11) • Leukopenia, Neutropenia, and Agranulocytosis: Has been reported with antipsychotics, including olanzapine and fluoxetine hydrochloride. Patients with a history of a clinically significant low white blood cell count (WBC) or drug induced leukopenia/ neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine and fluoxetine hydrochloride should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors (5.12) • Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold (5.14) • 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 (5.15) • Hyponatremia: Has been reported with olanzapine and fluoxetine hydrochloride in association with syndrome of inappropriate antidiuretic hormone (SIADH) (5.16) • Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills. Use caution when operating machinery (5.17) • Hyperprolactinemia: May elevate prolactin levels (5.20) • Long Elimination Half-Life of Fluoxetine: Changes in dose will not be fully reflected in plasma for several weeks (5.22) • Laboratory Tests: Monitor fasting blood glucose and lipid profiles at the beginning of, and periodically during, treatment (5.24) Side Effects To report SUSPECTED ADVERSE REACTIONS, contact Par Pharmaceutical Companies, Inc. 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Most common adverse reactions (≥5% and at least twice that for placebo) are disturbance in attention, dry mouth, fatigue, hypersomnia, increased appetite, peripheral edema, sedation, somnolence, tremor, vision blurred, and weight increased ( 6.1)DRUG INTERACTIONS • Monoamine Oxidase Inhibitor (MAOI): (2.4, 2.5, 4.1, 5.7, 7.1) • Pimozide: Olanzapine and fluoxetine hydrochloride is contraindicated for use with pimozide due to risk of risk of drug interaction or QTc prolongation (4, 7.7) • Thioridazine: Olanzapine and fluoxetine hydrochloride is contraindicated for use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels. Do not use thioridazine within 5 weeks of discontinuing olanzapine and fluoxetine hydrochloride (4, 7.7) • Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7) • Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with olanzapine and fluoxetine hydrochloride or when olanzapine and fluoxetine hydrochloride has been recently discontinued (5.7, 7.7) • CNS Acting Drugs: Caution is advised if the concomitant administration of olanzapine and fluoxetine hydrochloride and other CNS-active drugs is required (7.2) • Antihypertensive Agent: Enhanced antihypertensive effect (7.7) • Levodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists (7.7) • Benzodiazepines: May potentiate orthostatic hypotension and sedation (7.6, 7.7) • Clozapine: May elevate clozapine levels (7.7) • Haloperidol: Elevated haloperidol levels have been observed (7.7) • Carbamazepine: Potential for elevated carbamazepine levels and clinical anticonvulsant toxicity (7.7) • Phenytoin: Potential for elevated phenytoin levels and clinical anticonvulsant toxicity (7.7) • Alcohol: May potentiate sedation and orthostatic hypotension (7.7) • Serotonergic Drugs: (2.4, 2.5, 4.1, 5.7) • Fluvoxamine: May increase olanzapine levels; a lower dose of the olanzapine component of olanzapine and fluoxetine hydrochloride should be considered (7.6) • Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin, etc.): May potentiate the risk of bleeding (7.4) • Drugs Tightly Bound to Plasma Proteins: Fluoxetine may cause shift in plasma concentrations (7.7) USE IN SPECIFIC POPULATIONS • Pregnancy: Olanzapine and fluoxetine hydrochloride should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus (8.1) • Nursing Mothers: Breast feeding is not recommended (8.3) • Pediatric Use: Safety and effectiveness of olanzapine and fluoxetine hydrochloride in children and adolescent patients have not been established (8.4) • Hepatic Impairment: Use a lower or less frequent dose in patients with cirrhosis (8.6)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING
• RECENT MAJOR CHANGES
• 1 OLANZAPINE AND FLUOXETINE INDICATIONS AND USAGE
  • 1.1 Depressive Episodes Associated with Bipolar I Disorder
• 2 OLANZAPINE AND FLUOXETINE DOSAGE AND ADMINISTRATION
  • 2.1 Depressive Episodes Associated with Bipolar I Disorder
  • 2.3 Specific Populations
  • 2.4 Switching a Patient To or From a Monamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders
  • 2.5 Use of Olanzapine and Fluoxetine Capsules with Other MAOIs such as Linezolid or Methylene Blue
• 3 DOSAGE FORMS AND STRENGTHS
• 4 OLANZAPINE AND FLUOXETINE CONTRAINDICATIONS
  • 4.1 Monoamine Oxidase Inhibitors (MAOIs)
  • 4.2 Other Containdications
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Clinical Worsening and Suicide Risk
  • 5.2 Elderly Patients with Dementia-Related Psychosis
  • 5.3 Neuroleptic Malignant Syndrome (NMS)
  • 5.4 Hyperglycemia
  • 5.5 Hyperlipidemia
  • 5.6 Weight Gain
  • 5.7 Serotonin Syndrome
  • 5.8 Allergic Reactions and Rash
  • 5.9 Activation of Mania/Hypomania
  • 5.10 Tardive Dyskinesia
  • 5.11 Orthostatic Hypotension
  • 5.12 Leukopenia, Neutropenia, and Agranulocytosis
  • 5.13 Dysphagia
  • 5.14 Seizures
  • 5.15 Abnormal Bleeding
  • 5.16 Hyponatremia
  • 5.17 Potential for Cognitive and Motor Impairment
  • 5.18 Body Temperature Regulation
  • 5.19 Use in Patients with Concomitant Illness
  • 5.20 Hyperprolactinemia
• 6 OLANZAPINE AND FLUOXETINE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Vital Signs and Laboratory Studies
  • 6.3 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Monoamine Oxidase Inhibitors (MAOI)
  • 7.2 CNS Acting Drugs
  • 7.3 Serotonergic Drugs
  • 7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin)
  • 7.5 Electroconvulsive Therapy (ECT)
  • 7.6 Potential for Other Drugs to Affect Olanzapine and Fluoxetine HCl
  • 7.7 Potential for Olanzapine and Fluoxetine HCl to Affect Other Drugs
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.2 Labor and Delivery
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Hepatic Impairment
• 9 DRUG ABUSE AND DEPENDENCE
  • 9.3 Dependence
• 10 OVERDOSAGE
  • 10.1 Management of Overdose
• 11 OLANZAPINE AND FLUOXETINE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.4 Specific Populations
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Depressive Episodes Associated with Bipolar I Disorder
• 16 HOW SUPPLIED/STORAGE AND HANDLING
  • 16.1 How Supplied
  • 16.2 Storage and Handling
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Information on Medication Guide
  • 17.2 Clinical Worsening and Suicide Risk
  • 17.3 Elderly Patients with Dementia-Related Psychosis: Increased Mortality and Cerebrovascular Adverse Events (CVAE), Including Stroke
  • 17.4 Neuroleptic Malignant Syndrome (NMS)
  • 17.5 Hyperglycemia
  • 17.6 Hyperlipidemia
  • 17.7 Weight Gain
  • 17.8 Serotonin Syndrome
  • 17.9 Allergic Reactions and Rash
  • 17.10 Orthostatic Hypotension
  • 17.11 Abnormal Bleeding
  • 17.12 Hyponatremia
  • 17.13 Potential for Cognitive and Motor Impairment
  • 17.14 Body Temperature Regulation
  • 17.15 Concomitant Medication
  • 17.16 Discontinuation of Treatment with Olanzapine and Fluoxetine HCl
  • 17.17 Alcohol
  • 17.18 Use in Specific Populations
• MEDICATION GUIDE
• PRINCIPAL DISPLAY PANEL – 100 CAPSULES
• PRINCIPAL DISPLAY PANEL –30 CAPSULES
• PRINCIPAL DISPLAY PANEL – 1000 CAPSULES
• PRINCIPAL DISPLAY PANEL – 100 CAPSULES
• PRINCIPAL DISPLAY PANEL – 30 CAPSULES

FULL PRESCRIBING INFORMATION

RECENT MAJOR CHANGES

1 INDICATIONS AND USAGE

1.1 Depressive Episodes Associated with Bipolar I Disorder

Olanzapine and fluoxetine HCl is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder in adults [see Clinical Studies (14.1)].

2 DOSAGE AND ADMINISTRATION

2.1 Depressive Episodes Associated with Bipolar I Disorder

Olanzapine and Fluoxetine Capsules should be administered once daily in the evening, generally beginning with the 6 mg/25 mg capsule. While food has no appreciable effect on the absorption of olanzapine and fluoxetine given individually, the effect of food on the absorption of olanzapine and fluoxetine HCl has not been studied. Dosage adjustments, if indicated, can be made according to efficacy and tolerability. Antidepressant efficacy was demonstrated with olanzapine and fluoxetine HCl in a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg [see Clinical Studies ( 14.1)]. The safety of doses above 18 mg per 75 mg has not been evaluated in clinical studies.

While there is no body of evidence to answer the question of how long a patient treated with olanzapine and fluoxetine HCl 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.

2.3 Specific Populations

The starting dose of Olanzapine and Fluoxetine Capsules 3 mg/25 mg to 6 mg/25 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 and fluoxetine HCl (female gender, geriatric age, nonsmoking status) or those patients who may be pharmacodynamically sensitive to olanzapine. Dosing modification 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. Olanzapine and fluoxetine HCl has not been systematically studied in patients >65 years of age or in patients <18 years of age [see Warnings and Precautions (5.19), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3, 12.4)].

Treatment of Pregnant Women — When treating pregnant women with fluoxetine, a component of olanzapine and fluoxetine HCl, during the third trimester, 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 hospitalizations, respiratory support, and tube feeding. The physician may consider tapering the dose of fluoxetine in the third trimester [see Use in Specific Populations (8.1)].

2.4 Switching a Patient To or From a Monamine 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 olanzapine and fluoxetine. Conversely, at least 5 weeks should be allowed after stopping olanzapine and fluoxetine before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4.1)].

2.5 Use of Olanzapine and Fluoxetine Capsules with Other MAOIs such as Linezolid or Methylene Blue

Do not start olanzapine and fluoxetine in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4.1)].

In some cases, a patient already receiving olanzapine and fluoxetine therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue are judged to outweigh the risks of serotonin syndrome in a particular patient, olanzapine and fluoxetine should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for five weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with Olanzapine and Fluoxetine Capsules may be resumed 24 hours after the last dose of linezolid and intravenous methylene blue [see Warning and Precautions (5.7)].

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 1mg/kg with olanzapine and fluoxetine in unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.7).

3 DOSAGE FORMS AND STRENGTHS

Capsules (mg equivalent olanzapine/mg equivalent fluoxetine):

• •3 mg/25 mg
• •6 mg/25 mg
• •6 mg/50 mg
• •12 mg/25 mg
• •12 mg/50 mg

4 CONTRAINDICATIONS

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4.1 Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with olanzapine and fluoxetine or within 5 weeks of stopping treatment with olanzapine and fluoxetine is contraindicated because of an increased risk of sertotonin syndrome. The use of olanzapine and fluoxetine with 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated. [ see Dosage and Administration (2.4) and Warnings and Precautions (5.7)].

4.2 Other Containdications

The use of olanzapine and fluoxetine is contraindicated with the following:

• •Pimozide – [see Drug Interactions (7.7)]
• •Thioridazine – [see Drug Interactions (7.7)

5 WARNINGS AND PRECAUTIONS

5.1 Clinical Worsening and Suicide Risk

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

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, Obsessive Compulsive Disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.

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 (5.23)].

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 olanzapine and fluoxetine HCl 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 olanzapine and fluoxetine HCl is not approved for use in treating any indications in the pediatric population [see Use in Specific Populations (8.4)].

5.2 Elderly Patients with Dementia-Related Psychosis

Increased Mortality — Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Olanzapine and fluoxetine HCl is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.19), and Patient Counseling Information (17.3)].

In olanzapine placebo-controlled clinical trials of elderly patients with dementia-related psychosis, the incidence of death in olanzapine-treated patients was significantly greater than placebo-treated patients (3.5% vs 1.5%, respectively).

Cerebrovascular Adverse Events (CVAE), Including Stroke — Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with olanzapine compared to patients treated with placebo. Olanzapine and olanzapine and fluoxetine HCl are not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Patient Counseling Information (17.3)].

5.3 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as NMS has been reported in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

If after recovering from NMS, a patient requires treatment with an antipsychotic, the patient should be carefully monitored, since recurrences of NMS have been reported [see Warnings and Precautions (5.7) and Patient Counseling Information (17.4, 17.8)].

5.4 Hyperglycemia

Physicians should consider the risks and benefits when prescribing olanzapine and fluoxetine HCl to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100 to 126 mg/dL, nonfasting 140 to 200 mg/dL). Patients taking olanzapine and fluoxetine HCl should be monitored regularly for worsening of glucose control. Patients starting treatment with olanzapine and fluoxetine HCl should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug [see Patient Counseling Information (17.5)].

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics, including olanzapine alone, as well as olanzapine taken concomitantly with fluoxetine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.

Mean increases in blood glucose have been observed in patients treated (median exposure of 9.2 months) with olanzapine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE). The mean increase of serum glucose (fasting and nonfasting samples) from baseline to the average of the 2 highest serum concentrations was 15.0 mg/dL.

In a study of healthy volunteers, subjects who received olanzapine (N=22) for 3 weeks had a mean increase compared to baseline in fasting blood glucose of 2.3 mg/dL. Placebo-treated subjects (N=19) had a mean increase in fasting blood glucose compared to baseline of 0.34 mg/dL.

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, with treatment duration up to 12 weeks, olanzapine and fluoxetine HCl was associated with a greater mean change in random glucose compared to placebo (8.65 mg/dL vs -3.86 mg/dL). The difference in mean changes between olanzapine and fluoxetine HCl and placebo was greater in patients with evidence of glucose dysregulation at baseline (including those patients diagnosed with diabetes mellitus or related adverse reactions, patients treated with anti-diabetic agents, patients with a baseline random glucose level ≥200 mg/dL, or a baseline fasting glucose level ≥126 mg/dL). Olanzapine and fluoxetine HCl - treated patients had a greater mean HbA _1c increase from baseline of 0.15% (median exposure 63 days), compared to a mean HbA_1c decrease of 0.04% in fluoxetine-treated subjects (median exposure 57 days) and a mean HbA_1c increase of 0.12% in olanzapine- treated patients (median exposure 56 days).

In an analysis of 6 controlled clinical studies, a larger proportion of olanzapine and fluoxetine HCl -treated subjects had glycosuria (4.4%) compared to placebo-treated subjects (1.4%).

The mean change in nonfasting glucose in patients exposed at least 48 weeks was 5.9 mg/dL (N=425).

Table 2 shows short-term and long-term changes in random glucose levels from adult olanzapine and fluoxetine HCl studies.

Controlled fasting glucose data is limited for olanzapine and fluoxetine HCl; however, in an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine was associated with a greater mean change in fasting glucose levels compared to placebo (2.76 mg/dL vs 0.17 mg/dL).

The mean change in fasting glucose for olanzapine-treated patients exposed at least 48 weeks was 4.2 mg/dL (N=487). In analyses of patients who completed 9 to 12 months of olanzapine therapy, mean change in fasting and nonfasting glucose levels continued to increase over time.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine and fluoxetine in combination have not been established in patients under the age of 18 years. The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescent patients, including those with Schizophrenia (6 weeks) or Bipolar I Disorder (manic or mixed episodes) (3 weeks), olanzapine was associated with a greater mean change from baseline in fasting glucose levels compared to placebo (2.68 mg/dL vs -2.59 mg/dL). The mean change in fasting glucose for adolescents exposed at least 24 weeks was 3.1 mg/dL (N=121). Table 3 shows short-term and long-term changes in fasting blood glucose from adolescent olanzapine monotherapy studies.

5.5 Hyperlipidemia

Undesirable alterations in lipids have been observed with olanzapine and fluoxetine HCl use. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine and fluoxetine HCl, is recommended [see Patient Counseling Information (17.6)].

Clinically meaningful, and sometimes very high (>500 mg/dL), elevations in triglyceride levels have been observed with olanzapine and fluoxetine HCl use. Clinically meaningful increases in total cholesterol have also been seen with olanzapine and fluoxetine HCl use.

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, with treatment duration up to 12 weeks, olanzapine and fluoxetine HCl -treated patients had an increase from baseline in mean random total cholesterol of 12.1 mg/dL compared to an increase from baseline in mean random total cholesterol of 4.8 mg/dL for olanzapine-treated patients and a decrease in mean random total cholesterol of 5.5 mg/dL for placebo-treated patients. Table 4 shows categorical changes in nonfasting lipid values.

In long-term olanzapine and fluoxetine in combination studies (at least 48 weeks), changes (at least once) in nonfasting total cholesterol from normal at baseline to high occurred in 12% (N=150) and changes from borderline to high occurred in 56.6% (N=143) of patients. The mean change in nonfasting total cholesterol was 11.3 mg/dL (N= 426).

Fasting lipid data is limited for olanzapine and fluoxetine HCl; however, in an analysis of 5 placebo-controlled olanzapine monotherapy studies with treatment duration up to 12 weeks, olanzapine-treated patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.3 mg/dL, 3.0 mg/dL, and 20.8 mg/dL respectively compared to decreases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 6.1 mg/dL, 4.3 mg/dL, and 10.7 mg/dL for placebo-treated patients. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated patients and placebo-treated patients. Mean increases in fasting lipid values (total cholesterol, LDL cholesterol, and triglycerides) were greater in patients without evidence of lipid dysregulation at baseline, where lipid dysregulation was defined as patients diagnosed with dyslipidemia or related adverse reactions, patients treated with lipid lowering agents, patients with high baseline lipid levels.

In long-term olanzapine studies (at least 48 weeks), patients had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.6 mg/dL, 2.5 mg/dL, and 18.7 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 0.16 mg/dL. In an analysis of patients who completed 12 months of therapy, the mean nonfasting total cholesterol did not increase further after approximately 4 to 6 months.

The proportion of olanzapine-treated patients who had changes (at least once) in total cholesterol, LDL cholesterol or triglycerides from normal or borderline to high, or changes in HDL cholesterol from normal or borderline to low, was greater in long-term studies (at least 48 weeks) as compared with short-term studies. Table 5 shows categorical changes in fasting lipids values.

In phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), over a median exposure of 9.2 months, the mean increase in triglycerides in patients taking olanzapine was 40.5 mg/dL. In phase 1 of CATIE, the median increase in total cholesterol was 9.4 mg/dL.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine and fluoxetine in combination have not been established in patients under the age of 18 years. The safety and efficacy of olanzapine have not been established in patients under the age of 13 years.

In an analysis of 3 placebo-controlled olanzapine monotherapy studies of adolescents, including those with Schizophrenia (6 weeks) or Bipolar I Disorder (manic or mixed episodes) (3 weeks), olanzapine-treated adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 12.9 mg/dL, 6.5 mg/dL, and 28.4 mg/dL, respectively, compared to increases from baseline in mean fasting total cholesterol and LDL cholesterol of 1.3 mg/dL and 1.0 mg/dL, and a decrease in triglycerides of 1.1 mg/dL for placebo-treated adolescents. For fasting HDL cholesterol, no clinically meaningful differences were observed between olanzapine-treated adolescents and placebo-treated adolescents.

In long-term olanzapine studies (at least 24 weeks), adolescents had increases from baseline in mean fasting total cholesterol, LDL cholesterol, and triglycerides of 5.5 mg/dL, 5.4 mg/dL, and 20.5 mg/dL, respectively, and a mean decrease in fasting HDL cholesterol of 4.5 mg/dL. Table 6 shows categorical changes in fasting lipids values in adolescents.

5.6 Weight Gain

Potential consequences of weight gain should be considered prior to starting olanzapine and fluoxetine HCl. Patients receiving olanzapine and fluoxetine HCl should receive regular monitoring of weight [see Patient Counseling Information (17.7)].

In an analysis of 7 controlled clinical studies, 2 of which were placebo-controlled, the mean weight increase for olanzapine and fluoxetine HCl -treated patients was greater than placebo-treated patients [4 kg (8.8 lb) vs -0.3 kg (-0.7 lb)]. Twenty-two percent of olanzapine and fluoxetine HCl-treated patients gained at least 7% of their baseline weight, with a median exposure to event of 6 weeks. This was greater than in placebo-treated patients (1.8%). Approximately 3% of olanzapine and fluoxetine HCl -treated patients gained at least 15% of their baseline weight, with a median exposure to event of 8 weeks. This was greater than in placebo-treated patients (0%). Clinically significant weight gain was observed across all baseline Body Mass Index (BMI) categories. Discontinuation due to weight gain occurred in 2.5% of olanzapine and fluoxetine HCl -treated patients and 0% of placebo-treated patients.

In long-term olanzapine and fluoxetine in combination studies (at least 48 weeks), the mean weight gain was 6.7 kg (14.7 lb) (median exposure of 448 days, N=431). The percentages of patients who gained at least 7%, 15% or 25% of their baseline body weight with long-term exposure were 66%, 33%, and 10%, respectively. Discontinuation due to weight gain occurred in 1.2% of patients treated with olanzapine and fluoxetine in combination following at least 48 weeks of exposure.

In long-term olanzapine studies (at least 48 weeks), the mean weight gain was 5.6 kg (12.3 lb) (median exposure of 573 days, N=2021). The percentages of patients who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 64%, 32%, and 12%, respectively. Discontinuation due to weight gain occurred in 0.4% of olanzapine-treated patients following at least 48 weeks of exposure.

Table 7 includes data on adult weight gain with olanzapine pooled from 86 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified.

Olanzapine Monotherapy in Adolescents — The safety and efficacy of olanzapine and fluoxetine in combination have not been established in patients under the age of 18 years. The safety and efficacy of olanzapine have not been established in patients under the age of 13 years. Mean increase in weight in adolescents was greater than in adults. In 4 placebo-controlled trials, discontinuation due to weight gain occurred in 1% of olanzapine-treated patients, compared to 0% of placebo-treated patients.

In long-term olanzapine studies (at least 24 weeks), the mean weight gain was 11.2 kg (24.6 lb) (median exposure of 201 days, N=179). The percentages of adolescents who gained at least 7%, 15%, or 25% of their baseline body weight with long-term exposure were 89%, 55%, and 29%, respectively. Among adolescent patients, mean weight gain by baseline BMI category was 11.5 kg (25.3 lb), 12.1 kg (26.6 lb), and 12.7 kg (27.9 lb), respectively, for normal (N=106), overweight (N=26) and obese (N=17). Discontinuation due to weight gain occurred in 2.2% of olanzapine-treated patients following at least 24 weeks of exposure.

Table 9 shows data on adolescent weight gain with olanzapine pooled from 6 clinical trials. The data in each column represent data for those patients who completed treatment periods of the durations specified. Little clinical trial data is available on weight gain in adolescents with olanzapine beyond 6 months of treatment.

5.7 Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs including olanzapine and fluoxetine, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants ), fentanyl, lithium, tramadol, tryptophan, buspirone, 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 olanzapine and fluoxetine with MAOIs intended to treat psychiatric disorders is contraindicated. Olanzapine and fluoxetine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided informations on the route of administration involved intravenous administration in the dose range of 1mg/kg to 8mg/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 olanzapine and fluoxetine. Olanzapine and fluoxetine should be discontinued before initiating treatment with the MAOI [see Dosage and Adminstration (2.4, and 2.5) and Contraindications (4.1)].

If concomitant use of olanzapine and fluoxetine with other serotonergic drugs including triptans, tricyclic anitdepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initation and dose increases.

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

5.8 Allergic Reactions and Rash

In olanzapine and fluoxetine HCl premarketing controlled clinical studies, the overall incidence of rash or allergic reactions in olanzapine and fluoxetine HCl -treated patients [4.6% (26/571)] was similar to that of placebo [5.2% (25/477)]. The majority of the cases of rash and/or urticaria were mild; however, 3 patients discontinued (1 due to rash, which was moderate in severity and 2 due to allergic reactions, 1 of which included face edema).

In fluoxetine US clinical studies, 7% of 10,782 fluoxetine-treated patients developed various types of rashes and/or urticaria. Among the cases of rash and/or urticaria reported in premarketing clinical studies, 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 fluoxetine premarketing clinical studies, 2 patients are known to have developed a serious cutaneous systemic illness. In neither patient was there an unequivocal diagnosis, but 1 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, 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, 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 possible allergic phenomena for which an alternative etiology cannot be identified, olanzapine and fluoxetine HCl should be discontinued.

5.9 Activation of 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 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 olanzapine and fluoxetine HCl is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder.

In the 2 controlled bipolar depression studies there was no statistically significant difference in the incidence of manic reactions (manic reaction or manic depressive reaction) between olanzapine and fluoxetine HCl -and placebo-treated patients. In 1 of the studies, the incidence of manic reactions was (7% [3/43]) in olanzapine and fluoxetine HCl -treated patients compared to (3% [5/184]) in placebo-treated patients. In the other study, the incidence of manic reactions was (2% [1/43]) in olanzapine and fluoxetine HCl -treated patients compared to (8% [15/193]) in placebo-treated patients. This limited controlled trial experience of olanzapine and fluoxetine HCl in the acute treatment of depressive episodes associated with Bipolar I Disorder makes it difficult to interpret these findings until additional data is obtained. Because of this and the cyclical nature of Bipolar I Disorder, patients should be monitored closely for the development of symptoms of mania/hypomania during treatment with olanzapine and fluoxetine HCl.

5.10 Tardive Dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment.

There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

The incidence of dyskinetic movement in olanzapine and fluoxetine HCl -treated patients was infrequent. The mean score on the Abnormal Involuntary Movement Scale (AIMS) in the olanzapine and fluoxetine HCl -controlled database across clinical studies involving olanzapine and fluoxetine HCl -treated patients decreased from baseline. Nonetheless, olanzapine and fluoxetine HCl should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine and fluoxetine HCl, drug discontinuation should be considered. However, some patients may require treatment with olanzapine and fluoxetine HCl despite the presence of the syndrome. The need for continued treatment should be reassessed periodically.

5.11 Orthostatic Hypotension

Olanzapine and fluoxetine HCl may induce orthostatic hypotension associated with dizziness, tachycardia, bradycardia and, in some patients, syncope, especially during the initial dose-titration period [see Patient Counseling Information (17.10)].

In the olanzapine and fluoxetine HCl -controlled clinical trials across all indications, there were no significant differences between olanzapine and fluoxetine HCl -treated patients and olanzapine, fluoxetine-or placebo-treated patients in exposure-adjusted rates of orthostatic systolic blood pressure decreases of at least 30 mm Hg. Orthostatic systolic blood pressure decreases of at least 30 mm Hg occurred in 4.0% (28/705), 2.3% (19/831), 4.5% (18/399), and 1.8% (8/442) of the olanzapine and fluoxetine HCl, olanzapine, fluoxetine, and placebo groups, respectively. In this group of studies, the incidence of syncope-related adverse reactions (i.e., syncope and/or loss of consciousness) in olanzapine and fluoxetine HCl -treated patients was 0.4% (3/771) compared to placebo 0.2% (1/477).

In a clinical pharmacology study of olanzapine and fluoxetine HCl, 3 healthy subjects were discontinued from the trial after experiencing severe, but self-limited, hypotension and bradycardia that occurred 2 to 9 hours following a single 12 mg/50 mg dose of olanzapine and fluoxetine HCl. Reactions consisting of this combination of hypotension and bradycardia (and also accompanied by sinus pause) have been observed in at least 3 other healthy subjects treated with various formulations of olanzapine (1 oral, 2 intramuscular). In controlled clinical studies, the incidence of patients with a ≥20 bpm decrease in orthostatic pulse concomitantly with a ≥20 mm Hg decrease in orthostatic systolic blood pressure was 0.3% (2/706) in the olanzapine and fluoxetine HCl group, 0.2% (1/445) in the placebo group, 0.7% (6/837) in the olanzapine group, and 0% (0/404) in the fluoxetine group.

Olanzapine and fluoxetine HCl should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, or conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).

5.12 Leukopenia, Neutropenia, and Agranulocytosis

Class Effect -In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including olanzapine and fluoxetine HCl. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count (WBC) and history of drug induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine and fluoxetine HCl should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm ³) should discontinue olanzapine and fluoxetine HCl and have their WBC followed until recovery.

5.13 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine and fluoxetine HCl is not approved for the treatment of patients with Alzheimer's disease.

5.14 Seizures

Seizures occurred in 0.2% (4/2547) of olanzapine and fluoxetine HCl -treated patients during open-label clinical studies. No seizures occurred in the controlled olanzapine and fluoxetine HCl studies. Seizures have also been reported with both olanzapine and fluoxetine monotherapy. Olanzapine and fluoxetine HCl should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold, e.g., Alzheimer's dementia. Olanzapine and fluoxetine HCl is not approved for the treatment of patients with Alzheimer's disease. Conditions that lower the seizure threshold may be more prevalent in a population of ≥65 years of age.

5.15 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 olanzapine and fluoxetine HCl and NSAIDs, aspirin, or other drugs that affect coagulation [see Drug Interactions (7.6) and Patient Counseling Information (17.11)].

5.16 Hyponatremia

Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine and olanzapine and fluoxetine HCl. 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 olanzapine and fluoxetine HCl 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 olanzapine and fluoxetine HCl 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. [See Patient Counseling Information (17.12)].

5.17 Potential for Cognitive and Motor Impairment

Sedation-related adverse reactions were commonly reported with olanzapine and fluoxetine HCl treatment occurring at an incidence of 26.6% in olanzapine and fluoxetine HCl -treated patients compared with 10.9% in placebo-treated patients. Sedation-related adverse reactions (sedation, somnolence, hypersomnia, and lethargy) led to discontinuation in 2% (15/771) of patients in the controlled clinical studies. As with any CNS-active drug, olanzapine and fluoxetine HCl 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 olanzapine and fluoxetine HCl therapy does not affect them adversely [see Patient Counseling Information (17.13)].

5.18 Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic drugs. Appropriate care is advised when prescribing olanzapine and fluoxetine HCl for patients who will be experiencing conditions which may contribute to an elevation in core body temperature (e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration). [See Patient Counseling Information (17.13)].

5.19 Use in Patients with Concomitant Illness

Clinical experience with olanzapine and fluoxetine HCl in patients with concomitant systemic illnesses is limited [see Clinical Pharmacology (12.4)]. The following precautions for the individual components may be applicable to olanzapine and fluoxetine HCl.

Olanzapine exhibits in vitro muscarinic receptor affinity. In premarketing clinical studies, olanzapine and fluoxetine HCl was associated with constipation, dry mouth, and tachycardia, all adverse reactions possibly related to cholinergic antagonism. Such adverse reactions were not often the basis for study discontinuations; olanzapine and fluoxetine HCl should be used with caution in patients with clinically significant prostatic hypertrophy, narrow angle glaucoma, a history of paralytic ileus, or related conditions.

In 5 placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis (n=1184), the following treatment-emergent adverse reactions were reported in olanzapine-treated patients at an incidence of at least 2% and significantly greater than placebo-treated patients: falls, somnolence, peripheral edema, abnormal gait, urinary incontinence, lethargy, increased weight, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations. The rate of discontinuation due to adverse reactions was significantly greater with olanzapine than placebo (13% vs 7%). Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.2), and Patient Counseling Information (17.3)].

As with other CNS-active drugs, olanzapine and fluoxetine HCl should be used with caution in elderly patients with dementia. Olanzapine is not approved for the treatment of patients with dementia-related psychosis. If the prescriber elects to treat elderly patients with dementia-related psychosis, vigilance should be exercised [see Boxed Warning and Warnings and Precautions (5.2), and Patient Counseling Information (17.3)].

Olanzapine and fluoxetine HCl 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 excluded from clinical studies during the premarket testing.

Caution is advised when using olanzapine and fluoxetine HCl in cardiac patients and in patients with diseases or conditions that could affect hemodynamic responses [see Warnings and Precautions (5.11)].

5.20 Hyperprolactinemia

As with other drugs that antagonize dopamine D ₂ receptors, olanzapine and fluoxetine HCl elevates prolactin levels, and the elevation persists during administration. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and erectile dysfunction have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. As is common with compounds that increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time.

In controlled clinical studies of olanzapine and fluoxetine HCl (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 28% of adults treated with olanzapine and fluoxetine HCl as compared to 5% of placebo-treated patients. The elevations persisted throughout administration of olanzapine and fluoxetine HCl. In a pooled analysis from clinical studies including 2929 adults treated with olanzapine and fluoxetine HCl, potentially associated clinical manifestations included menstrual-related events ¹ (1% [20/1946] of females), sexual function-related events² (7% [192/2929] of females and males), and breast-related events³ (0.8% [16/1946] of females, 0.2% [2/983] of males).

In placebo-controlled olanzapine clinical studies (up to 12 weeks), changes from normal to high in prolactin concentrations were observed in 30% of adults treated with olanzapine as compared to 10.5% of adults treated with placebo. In a pooled analysis from clinical studies including 8136 adults treated with olanzapine, potentially associated clinical manifestations included menstrual-related events ¹ (2% [49/3240] of females), sexual function-related events² (2% [150/8136] of females and males), and breast-related events³ (0.7% [23/3240] of females, 0.2% [9/4896] of males).

In placebo-controlled olanzapine monotherapy studies in adolescent patients (up to 6 weeks) with schizophrenia or bipolar I disorder (manic or mixed episodes), changes from normal to high in prolactin concentrations were observed in 47% of olanzapine-treated patients compared to 7% of placebo-treated patients. In a pooled analysis from clinical trials including 454 adolescents treated with olanzapine, potentially associated clinical manifestations included menstrual-related events ¹ (1% [2/168] of females), sexual function-related events² (0.7% [3/454] of females and males), and breast-related events³ (2% [3/168] of females, 2% [7/286] of males), [see Use in Specific Populations (8.4)].

^1.Based on a search of the following terms: amenorrhea, hypomenorrhea, menstruation delayed, and oligomenorrhea.

^2.Based on a search of the following terms: anorgasmia, delayed ejaculation, erectile dysfunction, decreased libido, loss of libido, abnormal orgasm, and sexual dysfunction.

^3.Based on a search of the following terms: breast discharge, enlargement or swelling, galactorrhea, gynecomastia, and lactation disorder.

5.21 Concomitant Use of Olanzapine and Fluoxetine Products

Olanzapine and fluoxetine HCl contains the same active ingredients that are in Zyprexa ^®, ZyprexaZydis^® (olanzapine), and in Prozac^®, ProzacWeekly^™, and Sarafem^® (fluoxetine HCl). Caution should be exercised when prescribing these medications concomitantly with olanzapine and fluoxetine HCl [see Overdosage (10)].

5.22 Long Elimination Half-Life of Fluoxetine

Because of the long elimination half-lives of fluoxetine 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)].

5.23 Discontinuation of Treatment with Olanzapine and Fluoxetine HCl

During marketing of fluoxetine, a component of olanzapine and fluoxetine HCl, 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 [see Dosage and Administration (2.4) and Patient Counseling Information (17.16)].

5.24 Laboratory Tests

Fasting blood glucose testing and lipid profile at the beginning of, and periodically during, treatment is recommended [see Warnings and Precautions (5.4, 5.5) and Patient Counseling Information (17.5, 17.6)].

6 ADVERSE REACTIONS

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.

6.1 Clinical Trials Experience

The information below is derived from a clinical study database for olanzapine and fluoxetine HCl consisting of 2547 patients with approximately 1085 patient-years of exposure. The conditions and duration of treatment with olanzapine and fluoxetine HCl varied greatly and included (in overlapping categories) open-label and double-blind phases of studies, inpatients and outpatients, fixed-dose and dose-titration studies, and short-term or long-term exposure.

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, MedDRA or COSTART Dictionary terminology has been used to classify reported adverse reactions. The data in the tables represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. It is possible that reactions reported during therapy were not necessarily related to drug exposure.

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 studies. 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 clinician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence rate in the population studied.

Adverse Reactions Associated with Discontinuation of Treatment in Short-Term, Controlled Studies Depressive Episodes Associated with Bipolar 1 Disorder— Overall, 11.3% of the 771 patients in the olanzapine and fluoxetine HCl group discontinued due to adverse reactions compared with 4.4% of the 477 patients for placebo. Adverse reactions leading to discontinuation associated with the use of olanzapine and fluoxetine HCl (incidence of at least 1% for olanzapine and fluoxetine HCl and greater than that for placebo) using MedDRA Dictionary coding were weight increased (2%) and sedation (1%) versus placebo patients which had 0% incidence of weight increased and sedation.

Commonly Observed Adverse Reactions in Short-Term, Controlled Studies Depressive Episodes Associated with Bipolar 1 Disorder— The most commonly observed adverse reactions associated with the use of olanzapine and fluoxetine HCl (incidence ≥5% and at least twice that for placebo in the olanzapine and fluoxetine HCl -controlled database) using MedDRA Dictionary coding were: disturbance in attention, dry mouth, fatigue, hypersomnia, increased appetite, peripheral edema, sedation, somnolence, tremor, vision blurred, and weight increased. Adverse reactions reported in clinical trials of olanzapine and fluoxetine in combination are generally consistent with treatment-emergent adverse reactions during olanzapine or fluoxetine monotherapy.

Adverse Reactions Occurring at an Incidence of 2% or More in Short-Term Controlled Studies Depressive Episodes Associated with Bipolar 1 Disorder— Table 10 enumerates the treatment-emergent adverse reactions associated with the use of olanzapine and fluoxetine HCl (incidence of at least 2% for olanzapine and fluoxetine HCl and twice or more than for placebo). The olanzapine and fluoxetine HCl -controlled column includes patients with various diagnoses while the placebo column includes only patients with bipolar depression and major depression with psychotic features.

Extrapyramidal Symptoms

Dystonia, Class Effect for Antipsychotics — Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, the frequency and severity are greater with high potency and at higher doses of first generation antipsychotic drugs. In general, an elevated risk of acute dystonia may be observed in males and younger age groups receiving antipsychotics; however, events of dystonia have been reported infrequently (<1%) with the olanzapine and fluoxetine combination.

Additional Findings Observed in Clinical Studies

Sexual Dysfunction — In the pool of controlled olanzapine and fluoxetine HCl studies in patients with bipolar depression, there were higher rates of the treatment-emergent adverse reactions decreased libido, anorgasmia, erectile dysfunction and abnormal ejaculation in the olanzapine and fluoxetine HCl group than in the placebo group. One case of decreased libido led to discontinuation in the olanzapine and fluoxetine HCl group. In the controlled studies that contained a fluoxetine arm, the rates of decreased libido and abnormal ejaculation in the olanzapine and fluoxetine HCl group were less than the rates in the fluoxetine group. None of the differences were statistically significant.

Sexual dysfunction, including 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.

There are no adequate and well-controlled studies examining dysfunction with olanzapine and fluoxetine HCl or fluoxetine treatment. Symptoms of sexual dysfunction occasionally persist after discontinuation of fluoxetine treatment.

Difference Among Dose Levels Observed in Other Olanzapine Clinical Trials

In a single 8-week randomized, double-blind, fixed-dose study comparing 10 (N=199), 20 (N=200), and 40 (N=200) mg/day of olanzapine in patients with Schizophrenia or Schizoaffective Disorder, statistically significant differences among 3 dose groups were observed for the following safety outcomes: weight gain, prolactin elevation, fatigue, and dizziness. Mean baseline to endpoint increase in weight (10 mg/day: 1.9 kg; 20 mg/day: 2.3 kg; 40 mg/day: 3 kg) was observed with significant differences between 10 vs 40 mg/day. Incidence of treatment-emergent prolactin elevation >24.2 ng/mL (female) or >18.77 ng/mL (male) at any time during the trial (10 mg/day: 31.2%; 20 mg/day: 42.7%; 40 mg/day: 61.1%) with significant differences between 10 vs 40 mg/day and 20 vs 40 mg/day; fatigue (10 mg/day: 1.5%; 20 mg/day: 2.1%; 40 mg/day: 6.6%) with significant differences between 10 vs 40 and 20 vs 40 mg/day; and dizziness (10 mg/day: 2.6%; 20 mg/day: 1.6%; 40 mg/day: 6.6%) with significant differences between 20 vs 40 mg, was observed.

Other Adverse Reactions Observed in Clinical Studies

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

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

Body as a Whole — Frequent: chills, neck rigidity, photosensitivity reaction; Rare: death¹.

Cardiovascular System — Frequent: vasodilatation; Infrequent: QT-interval prolonged.

Digestive System — Frequent: diarrhea; Infrequent: gastritis, gastroenteritis, nausea and vomiting, peptic ulcer; Rare: gastrointestinal hemorrhage, intestinal obstruction, liver fatty deposit, pancreatitis.

Hemic and Lymphatic System — Frequent: ecchymosis; Infrequent: anemia, thrombocytopenia; Rare: leukopenia, purpura.

Metabolic and Nutritional — Frequent: generalized edema, weight loss; Rare: bilirubinemia, creatinine increased, gout.

Musculoskeletal System — Rare: osteoporosis.

Nervous System — Frequent: amnesia; Infrequent: ataxia, buccoglossal syndrome, coma, depersonalization, dysarthria, emotional lability, euphoria, hypokinesia, movement disorder, myoclonus; Rare: hyperkinesia, libido increased, withdrawal syndrome.

Respiratory System — Infrequent: epistaxis, yawn; Rare: laryngismus.

Skin and Appendages — Infrequent: alopecia, dry skin, pruritis; Rare: exfoliative dermatitis.

Special Senses — Frequent: taste perversion; Infrequent: abnormality of accommodation, dry eyes.

Urogenital System — Frequent: breast pain, menorrhagia², urinary frequency, urinary incontinence; Infrequent: amenorrhea², female lactation², hypomenorrhea², metrorrhagia², urinary retention, urinary urgency, urination impaired; Rare: breast engorgement².

¹This term represents a serious adverse event but does not meet the definition for adverse drug reactions. It is included here because of its seriousness.

²Adjusted for gender.

Other Adverse Reactions Observed with Olanzapine or Fluoxetine Monotherapy

The following adverse reactions were not observed in olanzapine and fluoxetine HCl -treated patients during premarketing clinical studies but have been reported with olanzapine or fluoxetine monotherapy: aplastic anemia, bruxism, cholestatic jaundice, diabetic coma, dyskinesia, eosinophilic pneumonia ³, erythema multiforme, espohgeal ulcer, gynecological bleeding, headache, hypotension, jaundice, neutropenia, sudden unexpected death³, sweating, and violent behaviors³. Random triglyceride levels of ≥1000 mg/dL have been reported.

³These terms represent serious adverse events but do not meet the definition for adverse drug reactions. They are included here because of their seriousness.

6.2 Vital Signs and Laboratory Studies

Vital Signs — Tachycardia, bradycardia, and orthostatic hypotension have occurred in olanzapine and fluoxetine HCl -treated patients [see Warnings and Precautions (5.11)]. The mean standing pulse rate of olanzapine and fluoxetine HCl -treated patients was reduced by 0.7 beats/min.

Laboratory Changes — In olanzapine and fluoxetine HCl clinical studies, olanzapine and fluoxetine HCl was associated with statistically significantly greater frequencies for the following treatment-emergent findings in laboratory analytes (normal at baseline to abnormal at any time during the trial) compared to placebo: elevated prolactin (28% vs 5%); elevated urea nitrogen (3% vs 0.8%); elevated uric acid (3% vs 0.5%); low albumin (3% vs 0.3%); low bicarbonate (14% vs 9%); low hemoglobin (3% vs 0%); low inorganic phosphorus (2% vs 0.3%); low lymphocytes (2% vs 0%); and low total bilirubin (15% vs 4%).

As with olanzapine, asymptomatic elevations of hepatic aminotransferases [ALT, AST, and GGT] and alkaline phosphatase have been observed with olanzapine and fluoxetine HCl. In the olanzapine and fluoxetine HCl -controlled database, clinically significant ALT elevations (change from <3 times the upper limit of normal [ULN] at baseline to ≥3 times ULN) were observed in 5% (38/698) of patients exposed to olanzapine and fluoxetine HCl compared with 0.5% (2/378) of placebo-treated patients and 4% (33/751) of olanzapine-treated patients. ALT elevations ≥5 times ULN were observed in 2% (11/701 of olanzapine and fluoxetine HCl-treated patients, compared to 0.3% (1/379) of placebo-treated patients and 1% (11/760) of olanzapine-treated patients. No patient with elevated ALT values experienced jaundice or liver failure, or met the criteria for Hy’s Rule. ALT values returned to normal, or were decreasing, at last follow-up in the majority of patients who either continued treatment with olanzapine and fluoxetine HCl or discontinued olanzapine and fluoxetine HCl.

Rare postmarketing reports of hepatitis have been received in patients treated with olanzapine. Very rare cases of cholestatic or mixed liver injury have also been reported in the postmarketing period in patients treated with olanzapine.

Caution should be exercised in patients with signs and symptoms of hepatic impairment, in patients with pre-existing conditions associated with limited hepatic functional reserve, and in patients who are being treated with potentially hepatotoxic drugs.

An increase in creatine phosphokinase has been reported very rarely in olanzapine and fluoxetine HCl-treated patients and infrequently in clinical trials of olanzapine-treated patients.

Effect on Cardiac Repolarization — The mean increase in QT_c interval for olanzapine and fluoxetine HCl-treated patients (4.4 msec) in clinical studies was significantly greater than that for placebo-treated (-0.8 msec), olanzapine-treated (-0.3 msec) patients, and fluoxetine treated (1.7 msec) patients. There were no significant differences between patients treated with olanzapine and fluoxetine HCl, placebo, olanzapine, or fluoxetine in the incidence of QT_c outliers (>500 msec).

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of olanzapine and fluoxetine HCl. 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.

Adverse reactions reported since market introduction that were temporally (but not necessarily causally) related to olanzapine and fluoxetine HCl therapy include the following: rhabdomyolysis and venous thromboembolic events (including pulmonary embolism and deep venous thrombosis).

7 DRUG INTERACTIONS

The risks of using olanzapine and fluoxetine HCl in combination with other drugs have not been extensively evaluated in systematic studies. The drug-drug interactions sections of fluoxetine and olanzapine are applicable to olanzapine and fluoxetine HCl. As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)].

7.1 Monoamine Oxidase Inhibitors (MAOI)

[see Dosage and Administration (2.4) (2.5), Contraindications ( 4.1 ), Warnings and Precautions (5.7)].

7.2 CNS Acting Drugs

Caution is advised if the concomitant administration of olanzapine and fluoxetine HCl and other CNS-active drugs is required. In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see Clinical Pharmacology (12.3)].

7.3 Serotonergic Drugs

[see Dosage and Administration (2.4) (2.5), Contraindications (4.1) and Warnings and Precations (5.7)].

7.4 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin [see Warnings and Precautions (5.15)]. Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics. Single doses of olanzapine did not affect the pharmacokinetics of warfarin. Patients receiving warfarin therapy should be carefully monitored when olanzapine and fluoxetine HCl is initiated or discontinued.

7.5 Electroconvulsive Therapy (ECT)

There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine. There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment [see Warnings and Precautions (5.14)].

7.6 Potential for Other Drugs to Affect Olanzapine and Fluoxetine HCl

Benzodiazepines — Co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.7)].

Inducers of 1A2 — Carbamazepine therapy (200 mg BID) causes an approximate 50% increase in the clearance of olanzapine. This increase is likely due to the fact that carbamazepine is a potent inducer of CYP1A2 activity. Higher daily doses of carbamazepine may cause an even greater increase in olanzapine clearance [see Drug Interactions (7.7)].

Alcohol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics [see Drug Interactions (7.7)].

Inhibitors of CYP1A2 — Fluvoxamine decreases the clearance of olanzapine. This results in a mean increase in olanzapine C_max following fluvoxamine administration of 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC is 52% and 108%, respectively. Lower doses of the olanzapine component of olanzapine and fluoxetine HCl should be considered in patients receiving concomitant treatment with fluvoxamine.

The Effect of Other Drugs on Olanzapine — Fluoxetine, an inhibitor of CYP2D6, decreases olanzapine clearance a small amount [see Clinical Pharmacology (12.3)]. Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine clearance. The effect of CYP1A2 inhibitors, such as fluvoxamine and some fluoroquinolone antibiotics, on olanzapine and fluoxetine HCl has not been evaluated. Although olanzapine is metabolized by multiple enzyme systems, induction or inhibition of a single enzyme may appreciably alter olanzapine clearance. Therefore, a dosage increase (for induction) or a dosage decrease (for inhibition) may need to be considered with specific drugs.

7.7 Potential for Olanzapine and Fluoxetine HCl to Affect Other Drugs

Pimozide — Concomitant use of fluoxetine and pimozide is contraindicated. Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QT_c prolongation. While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QT_c prolongation warrants restricting the concurrent use of pimozide and fluoxetine. [See Contraindications (4)].

Carbamazepine — Patients on stable doses of carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.

Alcohol — The coadministration of ethanol with olanzapine and fluoxetine HCl may potentiate sedation and orthostatic hypotension [see Drug Interactions (7.6)].

Thioridazine — Thioridazine should not be administered with olanzapine and fluoxetine HCl or administered within a minimum of 5 weeks after discontinuation of olanzapine and fluoxetine HCl.

In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C _max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators. The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity. Thus, this study suggests that drugs that inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine [see Contraindications (4)].

Thioridazine administration produces a dose-related prolongation of the QT _c interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias and sudden death. This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism [see Contraindications (4)].

Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated thioridazine plasma levels, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see Contraindications (4)].

Tricyclic Antidepressants (TCAs) — Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.

In 2 fluoxetine studies, previously stable plasma levels of imipramine and desipramine have increased >2-to 10-fold when fluoxetine has been administered in combination. This influence may persist for 3 weeks or longer after fluoxetine is discontinued. Thus, the dose of TCA may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when olanzapine and fluoxetine HCl is coadministered or has been recently discontinued [see Clinical Pharmacology (12.3)].

Antihypertensive Agents — Because of the potential for olanzapine to induce hypotension, olanzapine and fluoxetine HCl may enhance the effects of certain antihypertensive agents [see Warnings and Precautions (5.11)].

Levodopa and Dopamine Agonists — The olanzapine component of olanzapine and fluoxetine HCl may antagonize the effects of levodopa and dopamine agonists.

Benzodiazepines — Multiple doses of olanzapine did not influence the pharmacokinetics of diazepam and its active metabolite N desmethyldiazepam.

When concurrently administered with fluoxetine, the half-life of diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3)]. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Clozapine — Elevation of blood levels of clozapine has been observed in patients receiving concomitant fluoxetine.

Haloperidol — Elevation of blood levels of haloperidol has been observed in patients receiving concomitant fluoxetine.

Phenytoin — Patients on stable doses of phenytoin have developed elevated plasma levels of phenytoin with clinical phenytoin toxicity following initiation of concomitant fluoxetine.

Drugs Metabolized by CYP2D6 — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP2D6. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by this enzyme.

Fluoxetine inhibits the activity of CYP2D6 and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer. Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution. Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks. If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for a decreased dose of the original medication should be considered. Drugs with a narrow therapeutic index represent the greatest concern (including but not limited to, flecainide, propafenone, vinblastine, and TCAs).

Drugs Metabolized by CYP3A — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

In an in vivo interaction study involving the coadministration of fluoxetine with single doses of terfenadine (a CYP3A substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam. These data indicate that fluoxetine's extent of inhibition of CYP3A activity is not likely to be of clinical significance.

Effect of Olanzapine on Drugs Metabolized by Other CYP Enzymes — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, and CYP2C19. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

Lithium — Multiple doses of olanzapine did not influence the pharmacokinetics of lithium.

There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine. Cases of lithium toxicity and increased serotonergic effects have been reported. Lithium levels should be monitored in patients taking olanzapine and fluoxetine HCl concomitantly with lithium.

Drugs Tightly Bound to Plasma Proteins — The in vitro binding of olanzapine and fluoxetine HCl to human plasma proteins is similar to the individual components. The interaction between olanzapine and fluoxetine HCl and other highly protein-bound drugs has not been fully evaluated. Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect. Conversely, adverse effects may result from displacement of protein-bound fluoxetine by other tightly bound drugs [see Clinical Pharmacology (12.3)].

Valproate — In vitro studies using human liver microsomes determined that olanzapine has little potential to inhibit the major metabolic pathway, glucuronidation, of valproate. Further, valproate has little effect on the metabolism of olanzapine in vitro. Thus, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely.

Biperiden — Multiple doses of olanzapine did not influence the pharmacokinetics of biperiden.

Theophylline — Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Olanzapine and Fluoxetine HCl – Olanzapine and fluoxetine HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, taking into account the risk of untreated Bipolar I Depression. [see fluoxetine safety information under Treatment of Pregnant Women during the First Trimester and Clinical Considerations below.]

Teratogenic Effects

Animal Data — Animal Data — Embryo fetal development studies were conducted in rats and rabbits with olanzapine and fluoxetine in low-dose and high-dose combinations. In rats, the doses were: 2 and 4 mg/kg/day (low-dose) [1 and 0.5 times the maximum recommended human dose (MRHD) for olanzapine (20 mg) and fluoxetine (80 mg), respectively, on a mg/m2 body surface area], and 4 and 8 mg/kg/day (high-dose) [2 and 1 times the MRHD on a mg/m2 body surface area, respectively]. In rabbits, the doses were 4 and 4 mg/kg/day (low-dose) [4 and 1 times the MRHD on a mg/m² basis, respectively], and 8 and 8 mg/kg/day (high-dose) [9 and 2 times the MRHD on a mg/m² basis, respectively]. In these studies, olanzapine and fluoxetine were also administered alone at the high-doses (4 and 8 mg/kg/day, respectively, in the rat; 8 and 8 mg/kg/day, respectively, in the rabbit). In the rabbit, there was no evidence of teratogenicity; however, the high-dose combination produced decreases in fetal weight and retarded skeletal ossification in conjunction with maternal toxicity. Similarly, in the rat there was no evidence of teratogenicity; however, a decrease in fetal weight was observed with the high-dose combination.

In a pre-and postnatal study conducted in rats, olanzapine and fluoxetine were orally administered during pregnancy and throughout lactation in combination at dose levels up to 2 (olanzapine) plus 4 (fluoxetine) mg/kg/day (1 and 0.5 times the MRHD on a mg/m ² body surface area. An elevation of early postnatal mortality (survival through postnatal day 4 was 69% per litter) and reduced bodyweight (approximately 8% in females) occurred among offspring at the highest dose: the no-effect dose was 0.5 (olanzapine) plus 1 (floxetine) mg/kg/day (0.25 and 0.13 times the MRHD on a mg/m² body surface area). Among the surviving progeny, there were no adverse effects on physical or neurobehavioral development and reproductive performance at any dose.

Olanzapine — In oral reproduction studies in rats at doses up to 18 mg/kg/day and in rabbits at doses up to 30 mg/kg/day (9 and 30 times the MRHD on a mg/m² basis, respectively), no evidence of teratogenicity was observed. In a rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the MRHD on a mg/m² basis). Gestation was prolonged at 10 mg/kg/day (5 times the MRHD on a mg/m² basis). In a rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the MRHD on a mg/m² basis). Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Placental transfer of olanzapine occurs in rat pups.

There are no adequate and well-controlled clinical studies with olanzapine in pregnant women. Seven pregnancies were observed during premarketing clinical studies with olanzapine, including 2 resulting in normal births, 1 resulting in neonatal death due to a cardiovascular defect, 3 therapeutic abortions, and 1 spontaneous abortion.

Fluoxetine —

Treatment of Pregnant Women during the First Trimester – There are no adequate and well-controlled clinical studies on the use of fluoxetine in pregnant women. Results of a number of published epidemiological studies assessing the risk of fluoxetine exposure during the first trimester of pregnancy have demonstrated inconsistent results. More than 10 cohort studies and case-control studies failed to demonstrate an increased risk for congenital malformations overall. However, one prospective cohort study conducted by the European Network of Teratology Information Services reported an increased risk of cardiovascular malformations in infants born to women (N – 253) exposed to fluoxetine during the first trimester of pregnancy compared to infants of women (N = 1359) who were not exposed to fluoxetine. There was no specific pattern of cardiovascular malformations. Overall, however, a causal relationship has not been established.

Animal Data - In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration fluoxetine at doses up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the maximum recommended human dose (MRHD) of 80 mg on a mg/m² basis) throughout organogenesis. However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the MRHD on a mg/ m² basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m² basis) during gestation and lactation. There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation. The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m² basis).

Nonteratogenic Effects

Neonates exposed to fluoxetine, a component of olanzapine and fluoxetine, and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Dosage and Administration (2.3), and Warnings and Precautions (5.7).].

Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI (including fluoxetine) use in pregnancy and PPHN. Other studies do not show a significant statistical association.

Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

Neonates exposed to antipsychotic drugs (including olanzapine), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

When treating pregnant women with olanzapine and fluoxetine, the physician should carefully consider both the potential risks of taking and SSRI, along with established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis [see Dosage and Administration (2.3)].

8.2 Labor and Delivery

Olanzapine and Fluoxetine HCl — The effect of olanzapine and fluoxetine HCl on labor and delivery in humans is unknown. Parturition in rats was not affected by olanzapine and fluoxetine HCl. Olanzapine and fluoxetine HCl should be used during labor and delivery only if the potential benefit justifies the potential risk.

Olanzapine — The effect of olanzapine on labor and delivery in humans is unknown. Parturition in rats was not affected by olanzapine.

Fluoxetine — The effect of fluoxetine on labor and delivery in humans is unknown. Fluoxetine crosses the placenta; therefore, there is a possibility that fluoxetine may be associated with adverse effects on the newborn.

8.3 Nursing Mothers

Olanzapine and Fluoxetine HCl — Studies evaluating the individual components of olanzapine and fluoxetine HCl in nursing mothers are described below. Because of the potential for serious adverse reactions in nursing infants from olanzapine and fluoxetine HCl, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is recommended that women not breast-feed when receiving olanzapine and fluoxetine HCl.

Olanzapine — In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant dose at steady-state was estimated to be 1.8% of the maternal olanzapine dose. It is recommended that women receiving olanzapine should not breast-feed.

Fluoxetine — Fluoxetine is excreted in human breast milk. In 1 breast milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL. The concentration in the mother's plasma was 295.0 ng/mL. No adverse effects on the infant were reported. In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools. The infant's plasma drug levels were 340 ng/mL of fluoxetine and 208/mL of norfluoxetine on the 2nd day of feeding.

8.4 Pediatric Use

Olanzapine and Fluoxetine — Safety and effectiveness in children and adolescent patients have not been established. Anyone considering the use of olanzapine and fluoxetine HCl in a child or adolescent must balance the potential risks with the clinical need [see Boxed Warning and Warnings and Precautions (5.1)].

Safety and effectiveness of olanzapine and fluoxetine in combination in children and adolescents <18 years of age have not been established.

Olanzapine – Safety and effectiveness of olanzapine in children <13 years of age have not been established.

Compared to patients from adult clinical trials, adolescents treated with oral olanzapine were likely to gain more weight, experience increased sedation, and have greater increases in total cholesterol, triglycerides, LDL cholesterol, prolactin and hepatic aminotransferase levels.

Fluoxetine — Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine. Some of these effects occurred at clinically relevant exposures.

In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose. At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose. When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible. The reversibility of fluoxetine-induced muscle damage was not assessed. Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals. Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day. Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, pediatric exposure at the MRD.

A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period. When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density. These doses did not affect overall growth (body weight gain or femoral length). The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m ²) basis.

In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increased shock avoidance latency) in adulthood (12 weeks of age). The dose used in this study is approximately equal to the pediatric MRD on a mg/m ² basis. Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain.

8.5 Geriatric Use

Olanzapine and Fluoxetine — Clinical studies of olanzapine and fluoxetine HCl did not include sufficient numbers of patients ≥65 years of age to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Dosage and Administration (2.3)].

Olanzapine — Of the 2500 patients in premarketing clinical studies with olanzapine, 11% (263 patients) were ≥65 years of age. In patients with Schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared with younger patients. Studies in patients with dementia-related psychosis have suggested that there may be a different tolerability profile in this population compared with younger patients with Schizophrenia. Elderly patients with dementia-related psychosis treated with olanzapine are at an increased risk of death compared to placebo. In placebo-controlled studies of olanzapine in elderly patients with dementia-related psychosis, there was a higher incidence of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack) in patients treated with olanzapine compared to patients treated with placebo. Olanzapine is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Dosage and Administration (2.3), and Warnings and Precautions (5.2)].

Also, the presence of factors that might decrease pharmacokinetic clearance or increase the pharmacodynamic response to olanzapine should lead to consideration of a lower starting dose for any geriatric patient.

Fluoxetine — U.S. fluoxetine clinical studies included 687 patients ≥65 years of age and 93 patients ≥75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. SNRIs and SSRIs, including olanzapine and fluoxetine HCl, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see Warnings and Precautions (5.16)].

8.6 Hepatic Impairment

In subjects with cirrhosis of the liver, the clearances of fluoxetine and its active metabolite, norfluoxetine, were decreased, thus increasing the elimination half-lives of these substances. A lower or less frequent dose of the fluoxetine-component of olanzapine and fluoxetine HCl should be used in patients with cirrhosis. Caution is advised when using olanzapine and fluoxetine HCl in patients with diseases or conditions that could affect its metabolism [see Dosage and Administration (2.3) and Clinical Pharmacology (12.4)].

9 DRUG ABUSE AND DEPENDENCE

9.3 Dependence

Olanzapine and fluoxetine HCl, as with fluoxetine and olanzapine, has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical studies did not reveal any tendency for any drug-seeking behavior, these observations were not systematic, and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of olanzapine and fluoxetine HCl (e.g., development of tolerance, incrementation of dose, drug-seeking behavior).

In studies in rats and rhesus monkeys designed to assess abuse and dependence potential, olanzapine alone was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence at oral doses up to 15 (rat) and 8 (monkey) times the MRHD (20 mg) on a mg/m ² basis.

10 OVERDOSAGE

Olanzapine and Fluoxetine HCl — During premarketing clinical studies of olanzapine and fluoxetine in combination, overdose of both fluoxetine and olanzapine were reported in 5 study subjects. Four of the 5 subjects experienced loss of consciousness (3) or coma (1). No fatalities occurred.

Adverse reactions involving overdose of fluoxetine and olanzapine in combination, and olanzapine and fluoxetine HCl, have been reported. An overdose of combination therapy is defined as confirmed or suspected ingestion of a dose of >20 mg olanzapine in combination with a dose of >80 mg fluoxetine. Adverse reactions associated with these reports included somnolence (sedation), impaired consciousness (coma), impaired neurologic function (ataxia, confusion, convulsions, dysarthria), arrhythmias, lethargy, essential tremor, agitation, acute psychosis, hypotension, hypertension, and aggression. Fatalities have been confounded by exposure to additional substances including alcohol, thioridazine, oxycodone, and propoxyphene.

Olanzapine — In postmarketing reports of overdose with olanzapine alone, symptoms have been reported in the majority of cases. In symptomatic patients, symptoms with ≥10% incidence included agitation/aggressiveness, dysarthria, tachycardia, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Among less commonly reported symptoms were the following potentially medically serious reactions: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia as well as a patient that experienced sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. There have been reports of fatality in association with overdose of olanzapine alone. In 1 case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg of oral olanzapine; however, in another case, a patient was reported to survive an acute olanzapine ingestion of approximately 2 g of oral olanzapine.

Fluoxetine — Worldwide exposure to fluoxetine is estimated to be over 38 million patients (circa 1999). Of the 1578 cases of overdose involving fluoxetine, alone or with other drugs, reported from this population, there were 195 deaths.

Among 633 adult patients who overdosed on fluoxetine alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdose, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, erectile dysfunction, movement disorder, and hypomania. The remaining 206 patients had an unknown outcome. The most common signs and symptoms associated with non-fatal overdose were seizures, somnolence, nausea, tachycardia, and vomiting. The largest known ingestion of fluoxetine in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered. However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established.

Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs. Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome. One of the 6 fatalities was a 9-year-old boy who had a history of OCD, Tourette's Syndrome with tics, attention deficit disorder, and fetal alcohol syndrome. He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine. Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities. The largest ingestion in pediatric patients was 3 grams, which was non-lethal.

Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) included coma, delirium, ECG abnormalities (such as QT-interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope.

10.1 Management of Overdose

In managing overdose, the possibility of multiple drug involvement should be considered. In case of acute overdose, establish and maintain an airway and ensure adequate ventilation, which may include intubation. Induction of emesis is not recommended as the possibility of obtundation, seizures, or dystonic reactions of the head and neck following overdose may create a risk for aspiration. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

A specific precaution involves patients who are taking or have recently taken olanzapine and fluoxetine HCl and may have ingested excessive quantities of a TCA (tricyclic antidepressant). In such cases, accumulation of the parent TCA and/or an active metabolite may increase the possibility of serious sequelae and extend the time needed for close medical observation.

Due to the large volume of distribution of olanzapine and fluoxetine, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. No specific antidote for either fluoxetine or olanzapine overdose is known. Hypotension and circulatory collapse should be treated with appropriate measures such as intravenous fluids and/or sympathomimetic agents. Do not use epinephrine, dopamine, or other sympathomimetics with β-agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade.

The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).

11 DESCRIPTION

Olanzapine and fluoxetine capsules USP combines an atypical antipsychotic and a selective serotonin reuptake inhibitor, olanzapine (the active ingredient in Zyprexa ^®*, and Zyprexa Zydis^®*) and fluoxetine hydrochloride (the active ingredient in Prozac^®*, Prozac Weekly^™*, and Sarafem^®*).

Olanzapine belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10 H thieno[2,3-b] [1,5]benzodiazepine. The molecular formula is C₁₇H₂₀N₄S, which corresponds to a molecular weight of 312.44.

Fluoxetine hydrochloride is a selective serotonin reuptake inhibitor (SSRI). The chemical designation is (±)-N-methyl-3-phenyl-3‑[(α,α,α-trifluoro- p-tolyl)oxy]propylamine hydrochloride. The molecular formula is C₁₇H₁₈F₃NO•HCl, which corresponds to a molecular weight of 345.79. The chemical structures are: