Date of Revision: April 3, 2008

Submission Control No: 118634

(r)

ZYPREXA is a trademark of Eli Lilly and Company

(r)

*Zydis is a trademark owned by R.P. Scherer Technologies, Inc., a Catalent Pharma Solutions Company

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 4 WARNINGS AND PRECAUTIONS 5 ADVERSE REACTIONS 13 DRUG INTERACTIONS 29 DOSAGE AND ADMINISTRATION 31 OVERDOSAGE 34 ACTION AND CLINICAL PHARMACOLOGY 36 STORAGE AND STABILITY 39 DOSAGE FORMS, COMPOSITION AND PACKAGING 39

PART II: SCIENTIFIC INFORMATION 41

PHARMACEUTICAL INFORMATION 41 CLINICAL TRIALS 42 DETAILED PHARMACOLOGY 55 TOXICOLOGY 58 REFERENCES 62

PART III: CONSUMER INFORMATION 66

ZYPREXA(r) (olanzapine) Tablets

2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg

ZYPREXA(r) Zydis(r) * (olanzapine) Orally Disintegrating Tablets

5 mg, 10 mg, 15 mg, 20 mg

ZYPREXA(r) IntraMuscular (olanzapine tartrate for injection)

10 mg olanzapine/vial

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

*For a complete listing see Dosage Forms, Composition and Packaging section.

CONTRAINDICATIONS

ZYPREXA (olanzapine) is contraindicated in those patients with a known hypersensitivity to the drug or the excipients of the product. For a complete listing, see DOSAGE FORMS, COMPOSITION and PACKAGING section.

WARNINGS AND PRECAUTIONS

SERIOUS WARNINGS AND PRECAUTIONS

Increased Mortality in Elderly Patients with Dementia:

Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6 fold increase in death rate in the drug-treated patients Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. (See WARNINGS AND PRECAUTIONS, Special Populations, Use in Geriatric Patients with Dementia)

General

Neuroleptic Malignant Syndrome:

Neuroleptic Malignant Syndrome (NMS) has been reported very rarely (<=0.0025%) in pre-marketed and post-market surveillance. However, NMS is a potentially fatal symptom complex that has been reported in association with antipsychotic drugs. 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 creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include immediate discontinuation of all antipsychotic drugs including ZYPREXA, intensive monitoring of symptoms and treatment of any associated medical problems. There is no general agreement about specific pharmacological treatment for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the re-introduction of therapy should be very carefully considered, since recurrence of NMS has been reported.

Weight Gain: Olanzapine was associated with weight gain during clinical trials. Clinically significant weight gain was observed across all baseline body mass index (BMI) categories. Using pooled data from patients treated with olanzapine over the dosage range of 5 mg to 20 mg per day, weight gain tended to level off at 6 to 8 months of treatment, with a mean gain of 5.4 kg. The mean change in weight was comparable for patients with schizophrenia and bipolar mania. A retrospective analysis of 573 patients receiving olanzapine for up to 3 years found that dose was not a significant predictor of greater long-term changes in weight.

Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing ZYPREXA for patients who will be experiencing conditions which may contribute to an elevation of core temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

Potential Effect on Cognitive and Motor Performance:

Because ZYPREXA may cause somnolence, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that ZYPREXA therapy does not affect them adversely.

Carcinogenesis and Mutagenesis

For animal data, see Part II: TOXICOLOGY section.

Cardiovascular

Hypotension and Syncope: As with other drugs that have high alpha-1 adrenergic receptor blocking activity, ZYPREXA may induce orthostatic hypotension, tachycardia, dizziness, and sometimes syncope, especially at the initiation of treatment. In a clinical trial database of 2500 patients treated with oral ZYPREXA, syncope was reported in 0.6% (15/2500). The risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD (see DOSAGE AND ADMINISTRATION section). A more gradual titration to the target dose should be considered if hypotension occurs. Hypotension and/or syncope associated with bradycardia has been observed infrequently with ZYPREXA IntraMuscular. Patients receiving intramuscular olanzapine should be closely observed for hypotension including postural hypotension, bradyarrhythmia and/or hypoventilation, particularly for the first 2 to 4 hours following injection. Patients should remain recumbent if dizzy or drowsy after injection until examination indicates that they are not experiencing hypotension including postural hypotension, bradyarrhythmia and/or hypoventilation. Caution is necessary in patients who receive intramuscular olanzapine with other drugs having effects that can induce hypotension, bradycardia, respiratory or central nervous system depression. Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine and/or other drugs with CNS depressant activity has been associated with post-marketing reports of serious adverse events, including fatalities and is therefore not recommended. If use of intramuscular olanzapine in combination with parenteral benzodiazepines is considered necessary, careful evaluation of clinical status for excessive sedation and cardiorespiratory depression is recommended (see DRUG INTERACTIONS section). ZYPREXA 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, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications).

Endocrine and Metabolism

Hyperglycaemia:

As with some other antipsychotics, exacerbation of pre-existing diabetes and hyperglycaemia have been reported rarely and diabetic ketoacidosis and diabetic coma including some fatal cases have been reported very rarely during the use of ZYPREXA, sometimes in patients with no reported history of hyperglycaemia (see ADVERSE REACTIONS; Post-Market Adverse Drug Reactions section). In some cases, a prior increase in body weight has been reported which may be a predisposing factor. 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. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment- emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. 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. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.

Hyperprolactinemia:

As with other drugs that block dopamine D2 and/or serotonin 5-HT2 receptors, olanzapine may elevate prolactin levels. Elevations associated with ZYPREXA treatment are generally mild, and may decline during continued administration. Since tissue culture experiments indicate that approximately one third of human breast cancers are prolactin-dependent in vitro, ZYPREXA should only be administered to patients with previously detected breast cancer if the benefits outweigh the potential risks. Caution should also be exercised when considering ZYPREXA treatment in patients with pituitary tumours. Possible manifestations associated with elevated prolactin levels are amenorrhea, galactorrhea, and menorrhagia. As is common with compounds which stimulate prolactin release, the administration of olanzapine resulted in an increase in the incidence of mammary neoplasms in both rats and mice. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear. To date, neither clinical nor epidemiological studies have shown an association between chronic administration of these drugs and mammary tumorigenesis.

Lipids

Increases in lipids have been observed in olanzapine-treated patients in placebo- controlled clinical trials (see ADVERSE REACTIONS; Incidence of Laboratory Changes subsection). Appropriate clinical monitoring is recommended.

Gastrointestinal

Antiemetic Effect: Consistent with its dopamine antagonist effects, olanzapine may have an antiemetic effect. Such an effect may mask signs of toxicity due to overdosage of other drugs, or may mask symptoms of disease such as brain tumour or intestinal obstruction.

Genitourinary

Priapism: Rare cases of priapism have been reported with ZYPREXA. This adverse reaction, as with other psychotropic drugs, did not appear to be dose-dependent and did not correlate with the duration of treatment. The most likely mechanism of action of priapism is a relative decrease in sympathetic tone.

Hematologic

Hematologic Indices: In oral olanzapine clinical trials, there were no data to suggest ZYPREXA adversely affected bone marrow function, even in patients with a history of clozapine-associated neutropenia or leukopenia. ZYPREXA was associated with a 5.7% incidence of mainly transient treatment-emergent elevations of eosinophil counts above the normal range. Elevations were not associated with any symptoms, identifiable allergic phenomena, or changes in other hematologic indices. Rare cases of leukopenia have been reported with ZYPREXA. In case of symptoms of infection, WBC count and differential count should be considered.

Hepatic

Transaminase Elevations: During pre-marketing clinical trials, therapy with oral ZYPREXA was associated with elevation of hepatic transaminases, primarily ALT (SGPT). Within a clinical trial database of 2280 ZYPREXA-treated patients, with baseline ALT (SGPT) levels <=60 IU/L, 5.9% (134/2280) had treatment-emergent ALT (SGPT) elevations to >120 IU/L, 1.9% (44/2280) had elevations to >200 IU/L, and 0.2% (5/2280) had elevations to >400 IU/L. No patients had values in excess of 700 IU/L. None of the ZYPREXA-treated patients who had elevated transaminase values manifested clinical symptomatology associated with liver impairment. The majority of transaminase elevations were seen during the first six weeks of treatment. Most elevations were transient (66%) while patients continued on ZYPREXA therapy, or falling (11%) at the last available measurement. Of the 134 ZYPREXA-treated patients whose enzyme levels increased to >120 IU/L, 20 discontinued treatment (6 for hepatic, 14 for other reasons) while their ALT (SGPT) values were still rising. In 38 ZYPREXA-treated patients with baseline ALT (SGPT) >90 IU/L, none experienced an elevation to >400 IU/L. Rare post-marketing reports of hepatitis have been received. Very rare cases of cholestatic or mixed liver injury have also been reported in the post-marketing period. Hepatic failure, including fatalities have also been reported very rarely in the post- marketing period. See POST-MARKET ADVERSE DRUG REACTIONS section. Precaution should be exercised when using ZYPREXA in patients with pre-existing hepatic disorders, in patients who are being treated with potentially hepatotoxic drugs, or if treatment-emergent signs or symptoms of hepatic impairment appear. For patients who have known or suspected abnormal hepatic function prior to starting ZYPREXA, standard clinical assessment including measurement of transaminase levels is recommended. Periodic clinical reassessment with transaminase levels is recommended for such patients, as well as for patients who develop any signs and symptoms suggestive of a new onset liver disorder during ZYPREXA therapy.

Neurologic

Tardive Dyskinesia:

Tardive dyskinesia (TD), a syndrome consisting of potentially irreversible involuntary dyskinetic movements, is associated with the use of antipsychotic drugs. Tardive dyskinesia occurs more frequently in elderly patients; however, patients of any age can be affected. It is unknown whether antipsychotic drugs may differ in their potential to cause TD. However, during long-term, double-blind, extension schizophrenia maintenance trials (894 olanzapine-treated patients; median olanzapine treatment, 237 days), ZYPREXA was associated with a statistically significantly lower incidence of treatment-emergent dyskinesia compared to haloperidol. During long-term, double-blind, monotherapy extension bipolar maintenance trials (567 olanzapine-treated patients, for up to 1 year), there were no cases of TD in the ZYPREXA arms, as determined by either reported adverse events or the Abnormal Involuntary Movement Scale (AIMS). TD has been reported very rarely (<=0.0025%) in post-market surveillance. The risk of developing tardive dyskinesia and the chance of it becoming irreversible are believed to increase as the duration of treatment and the cumulative dose of antipsychotic drug increase. However, the syndrome can develop, although less commonly, after relatively brief periods of treatment at low doses. There is no known treatment for established cases of TD. The syndrome may remit, partially or completely, if antipsychotic drug treatment is withdrawn. Antipsychotic drug treatment itself, however, may suppress the signs and symptoms of tardive dyskinesia, thereby masking the underlying process. Given these considerations, ZYPREXA should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. As with any antipsychotic drug, ZYPREXA should be reserved for patients who appear to be receiving substantial benefit from the drug. In such patients the lowest effective dose and the shortest duration of treatment should be sought. The need for continued treatment should be reassessed periodically. If signs or symptoms of tardive dyskinesia appear in a patient on ZYPREXA, drug discontinuation should be considered. However, some patients may benefit from continued treatment with ZYPREXA despite the presence of the syndrome.

Seizures:

Conventional neuroleptics are known to lower seizure threshold. In clinical trials, seizures have occurred in a small number (0.9%, 22/2500) of ZYPREXA-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. ZYPREXA should be used cautiously in patients who have a history of seizures or have conditions associated with seizure or have a lowered seizure threshold.

Psychiatric

Suicide: The possibility of suicide or attempted suicide is inherent in psychosis, and thus close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.

Renal

Uric Acid:

In the pre-marketing clinical trial database, oral ZYPREXA was associated with mild elevations of uric acid in some patients. However, only 1 ZYPREXA-treated patient experienced treatment-emergent gout, and the baseline uric acid concentration for this patient was at least as large as all concentrations observed while the patient was receiving ZYPREXA.

Special Populations

Pregnant Women:

There are no adequate and well-controlled studies in pregnant women. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with ZYPREXA. Because human experience in pregnant females is limited, this drug should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labour and Delivery: Parturition in rats was not affected by olanzapine. The effect of ZYPREXA on labour and delivery in humans is not known.

Nursing Women:

Lactation: In a study in lactating, healthy women, olanzapine was excreted in breast milk. Mean infant exposure (mg/kg) at steady state was estimated to be 1.8% of the maternal olanzapine dose (mg/kg). Patients should be advised not to breast feed an infant if they are taking ZYPREXA.

Pediatrics (< 18 years of age):

The safety and efficacy of ZYPREXA in children under the age of 18 years have not been established.

Geriatrics (>= 65 years of age)

:

The number of patients 65 years of age or over with schizophrenia or related disorders exposed to oral ZYPREXA during clinical trials was limited (N=44). Caution should thus be exercised with the use of ZYPREXA in the elderly patient, recognizing the more frequent hepatic, renal, central nervous system, and cardiovascular dysfunctions, and more frequent use of concomitant medication in this population (see DOSAGE AND ADMINISTRATION section).

Use in Geriatric Patients with Dementia

Overall Mortality:

Elderly patients with dementia treated with atypical antipsychotic drugs showed increased mortality compared to placebo in a meta-analysis of 13 controlled trials of various atypical antipsychotic drugs. In five placebo-controlled trials with oral ZYPREXA in this population, the incidence of mortality was 3.5 % for ZYPREXA- treated patients compared to 1.5 % for placebo-treated patients. ZYPREXA is not indicated in elderly patients with dementia.

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 other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Cerebrovascular Adverse Events (CVAEs), Including Stroke, in Elderly Patients with Dementia: Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in trials of olanzapine in elderly patients with dementia-related psychosis. In placebo-controlled studies, there was a higher incidence of CVAEs in patients treated with ZYPREXA compared to patients treated with placebo (1.3% vs. 0.4%, respectively; see ADVERSE REACTIONS section). ZYPREXA is not approved for the treatment of elderly patients with dementia. There is insufficient evidence to determine whether CVAEs in elderly patients with dementia are associated specifically with ZYPREXA or all antipsychotic agents. Clinical trial data appear to suggest that patients with a dementia diagnosis of vascular or mixed type had a higher likelihood of experiencing CVAEs than other types of dementia. The risks and benefits of the use of ZYPREXA in elderly patients with dementia should be assessed taking into account the risk predictors for CVAEs in the individual patient. Patients/caregivers should be advised to immediately report signs and symptoms of potential CVAEs, such as sudden weakness or numbness in the face, arms, or legs, and speech or vision problems.

Use in Patients with Other Concomitant Illness:

Clinical experience with olanzapine in patients with concomitant illness is limited. Caution is thus advised when using ZYPREXA in patients with diseases or conditions that could affect the metabolism or the pharmacodynamic activity of olanzapine (see DOSAGE AND ADMINISTRATION section and Part II: DETAILED PHARMACOLOGY).

Use in Patients with Cardiac Disorders:

ZYPREXA has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these conditions were excluded from pre-marketing clinical trials. Due to the more rapid and higher peak plasma concentrations following intramuscular compared to oral administration (see Part II: DETAILED PHARMACOLOGY section), particular caution is advised with the use of ZYPREXA IntraMuscular. ZYPREXA IntraMuscular should not be administered to patients with unstable medical conditions, such as acute or unstable cardiovascular conditions such as myocardial infarction, unstable angina pectoris, severe hypotension and/or bradycardia, or sick sinus syndrome. If the patient's medical history with regard to unstable medical conditions cannot be determined, the risks and benefits of IM olanzapine should be considered in relation to other alternative treatments.

Use in Patients with Diabetes and Risk Factors for Development of Diabetes:

As with some other antipsychotics, exacerbation of pre-existing diabetes and hyperglycaemia have been reported rarely and diabetic ketoacidosis and diabetic coma including some fatal cases have been reported very rarely during the use of ZYPREXA, sometimes in patients with no reported history of hyperglycaemia (see ADVERSE REACTIONS, Post-Market Adverse Drug Reactions section). In some cases, a prior increase in body weight has been reported which may be a pre-disposing factor. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.

Use in Patients with Renal and Hepatic Impairment:

Small single-dose clinical pharmacology studies (see Part II: DETAILED PHARMACOLOGY section) did not reveal any major alterations in olanzapine pharmacokinetics in subjects with renal or hepatic impairment. Given the limited clinical experience with ZYPREXA in patients with these conditions, caution should be exercised (see DOSAGE AND ADMINISTRATION section).

Other Concomitant Illnesses:

As ZYPREXA demonstrated anticholinergic activity in vitro, caution is advised when prescribing for patients with symptomatic prostatic enlargement, narrow-angle glaucoma or paralytic ileus and related conditions. In clinical trials, a single case of pre-existing intracranial hypertension was exacerbated.

DRUG INTERACTIONS

Drug-Drug Interactions

Alcohol:

Given the primary CNS effects of ZYPREXA, caution should be used when it is taken in combination with other centrally acting drugs and alcohol.

Levodopa and Dopamine Agonists: As it exhibits in vitro dopamine antagonism, ZYPREXA may antagonize the effects of levodopa and dopamine agonists.

Antihypertensive Agents:

Because of its potential for inducing hypotension, olanzapine may enhance the effects of certain antihypertensive agents. Caution should be exercised in patients who receive medicinal products that can induce hypotension, bradycardia, or respiratory depression.

Potential for Other Drugs to Affect ZYPREXA:

Carbamazepine:

Concomitant carbamazepine therapy may induce the metabolism of olanzapine.

Activated Charcoal:

The concomitant administration of activated charcoal reduced the oral bioavailability of ZYPREXA by 50% to 60%.

Antacids:

Single doses of antacid (aluminium, magnesium) or cimetidine did not affect the oral bioavailability of ZYPREXA.

Valproate: Studies in vitro using human liver microsomes showed that olanzapine has little potential to inhibit the glucuronidation of valproate, which is the major metabolic pathway. Furthermore, valproate was found to have little effect on the metabolism of olanzapine in vitro. Daily concomitant in vivo administration of 10 mg olanzapine for 2 weeks did not affect steady state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate.

Fluoxetine:

Fluoxetine (60 mg single dose or 60 mg daily for 8 days) causes a mean 16% increase in the maximum concentration of olanzapine and a mean 16% decrease in olanzapine clearance. The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended.

CYP1A2 Inducers:

Agents that induce CYP1A2 such as omeprazole may increase clearance of olanzapine.

CYP1A2 Inhibitors: Fluvoxamine, a specific CYP1A2 inhibitor, has been shown to significantly inhibit the metabolism of olanzapine. The mean increase in olanzapine Cmax following fluvoxamine was 54% in female nonsmokers and 77% in male smokers. The mean increase in olanzapine AUC was 52% and 108%, respectively. A lower starting dose of olanzapine should be considered in patients who are using fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin or ketoconazole. A decrease in the dose of olanzapine should be considered if treatment with an inhibitor of CYP1A2 is initiated.

Potential for ZYPREXA to Affect Other Drugs:

Imipramine/Desipramine:

In clinical trials with single doses of oral ZYPREXA, no inhibition of the metabolism of imipramine/desipramine (P450-CYP2D6) was evident.

Warfarin:

In clinical trials with single doses of oral ZYPREXA, no inhibition of the metabolism of warfarin (P450 CYP2C9) was evident.

Diazepam:

In clinical trials with single doses of oral ZYPREXA, no inhibition of the metabolism of diazepam (P450 CYP3A4) was evident.

Lithium or Biperiden:

Oral ZYPREXA showed no interaction when coadministered with lithium or biperiden.

Drugs Metabolized via P450-CYP1A2, -CYP2C9, -CYP2C19, -CYP2D6, and -CYP3A4:

In in vitro studies with human microsomes, olanzapine showed little potential to inhibit cytochromes P450-CYP1A2, -CYP2C9, -CYP2C19, -CYP2D6, and -CYP3A4 (see PART II: DETAILED PHARMACOLOGY). Olanzapine is thus unlikely to cause clinically important drug-drug interactions mediated through the metabolic routes outlined above. However, the possibility that olanzapine may alter the metabolism of other drugs, or that other drugs may alter the metabolism of olanzapine, should be considered when prescribing ZYPREXA.

Lorazepam:

Simultaneous injection of intramuscular olanzapine and parenteral benzodiazepine is not recommended (see WARNINGS and PRECAUTIONS). In a clinical pharmacokinetic/ pharmacodynamic study, administration of intramuscular lorazepam (2 mg) two hours following intramuscular olanzapine (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. Administration of intramuscular lorazepam two hours after injection of intramuscular olanzapine however, added to the somnolence observed with either drug alone.

Phenylketonurics: ZYPREXA(r) Zydis(r) * contains phenylalanine (0.34, 0.45, 0.67, or 0.90 mg per 5, 10, 15, or 20 mg oral lyophilisate, respectively).

Drug-Food Interactions

Absorption of olanzapine is not affected by food.

Drug-Herb Interactions

Interactions with herbal products have not been identified.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been identified.

Drug-Lifestyle Interactions

Smoking:

Concomitant smoking may induce the metabolism of olanzapine.

DOSAGE AND ADMINISTRATION

ORAL ADMINISTRATION

Schizophrenia and Related Disorders

Adults: ZYPREXA(r) (olanzapine) should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg, with a target dose of 10 mg/day within several days. Further dosage adjustments, if indicated, should generally occur at intervals of not less than 1 week, since steady state for ZYPREXA would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/ decrements of 5 mg per day are recommended. An increase to a dose greater than target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is normally recommended only after clinical assessment. In clinical trials a dose range of 5-20 mg/day was studied (see Part II: CLINICAL TRIALS). Doses above 20mg/day have been evaluated from a safety perspective (see Table 4 in Adverse Events, Dose-Dependent Adverse Events subsection); however, efficacy at doses above 20mg/day has not been systematically evaluated.

Maintenance Therapy in Schizophrenia:

It is recommended that responding patients with schizophrenia be continued on ZYPREXA at the lowest dose needed to maintain remission. Patients should be reassessed periodically to determine the need for maintenance treatment. While there is no body of evidence available to answer the question of how long the patient should be treated with ZYPREXA, the effectiveness of maintenance treatment is well established for many other antipsychotic drugs.

Bipolar Disorder

Bipolar Mania

Adults: The recommended starting dose for olanzapine is 15 mg administered once a day in monotherapy and 10 mg daily in combination therapy. It may be given without regard to meals as its absorption is not affected by food. The dosage range of olanzapine is from 5 mg to 20 mg per day. Daily dosage should be adjusted in response to clinical assessment.

Maintenance Therapy in Bipolar Disorder:

Patients who have been receiving and responding to ZYPREXA for the treatment of acute manic or mixed episodes of bipolar disorder should initially continue maintenance therapy at the same dose (see Part II: CLINICAL TRIALS). Subsequent daily dosage should be adjusted on the basis of clinical status within a range of 5-20 mg per day. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.

General Considerations for Oral Dosing in Special Populations

The Elderly or Debilitated Patient: In clinical trials, 44 patients with schizophrenia or related disorders who were 65 years of age or over were treated with ZYPREXA (5-20 mg daily) (see WARNINGS AND PRECAUTIONS, Special Populations). Given the limited experience with ZYPREXA in the elderly, and the higher incidence of concomitant illness and concomitant medication in this population, ZYPREXA should be used with caution. The recommended starting dose is 5 mg in patients who are elderly, debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of ZYPREXA (e.g., nonsmoking female patients), or who may be pharmacodynamically more sensitive to ZYPREXA. When indicated, dose escalation should be performed with caution in these patients.

Patients with Hepatic and/or Renal Impairment: As clinical experience is lacking in these patients, the lower initial starting dose and slower titration to initial target dose should be considered. Further dose escalation, when indicated, should be conservative (see WARNINGS AND PRECAUTIONS, Special Populations).

Missed Dose

If a patient misses a dose by a few hours, advise patient to take as soon as he/she remembers. If most of the day has passed, advise patient to wait until the next scheduled dose. Advise patients to not take 2 doses of ZYPREXA at once.

Administration of ZYPREXA(r) Zydis(r) *

ZYPREXA(r) Zydis(r) * orally disintegrating tablet is intended for oral administration only. It begins disintegrating in the mouth within seconds, allowing its contents to be subsequently swallowed with or without liquid. The orally disintegrating tablet breaks easily and should be handled carefully, with dry hands. Direct contact with hands should be avoided if possible. One blister cell must be separated from the strip prior to peeling the blister backing. The blister backing should be carefully peeled back and the orally disintegrating tablet pushed out and placed directly in the mouth. The orally disintegrating tablet may also be stirred into 125 mL (4 ounces) of water, milk, coffee, orange juice or apple juice and the contents promptly consumed.

INTRAMUSCULAR ADMINISTRATION

In clinical trials, individual doses of 5 mg, 7.5 mg and 10 mg of intramuscular olanzapine for injection have been shown to be effective in controlling agitation in patients with schizophrenia (see Part II: CLINICAL TRIALS section). Individual doses of more than 10 mg of intramuscular olanzapine have not been studied and are not recommended.

Usual Dose for Agitated Patients with Schizophrenia and Bipolar Mania: The usual initial dose for olanzapine injection is 10 mg, administered as a single intramuscular injection. A lower dose (5 mg or 7.5 mg) may be given, on the basis of individual clinical status.

Repeat and Maximum Dose: In clinical trials over a 24 hour period, a minority of patients required a second dose, and only a small percent of patients required a third dose of ZYPREXA IntraMuscular (see Part II: CLINICAL TRIALS section). Thus safety information on the use of repeated doses of ZYPREXA IntraMuscular is limited. Nevertheless, if warranted by the clinical situation, a second dose, 5-10 mg, may be administered 2 hours after the first injection. A third dose, if required, should be given no sooner than four hours after the second dose. The safety of total daily doses greater than 30 mg has not been evaluated in clinical trials. The recommended maximum daily dose of olanzapine (oral and IM) is 20 mg, with no more than three injections in a 24 hour period.

General Considerations for Intramuscular Dosing in Special Populations

Elderly or Debilitated Patients: Lower doses (e.g. 2.5 mg) should be considered when clinical factors warrant.

Administration of ZYPREXA IntraMuscular:

Zyprexa IntraMuscular is intended for intramuscular use only. Do not administer intravenously or subcutaneously. Inject slowly, deep into the muscle mass. Concomitant administration of intramuscular olanzapine and parenteral benzodiazepine is not recommended (see WARNINGS and PRECAUTIONS). Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration, whenever solution and container permit.

Reconstitution:

The following table provides injection volumes for delivering various doses of intramuscular olanzapine for injection reconstituted with Sterile Water for Injection.

Physical Incompatibility Information

ZYPREXA IntraMuscular should be reconstituted only with Sterile Water for Injection. ZYPREXA IntraMuscular should not be combined in a syringe with diazepam injection because precipitation occurs when these products are mixed. Lorazepam injection should not be used to reconstitute ZYPREXA IntraMuscular as this combination results in a delayed reconstitution time. ZYPREXA IntraMuscular should not be combined in a syringe with haloperidol injection because the resulting low pH has been shown to degrade olanzapine over time.

Ongoing Therapy:

If ongoing olanzapine therapy is clinically indicated, treatment with intramuscular olanzapine for injection should be discontinued and oral olanzapine may be initiated in a range of 5-20 mg/day as soon as clinically appropriate (see DOSAGE AND ADMINISTRATION, Oral Administration subsection).

OVERDOSAGE

Signs and Symptoms

Very common symptoms reported in olanzapine overdose (>=10% incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma. Other medically significant sequelae of olanzapine overdose include delirium, convulsion, possible neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (<2% of overdose cases) and cardiopulmonary arrest. Fatal outcomes have been reported for acute overdoses as low as 450 mg but survival has also been reported following acute overdose of 1,500 mg.

Management of Overdose

There is no specific antidote for olanzapine. Induction of emesis is not recommended. Standard procedures for management of overdose may be indicated (i.e. gastric lavage, administration of activated charcoal). The concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50 to 60%. Symptomatic treatment and monitoring of vital organ function should be instituted according to clinical presentation, including treatment of hypotension and circulatory collapse and support of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetic agents with beta-agonist activity since beta stimulation may worsen hypotension. For up-to-date information on the management of a suspected drug overdose, the physician should consider contacting a regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Pharmacodynamics

Pharmacodynamic Properties: ZYPREXA(r) (olanzapine), a thienobenzodiazepine, is an antipsychotic and antimanic agent that demonstrates a broad pharmacologic profile across a number of receptor systems. Olanzapine displays high receptor affinity binding in vitro at dopamine D1, D3, D4 (Ki = 11-31 nM), 5-HT2A/C (Ki = 4 and 11 nM, respectively), 5-HT3, 5-HT6, muscarinic M1-M5 (Ki = 1.9-2.5 nM), adrenergic a1 (Ki = 19 nM), and histamine H1 (Ki = 7 nM) receptor subtypes. In a behavioural paradigm predictive of antipsychotic activity, olanzapine reduced conditioned avoidance response in rats at doses lower than 4 times those required to produce catalepsy. In a single dose (10 mg) PET study in healthy subjects, olanzapine produced higher 5-HT2A than dopamine D2 receptor occupancy. The percent of D2 occupancy was less than the threshold value predictive of extrapyramidal events. In animals olanzapine has been observed to produce a significant reduction in the firing of A10 dopaminergic cells. The number of spontaneously active A9 neurons either remained constant or was increased. This may explain the low incidence of extrapyramidal side effects with olanzapine usually associated with the typical antipsychotics. Olanzapine also increases extracellular levels of dopamine in a regionally specific manner in the prefrontal cortex, similar to mood stabilizers, lithium and valproate.

Pharmacokinetics

Oral Administration:

Absorption:

ZYPREXA is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food.

Distribution: Plasma concentrations of orally administered olanzapine were linear and dose proportional in trials studying doses from 1 to 15 mg. The maximum plasma concentrations (Cmax) of olanzapine after single oral doses of 5, 10 and 15 mg averaged 7, 14, and 21 ng/mL, respectively (20 ng/mL = 0.064 mM). In young healthy volunteers, after once-a-day repeated dosing, steady-state Cmax was approximately twice that achieved after a single dose (e.g. 23 ng/mL versus 12 ng/mL for a 10-mg dose). In the elderly, the steady state plasma concentration was approximately 3-fold higher than that achieved after a single dose (e.g. 16 ng/mL versus 5 ng/mL for a 5-mg dose). In both, young and elderly, steady-state concentrations of olanzapine were obtained after seven days of once daily dosing. Over time and dosage range, pharmacokinetic parameters within an individual are very consistent. However, plasma concentrations, half-life and clearance of olanzapine may vary between individuals on the basis of smoking status, gender, and age (see Special Populations). Data from pooled, single dose pharmacokinetic studies showed the half- life of olanzapine to range from 21 to 54 hours (5th to 95th percentile), and the apparent plasma clearance to range from 12 to 47 L/hr (5th to 95th percentile). The plasma protein binding of olanzapine was about 93% over the concentration range of about 7 to about 1000 ng/mL. Olanzapine is bound predominantly to albumin and a1- acid glycoprotein. Metabolism: Olanzapine is metabolized in the liver by conjugative and oxidative pathways. The major circulating metabolite is the 10-N-glucuronide, which is pharmacologically inactive and does not pass the blood brain barrier. Cytochrome P450 isoforms CYP1A2 and CYP2D6 contribute to the formation of the N-desmethyl and 2- hydroxymethyl metabolites. Both metabolites exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent olanzapine.

In vitro microsomal studies show that olanzapine is a weak inhibitor of CYP1A2 (Ki = 36 mM), CYP2D6 (Ki = 89 mM), and CYP3A4 (Ki = 490 mM). Based upon these Ki values, little inhibition of these cytochrome P-450 enzymes is expected in vivo at concentrations below 5 mM (roughly 1500 ng/mL) because the olanzapine concentration will be less than 10% of its Ki value. In clinical studies, observed steady-state plasma concentrations of olanzapine are rarely >150 ng/mL (approximately 0.5 mM). Olanzapine is thus not likely to cause clinically important pharmacokinetic drug-drug interactions mediated through the metabolic routes outlined above. (See DRUG INTERACTIONS section). Elimination: After oral administration to healthy subjects, the mean terminal elimination half-life was 33 hours (21 to 54 hours for 5th to 95th percentile) and the mean olanzapine plasma clearance was 26 L/hr (12 to 47 L/hr for the 5th to 95th percentile). Olanzapine pharmacokinetics varied on the basis of smoking status, gender, and age. Table 11 summarizes these effects:

Table 11: Olanzapine Key Pharmacokinetics

Although smoking status, gender, and, to a lesser extent, age may affect olanzapine clearance and half-life, the magnitude of the impact of these single factors is small in comparison to the overall variability between individuals. Pharmacokinetic studies demonstrate that ZYPREXA tablets and ZYPREXA ZYDIS dosage forms of olanzapine are bioequivalent. ZYPREXA ZYDIS orally disintegrating tablets can be used as an alternative to ZYPREXA tablets. See Part II: Comparative Bioavailability Studies.

Intramuscular Administration:

ZYPREXA IntraMuscular results in rapid absorption with peak plasma concentrations occurring within 15 to 45 minutes. The peak concentration is on average 4 to 5 fold higher than that of an equivalent oral dose. Area under the curve achieved after an intramuscular dose is equivalent to that achieved after oral administration of the same dose. The half-life observed after intramuscular administration is similar to that observed after oral dosing. The pharmacokinetics are linear over the clinical dosing range. Metabolic profiles after intramuscular administration are quantitatively similar and qualitatively identical to metabolic profiles after oral administration.

Special Populations and Conditions

Geriatrics:

In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (>65 years) than in non-elderly subjects (<= 65 years). Caution should be used in dosing the elderly, especially if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity (see DOSAGE AND ADMINISTRATION section).

Gender:

Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed.

Race:

In a study of Caucasians, Japanese, and Chinese subjects, there were no differences in olanzapine pharmacokinetics among the three populations. Cytochrome P450 isoform CYP2D6 status does not affect the metabolism of olanzapine.

Hepatic Insufficiency:

No differences in the single-dose pharmacokinetics of oral olanzapine were noted in subjects with clinically significant cirrhosis (who were mostly smokers) when compared to healthy subjects (all non-smokers). Multiple-dose studies in patients with hepatic impairment, however, have not been performed.

Renal Insufficiency:

There was no significant difference in mean elimination half-life or olanzapine plasma clearance between subjects with severely impaired renal function compared to individuals with normal renal function. Approximately 57% of radio- labelled olanzapine is excreted in urine, principally as metabolites.

STORAGE AND STABILITY

ZYPREXA(r) Tablets: Store tablets at 15deg-30degC. Protect from light and moisture.

ZYPREXA(r) Zydis(r) *: Sensitive to light, keep tablets in the original package in a dry place at 15-30degC.

ZYPREXA(r) IntraMuscular: Store ZYPREXA IntraMuscular (unconstituted) between 15-30degC. Reconstituted ZYPREXA IntraMuscular may be stored at controlled room temperature 20deg-25degC [See USP] for up to 1 hour if necessary. As with all parenteral drug products, reconstituted solutions should be inspected visually for clarity, particulate matter, precipitation, discolouration and leakage prior to administration, whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard any unused portion of reconstituted ZYPREXA IntraMuscular.

DOSAGE FORMS, COMPOSITION AND PACKAGING

ZYPREXA(r) (olanzapine) Tablets: Each ZYPREXA(r) (olanzapine) tablet contains the equivalent activity of 2.5 mg (8 umol), 5 mg (16 mmol), 7.5 mg (24 mmol), 10 mg (32 mmol), 15 mg (48 mmol), or 20 mg (64 mmol) of olanzapine. Nonmedicinal ingredients include: carnauba wax, crospovidone, FD&C Blue No.2 Aluminum Lake (15.0 mg tablets only), hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol (2.5 mg, 5.0 mg, 7.5 mg, 10.0 mg, and 20 mg tablets only), polysorbate 80 (2.5 mg, 5.0 mg, 7.5 mg, and 10.0 mg tablets only), titanium dioxide, triacetin (15.0 mg tablets only), and Synthetic Red Iron Oxide (20.0 mg tablets only). The 2.5 mg, 5.0 mg, 7.5 mg, and 10.0 mg tablets are imprinted with edible ink which contains FD&C Blue No.2 Aluminum Lake.

ZYPREXA(r) Zydis(r) *(olanzapine) Orally Disintegrating Tablet: Each tablet contains olanzapine equivalent to 5 mg (16 mmol), 10 mg (32 mmol), 15 mg (48 mmol), or 20 mg (64 mmol). Nonmedicinal ingredients include: aspartame, gelatin, mannitol, sodium methyl paraben and sodium propyl paraben.

ZYPREXA(r) IntraMuscular (olanzapine tartrate for injection): Each vial contains olanzapine, as the tartrate, equivalent to 10 mg olanzapine with inactive ingredients lactose monohydrate and tartaric acid. Hydrochloric acid and/or sodium hydroxide may have been added during manufacturing to adjust pH. For reconstitution information, please refer to the DOSAGE AND ADMINISTRATION section. ZYPREXA IntraMuscular is intended for intramuscular use only. AVAILABILITY OF DOSAGE FORMS:

ZYPREXA(r) Tablets: The 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets are white, round, film-coated, and imprinted in blue ink with "LILLY" and the tablet identification code. The 15 mg and 20 mg tablets are elliptical, film-coated light blue and pink, respectively, and debossed with ALILLY @ and the tablet identification code. The 2.5 mg, 5 mg, and 10 mg tablets are available in amber HDPE bottles of 7, 60, 100, 250, and 1000 tablets and in blisters. The 7.5 mg tablets are available in amber HDPE bottles of 60, 100, 250, and 1000 tablets and blisters. The 15 mg and 20 mg tablets are available in amber HDPE bottles of 7, 30, 100, and 1000 tablets and in blisters.

ZYPREXA(r) Zydis(r) *Orally Disintegrating Tablets: The 5 mg, 10 mg, 15 mg, and 20 mg tablets are yellow and round. The tablets are supplied in aluminum blister strips in cartons of 7 tablets or 28 tablets per carton.

ZYPREXA IntraMuscular:

ZYPREXA IntraMuscular is available as single use 5 mL vials in packages of 1s (VL7597).