Olanzapine

Brand Name: Zyprexa

Contents:

Description
Pharmacology
Indications and Usage
Contraindications
Warnings
Precautions
Drug Interactions
Adverse Reactions
Overdose
Dosage
Supplied

DESCRIPTION

ZYPREXA (olanzapine) is approved for the treatment of schizophrenia and acute mixed or manic episodes (bipolar mania) associated with Bipolar I Disorder. ZYPREXA (olanzapine) is a psychotropic agent that belongs to the thienobenzodiazepine class.

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CLINICAL PHARMACOLOGY

Pharmacodynamics
Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors: serotonin 5HT2A/2C (Ki=4 and 11 nM, respectively), dopamine D1-4 (Ki=11-31 nM), muscarinic M1-5 (Ki=1.9-25 nM), histamine H1 (Ki=7 nM), and adrenergic α1 receptors (Ki=19 nM). Olanzapine binds weakly to GABAA, BZD, and β adrenergic receptors (Ki>10 µM). The mechanism of action of olanzapine, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug’s efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT2) antagonism. The mechanism of action of olanzapine in the treatment of acute manic episodes associated with Bipolar I Disorder is unknown.

Antagonism at receptors other than dopamine and 5HT2 with similar receptor affinities may explain some of the other therapeutic and side effects of olanzapine. Olanzapine’s antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Olanzapine’s antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Olanzapine’s antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug.

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INDICATIONS AND USAGE
Schizophrenia
Oral ZYPREXA is indicated for the treatment of schizophrenia.

Bipolar Disorder Acute Monotherapy
Oral ZYPREXA is indicated for the treatment of acute mixed or manic episodes associated with Bipolar I Disorder.

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CONTRAINDICATIONS

ZYPREXA is contraindicated in patients with a known hypersensitivity to the product. For specific information about the contraindications of lithium or valproate, refer to the CONTRAINDICATIONS section of the package inserts for these other products.

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WARNINGS

Hyperglycemia and Diabetes Mellitus — 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. 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.

Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. 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. 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.

Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia — 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 is not approved for the treatment of patients with dementia-related psychosis.

Neuroleptic Malignant Syndrome (NMS) — A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (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 a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported.

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.

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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.

Given these considerations, olanzapine should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient on olanzapine, drug discontinuation should be considered. However, some patients may require treatment with olanzapine despite the presence of the syndrome.

For specific information about the warnings of lithium or valproate, refer to the WARNINGS section of the package inserts for these other products.

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PRECAUTIONS

General
Hemodynamic Effects — Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its α1-adrenergic antagonistic properties. Hypotension, bradycardia with or without hypotension, tachycardia, and syncope were also reported during the clinical trials with intramuscular olanzapine for injection. In an open-label clinical pharmacology study in non-agitated patients with schizophrenia in which the safety and tolerability of intramuscular olanzapine were evaluated under a maximal dosing regimen (three 10 mg doses administered 4 hours apart), approximately one-third of these patients experienced a significant orthostatic decrease in systolic blood pressure (i.e., decrease ≥30 mmHg) (see DOSAGE AND ADMINISTRATION). Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 oral olanzapine studies and in 0.3% (2/722) of olanzapine-treated patients with agitation in the intramuscular olanzapine for injection studies. Three normal volunteers in phase 1 studies with intramuscular olanzapine experienced hypotension, bradycardia, and sinus pauses of up to 6 seconds that spontaneously resolved (in 2 cases the events occurred on intramuscular olanzapine, and in 1 case, on oral olanzapine). The risk for this sequence of hypotension, bradycardia, and sinus pause may be greater in nonpsychiatric patients compared to psychiatric patients who are possibly more adapted to certain effects of psychotropic drugs.

For oral olanzapine therapy, the risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg QD (see DOSAGE AND ADMINISTRATION). A more gradual titration to the target dose should be considered if hypotension occurs.

For intramuscular olanzapine for injection therapy, patients should remain recumbent if drowsy or dizzy after injection until examination has indicated that they are not experiencing postural hypotension and/or bradycardia.

Olanzapine 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) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.

Seizures — During premarketing testing, seizures occurred in 0.9% (22/2500) of olanzapine-treated patients. There were confounding factors that may have contributed to the occurrence of seizures in many of these cases. Olanzapine 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. Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Hyperprolactinemia — As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels, and a modest elevation persists during chronic administration. 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 of this type. Although disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been reported with prolactin-elevating compounds, the clinical significance of elevated serum prolactin levels is unknown for most patients. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in the olanzapine carcinogenicity studies conducted in mice and rats (see Carcinogenesis). However, neither clinical studies nor epidemiologic studies 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.

Transaminase Elevations — In placebo-controlled studies, clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2% (6/243) of patients exposed to olanzapine compared to none (0/115) of the placebo patients. None of these patients experienced jaundice. In two of these patients, liver enzymes decreased toward normal despite continued treatment and in two others, enzymes decreased upon discontinuation of olanzapine. In the remaining two patients, one, seropositive for hepatitis C, had persistent enzyme elevation for four months after discontinuation, and the other had insufficient follow-up to determine if enzymes normalized.

Within the larger premarketing database of about 2400 patients with baseline SGPT ≤90 IU/L, the incidence of SGPT elevation to >200 IU/L was 2% (50/2381). Again, none of these patients experienced jaundice or other symptoms attributable to liver impairment and most had transient changes that tended to normalize while olanzapine treatment was continued.

Among 2500 patients in oral olanzapine clinical trials, about 1% (23/2500) discontinued treatment due to transaminase increases.

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. Periodic assessment of transaminases is recommended in patients with significant hepatic disease (see Laboratory Tests).

Potential for Cognitive and Motor Impairment — Somnolence was a commonly reported adverse event associated with olanzapine treatment, occurring at an incidence of 26% in olanzapine patients compared to 15% in placebo patients. This adverse event was also dose related. Somnolence led to discontinuation in 0.4% (9/2500) of patients in the premarketing database.

Since olanzapine 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 therapy does not affect them adversely.

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 olanzapine 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.

Dysphagia — Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Two olanzapine-treated patients (2/407) in two studies in patients with Alzheimer’s disease died from aspiration pneumonia during or within 30 days of the termination of the double-blind portion of their respective studies; there were no deaths in the placebo-treated patients. One of these patients had experienced dysphagia prior to the development of aspiration pneumonia. 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.

Suicide — The possibility of a suicide attempt is inherent in schizophrenia and in bipolar disorder, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for olanzapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Use in Patients with Concomitant Illness — Clinical experience with olanzapine in patients with certain concomitant systemic illnesses (see Renal Impairment and Hepatic Impairment under CLINICAL PHARMACOLOGY, Special Populations) is limited.

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

In a fixed-dose study of oral olanzapine (olanzapine at doses of 5, 10, and 15 mg/day) and placebo in nursing home patients (mean age: 83 years, range: 61-97; median Mini-Mental State Examination (MMSE): 5, range: 0-22) having various psychiatric symptoms in association with Alzheimer’s disease, the following treatment-emergent adverse events were reported in all (each and every) olanzapine-treated groups at an incidence of either (1) two-fold or more in excess of the placebo-treated group, where at least 1 placebo-treated patient was reported to have experienced the event, or (2) at least 2 cases if no placebo-treated patient was reported to have experienced the event: somnolence, abnormal gait, fever, dehydration, and back pain. The rate of discontinuation in this study for olanzapine was 12% vs 4% with placebo. Discontinuations due to abnormal gait (1% for olanzapine vs 0% for placebo), accidental injury (1% for olanzapine vs 0% for placebo), and somnolence (3% for olanzapine vs 0% for placebo) were considered to be drug related. As with other CNS-active drugs, olanzapine should be used with caution in elderly patients with dementia (see PRECAUTIONS).

Olanzapine 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 premarketing clinical studies. Because of the risk of orthostatic hypotension with olanzapine, caution should be observed in cardiac patients (see Hemodynamic Effects). For specific information about the precautions of lithium or valproate, refer to the PRECAUTIONS section of the package inserts for these other products.

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Drug Interactions

The risks of using olanzapine in combination with other drugs have not been extensively evaluated in systematic studies. Given the primary CNS effects of olanzapine, caution should be used when olanzapine is taken in combination with other centrally acting drugs and alcohol. Because of its potential for inducing hypotension, olanzapine may enhance the effects of certain antihypertensive agents.

Because of its potential for inducing hypotension, olanzapine may enhance the effects of certain antihypertensive agents.

Olanzapine may antagonize the effects of levodopa and dopamine agonists.

The Effect of Other Drugs on Olanzapine - Agents that induce CYP1A2 or glucuronyl transferase enzymes, such as omeprazole and rifampin, may cause an increase in olanzapine clearance. Inhibitors of CYP1A2 could potentially inhibit olanzapine clearance. 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.

Charcoal — The administration of activated charcoal (1 g) reduced the Cmax and AUC of oral olanzapine by about 60%. As peak olanzapine levels are not typically obtained until about 6 hours after dosing, charcoal may be a useful treatment for olanzapine overdose.

Cimetidine and Antacids — Single doses of cimetidine (800 mg) or aluminum- and magnesium-containing antacids did not affect the oral bioavailability of olanzapine.

Carbamazepine — Carbamazepine therapy (200 mg bid) causes an approximately 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.

Ethanol — Ethanol (45 mg/70 kg single dose) did not have an effect on olanzapine pharmacokinetics.

Fluoxetine — Fluoxetine (60 mg single dose or 60 mg daily for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (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.

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

Warfarin — Warfarin (20 mg single dose) did not affect olanzapine pharmacokinetics.

Effect of Olanzapine on Other Drugs — In vitro studies utilizing human liver microsomes suggest that olanzapine has little potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A. Thus, olanzapine is unlikely to cause clinically important drug interactions mediated by these enzymes.

Lithium — Multiple doses of olanzapine (10 mg for 8 days) did not influence the kinetics of lithium. Therefore, concomitant olanzapine administration does not require dosage adjustment of lithium.

Valproate — Studies in vitro 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. In vivo administration of olanzapine (10 mg daily for 2 weeks) did not affect the steady state plasma concentrations of valproate. Therefore, concomitant olanzapine administration does not require dosage adjustment of valproate.

Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine, and warfarin. Multiple doses of olanzapine did not influence the kinetics of diazepam and its active metabolite N-desmethyldiazepam, ethanol, or biperiden. However, the co-administration of either diazepam or ethanol with olanzapine potentiated the orthostatic hypotension observed with olanzapine. Multiple doses of olanzapine did not affect the pharmacokinetics of theophylline or its metabolites.

Lorazepam — Administration of intramuscular lorazepam (2 mg) 1 hour after intramuscular olanzapine for injection (5 mg) did not significantly affect the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, this co-administration of intramuscular lorazepam and intramuscular olanzapine for injection added to the somnolence observed with either drug alone.

Pregnancy
Pregnancy Category C — 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 maximum recommended human daily oral dose on a mg/m2 basis, respectively) no evidence of teratogenicity was observed. In an oral rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the maximum recommended human daily oral dose on a mg/m2 basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily oral dose on a mg/m2 basis). In an oral 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 maximum recommended human daily oral dose on a mg/m2 basis).

Placental transfer of olanzapine occurs in rat pups.

There are no adequate and well-controlled trials with olanzapine in pregnant females. Seven pregnancies were observed during clinical trials 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. 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.

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

Nursing Mothers
Olanzapine was excreted in milk of treated rats during lactation. It is not known if olanzapine is excreted in human milk. It is recommended that women receiving olanzapine should not breast-feed.

Pediatric Use
Safety and effectiveness in pediatric patients have not been established.

Geriatric Use
Of the 2500 patients in premarketing clinical studies with oral olanzapine, 11% (263) were 65 years of age or over. In patients with schizophrenia, there was no indication of any different tolerability of olanzapine in the elderly compared to younger patients. Studies in patients with various psychiatric symptoms in association with Alzheimer’s disease have suggested that there may be a different tolerability profile in this population compared to younger patients with schizophrenia. As with other CNS-active drugs, olanzapine should be used with caution in elderly patients with dementia. 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 (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

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ADVERSE REACTIONS

The information below is derived from a clinical trial database for olanzapine consisting of 8661 patients with approximately 4165 patient-years of exposure to oral olanzapine and 722 patients with exposure to intramuscular olanzapine for injection. This database includes: (1) 2500 patients who participated in multiple-dose oral olanzapine premarketing trials in schizophrenia and Alzheimer’s disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in oral olanzapine premarketing bipolar mania trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in an oral olanzapine trial of patients having various psychiatric symptoms in association with Alzheimer’s disease representing approximately 29 patient-years of exposure; (4) 5788 patients from 88 additional oral olanzapine clinical trials as of December 31, 2001; and (5) 722 patients who participated in intramuscular olanzapine for injection premarketing trials in agitated patients with schizophrenia, Bipolar I Disorder (manic or mixed episodes), or dementia. In addition, information from the premarketing 6-week clinical study database for olanzapine in combination with lithium or valproate, consisting of 224 patients who participated in bipolar mania trials with approximately 22 patient-years of exposure, is included below.

The conditions and duration of treatment with olanzapine 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 longer-term exposure. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analytes, ECGs, chest x-rays, and results of ophthalmologic examinations.

Certain portions of the discussion below relating to objective or numeric safety parameters, namely, dose-dependent adverse events, vital sign changes, weight gain, laboratory changes, and ECG changes are derived from studies in patients with schizophrenia and have not been duplicated for bipolar mania or agitation. However, this information is also generally applicable to bipolar mania and agitation.

Adverse events during exposure were obtained by spontaneous report and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard COSTART dictionary terminology has been used initially to classify reported adverse events.

The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. The reported events do not include those event terms that were so general as to be uninformative. Events listed elsewhere in labeling may not be repeated below. It is important to emphasize that, although the events occurred during treatment with olanzapine, they were not necessarily caused by it. The entire label should be read to gain a complete understanding of the safety profile of olanzapine.

The prescriber should be aware that the figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse event incidence in the population studied.

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DRUG ABUSE AND DEPENDENCE

Controlled Substance Class
Olanzapine is not a controlled substance.

Physical and Psychological Dependence
In studies prospectively designed to assess abuse and dependence potential, olanzapine was shown to have acute depressive CNS effects but little or no potential of abuse or physical dependence in rats administered oral doses up to 15 times the maximum recommended human daily oral dose (20 mg) and rhesus monkeys administered oral doses up to 8 times the maximum recommended human daily oral dose on a mg/m2 basis.

Olanzapine has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials 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, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of olanzapine (e.g., development of tolerance, increases in dose, drug-seeking behavior).

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OVERDOSAGE

Human Experience
In premarketing trials involving more than 3100 patients and/or normal subjects, accidental or intentional acute overdosage of olanzapine was identified in 67 patients. In the patient taking the largest identified amount, 300 mg, the only symptoms reported were drowsiness and slurred speech. In the limited number of patients who were evaluated in hospitals, including the patient taking 300 mg, there were no observations indicating an adverse change in laboratory analytes or ECG. Vital signs were usually within normal limits following overdoses.

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 events: aspiration, cardiopulmonary arrest, cardiac arrhythmias (such as supraventricular tachycardia and one patient experiencing sinus pause with spontaneous resumption of normal rhythm), delirium, possible neuroleptic malignant syndrome, respiratory depression/arrest, convulsion, hypertension, and hypotension. Eli Lilly and Company has received reports of fatality in association with overdose of olanzapine alone. In one case of death, the amount of acutely ingested olanzapine was reported to be possibly as low as 450 mg; however, in another case, a patient was reported to survive an acute olanzapine ingestion of 1500 mg.

Overdosage Management
The possibility of multiple drug involvement should be considered. In case of acute overdosage, establish and maintain an airway and ensure adequate oxygenation and ventilation, which may include intubation. Gastric lavage (after intubation, if patient is unconscious) and administration of activated charcoal together with a laxative should be considered. The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis. Cardiovascular monitoring should commence immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias.

There is no specific antidote to olanzapine. Therefore, appropriate supportive measures should be initiated. 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 beta-agonist activity, since beta stimulation may worsen hypotension in the setting of olanzapine-induced alpha blockade.) Close medical supervision and monitoring should continue until the patient recovers.

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DOSAGE AND ADMINISTRATION

Schizophrenia
Usual Dose — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 5 to 10 mg initially, 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 olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Efficacy in schizophrenia was demonstrated in a dose range of 10 to 15 mg/day in clinical trials. However, doses above 10 mg/day were not demonstrated to be more efficacious than the 10 mg/day dose. An increase to a dose greater than the target dose of 10 mg/day (i.e., to a dose of 15 mg/day or greater) is recommended only after clinical assessment. The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Dosing in Special Populations — The recommended starting dose is 5 mg in patients who are debilitated, who have a predisposition to hypotensive reactions, who otherwise exhibit a combination of factors that may result in slower metabolism of olanzapine (e.g., nonsmoking female patients ≥65 years of age), or who may be more pharmacodynamically sensitive to olanzapine (see CLINICAL PHARMACOLOGY; also see Use in Patients with Concomitant Illness and Drug Interactions under PRECAUTIONS). When indicated, dose escalation should be performed with caution in these patients.

Maintenance Treatment — While there is no body of evidence available to answer the question of how long the patient treated with olanzapine should remain on it, the effectiveness of oral olanzapine, 10 mg/day to 20 mg/day, in maintaining treatment response in schizophrenic patients who had been stable on ZYPREXA for approximately 8 weeks and were then followed for a period of up to 8 months has been demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY). Patients should be periodically reassessed to determine the need for maintenance treatment with appropriate dose.

Bipolar Disorder
Usual Monotherapy Dose — Oral olanzapine should be administered on a once-a-day schedule without regard to meals, generally beginning with 10 or 15 mg. Dosage adjustments, if indicated, should generally occur at intervals of not less than 24 hours, reflecting the procedures in the placebo-controlled trials. When dosage adjustments are necessary, dose increments/decrements of 5 mg QD are recommended.

Short-term (3-4 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Maintenance Monotherapy — The benefit of maintaining bipolar patients on monotherapy with oral ZYPREXA at a dose of 5 to 20 mg/day, after achieving a responder status for an average duration of two weeks, was demonstrated in a controlled trial (see Clinical Efficacy Data under CLINICAL PHARMACOLOGY). The physician who elects to use ZYPREXA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Bipolar Mania Usual Dose in Combination with Lithium or Valproate — When administered in combination with lithium or valproate, oral olanzapine dosing should generally begin with 10 mg once-a-day without regard to meals.

Short-term (6 weeks) antimanic efficacy was demonstrated in a dose range of 5 mg to 20 mg/day in clinical trials. The safety of doses above 20 mg/day has not been evaluated in clinical trials.

Dosing in Special Populations — See Dosing in Special Populations under DOSAGE AND ADMINISTRATION, Schizophrenia.

Administration of ZYPREXA ZYDIS (olanzapine orally disintegrating tablets)

After opening sachet, peel back foil on blister. Do not push tablet through foil. Immediately upon opening the blister, using dry hands, remove tablet and place entire ZYPREXA ZYDIS in the mouth. Tablet disintegration occurs rapidly in saliva so it can be easily swallowed with or without liquid.

Agitation Associated with Schizophrenia and Bipolar I Mania
Usual Dose for Agitated Patients with Schizophrenia or Bipolar Mania — The efficacy of intramuscular olanzapine for injection in controlling agitation in these disorders was demonstrated in a dose range of 2.5 mg to 10 mg. The recommended dose in these patients is 10 mg. A lower dose of 5 or 7.5 mg may be considered when clinical factors warrant (see CLINICAL PHARMACOLOGY). If agitation warranting additional intramuscular doses persists following the initial dose, subsequent doses up to 10 mg may be given. However, the efficacy of repeated doses of intramuscular olanzapine for injection in agitated patients has not been systematically evaluated in controlled clinical trials. Also, the safety of total daily doses greater than 30 mg, or 10 mg injections given more frequently than 2 hours after the initial dose, and 4 hours after the second dose have not been evaluated in clinical trials. Maximal dosing of intramuscular olanzapine (e.g., three doses of 10 mg administered 2-4 hours apart) may be associated with a substantial occurrence of significant orthostatic hypotension (see PRECAUTIONS, Hemodynamic Effects). Thus, it is recommended that patients requiring subsequent intramuscular injections be assessed for orthostatic hypotension prior to the administration of any subsequent doses of intramuscular olanzapine for injection. The administration of an additional dose to a patient with a clinically significant postural change in systolic blood pressure is not recommended.

If ongoing olanzapine therapy is clinically indicated, oral olanzapine may be initiated in a range of 5-20 mg/day as soon as clinically appropriate (see Schizophrenia or Bipolar Disorder under DOSAGE AND ADMINISTRATION).

Intramuscular Dosing in Special Populations — A dose of 5 mg per injection should be considered for geriatric patients or when other clinical factors warrant. A lower dose of 2.5 mg per injection should be considered for patients who otherwise might be debilitated, be predisposed to hypotensive reactions, or be more pharmacodynamically sensitive to olanzapine (see CLINICAL PHARMACOLOGY; also see Use in Patients with Concomitant Illness and Drug Interactions under PRECAUTIONS).

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.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Directions for preparation of ZYPREXA IntraMuscular with Sterile Water for Injection

Dissolve the contents of the vial using 2.1 mL of Sterile Water for Injection to provide a solution containing approximately 5 mg/mL of olanzapine. The resulting solution should appear clear and yellow. ZYPREXA IntraMuscular reconstituted with Sterile Water for Injection should be used immediately (within 1 hour) after reconstitution. Discard any unused portion.

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HOW SUPPLIED

The ZYPREXA 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets are white, round, and imprinted in blue ink with LILLY and tablet number. The 15 mg tablets are elliptical, blue, and debossed with LILLY and tablet number. The 20 mg tablets are elliptical, pink, and debossed with LILLY and tablet number.

ZYPREXA is a registered trademark of Eli Lilly and Company.

ZYDIS is a registered trademark of R. P. Scherer Corporation.

Revised March 29, 2004

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