Zyprexa

The following discussion relates primarily to weight gain, lipids, and glucose changes observed during clinical trials across all indications.

The safety and efficacy of ZYPREXA have not been established in pediatric populations and its use is not recommended.

ZYPREXA IntraMuscular is indicated for the rapid control of agitation in patients with schizophrenia and related psychotic disorders, and bipolar mania. The efficacy of ZYPREXA IntraMuscular for the control of agitation was established in 2 short-term (24 hours) placebo-controlled trials in agitated inpatients with schizophrenia and one short-term (24 hours) placebo-controlled trial in agitated patients with mania associated with bipolar disorder.

ZYPREXA (olanzapine) is indicated for the acute treatment of manic or mixed episodes in bipolar I disorder. Olanzapine may be used as monotherapy or cotherapy with agents commonly used in the treatment of acute bipolar disorder (e.g., lithium or divalproex sodium).

The efficacy of ZYPREXA as monotherapy maintenance treatment in bipolar patients with manic or mixed episodes who responded to acute treatment with ZYPREXA was demonstrated in two 1-year “time to relapse” trials.

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 (see Dosage and Administration).

ZYPREXA is not indicated in elderly patients with dementia. See Warnings and Precautions—Serious Warnings and Precautions Box and Special Populations. Caution should be used when treating geriatric patients with ZYPREXA. See Action and Clinical Pharmacology, Warnings and Precautions, Special Populations, and Dosage and Administration.

ZYPREXA (olanzapine) is indicated for the acute and maintenance treatment of schizophrenia and related psychotic disorders. In controlled clinical trials, ZYPREXA was found to improve both positive and negative symptoms.

ZYPREXA has been shown to be effective in maintaining clinical improvement during 1-year of continuation therapy in patients who had shown an initial treatment response.

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.

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 of oral olanzapine but survival has also been reported following acute overdose of approximately 2000 mg of oral olanzapine.

Each white, round, film-coated tablet, imprinted in blue ink with “LILLY” and the tablet identification code 4112, contains: olanzapine 2.5 mg (8 µmol). Nonmedicinal ingredients: carnauba wax, crospovidone, FD&C Blue No. 2 Aluminum Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide. Amber HDPE bottles of 7 and 100.

Each yellow, round, oral disintegrating tablet contains: olanzapine 10 mg (32 µmol). Nonmedicinal ingredients: aspartame, gelatin, mannitol, sodium methyl paraben and sodium propyl paraben. Aluminum blister strips in cartons of 7 and 28 tablets per carton.

Each yellow, round, oral disintegrating tablet contains: olanzapine 5 mg (16 µmol). Nonmedicinal ingredients: aspartame, gelatin, mannitol, sodium methyl paraben and sodium propyl paraben. Aluminum blister strips in cartons of 7 and 28 tablets per carton.

Each yellow, round, oral disintegrating tablet contains: olanzapine 15 mg (48 µmol). Nonmedicinal ingredients: aspartame, gelatin, mannitol, sodium methyl paraben and sodium propyl paraben. Aluminum blister strips in cartons of 7 and 28 tablets per carton.

Each vial contains: olanzapine, as the tartrate, equivalent to olanzapine 10 mg. Nonmedicinal ingredients: lactose monohydrate and tartaric acid. Hydrochloric acid and/or sodium hydroxide may have been added during manufacturing to adjust pH. Single use 5 mL vials in packages of 1 (VL7597).

For reconstitution information, please refer to Dosage and Administration. ZYPREXA IntraMuscular is intended for intramuscular use only.

Each white, round, film-coated tablet, imprinted in blue ink with “LILLY” and the tablet identification code 4116, contains: olanzapine 7.5 mg (24 µmol), Nonmedicinal ingredients: carnauba wax, crospovidone, FD&C Blue No. 2 Aluminum Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide. Amber HDPE bottles of 100.

Each yellow, round, oral disintegrating tablet contains: olanzapine 20 mg (64 µmol). Nonmedicinal ingredients: aspartame, gelatin, mannitol, sodium methyl paraben and sodium propyl paraben. Aluminum blister strips in cartons of 28 tablets per carton.

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). 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.

During pre-marketing clinical trials therapy with oral ZYPREXA was associated with elevation of hepatic transaminases, primarily ALT. Within a clinical trial database of 2280 ZYPREXA-treated patients, with baseline ALT levels ≤60 IU/L, 5.9% (134/2280) had treatment-emergent ALT 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 values were still rising. In 38 ZYPREXA-treated patients with baseline ALT >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, has also been reported very rarely in the post-marketing period. See Adverse Reactions, Post-Market Adverse Drug Reactions.

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.

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). 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).

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).

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.

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, 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.

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.

Olanzapine was associated with weight gain during clinical trials. Clinically significant weight gain was observed across all baseline body mass index (BMI) categories (see Adverse Reactions, Other Adverse Events Observed During Clinical Trials with Oral and Intramuscular Olanzapine Across All Indications, Weight Changes). Using pooled data from patients treated with olanzapine over the dosage range of 5 mg to 20 mg per day mean gain was 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.

In long-term studies (at least 48 weeks), both the magnitude of weight gain and the proportion of olanzapine-treated patients who had clinically significant weight gain were greater than in short-term studies. The percentage of patients who gained ≥25% of their baseline body weight with long-term exposure was very common (≥10%).

Small single-dose clinical pharmacology studies 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).

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.

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.

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).

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.

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). 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.

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.

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

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.

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.

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.

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.

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.

Increases in lipids have been observed in olanzapine-treated patients in placebo-controlled clinical trials. Treatment-emergent clinically significant changes in fasting lipids were observed in patients with or without evidence of dyslipidemia at baseline (see Adverse Reactions, Other Adverse Events Observed During Clinical Trials with Oral and Intramuscular Olanzapine Across All Indications, Lipids). Appropriate clinical monitoring is recommended, including baseline and follow-up lipid evaluations.

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).

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

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). In some cases, a prior increase in body weight has been reported which may be a predisposing factor.

In clinical trials (up to 52 weeks) olanzapine was associated with a greater mean change in glucose relative to placebo. Treatment-emergent clinically significant changes in fasting glucose were observed in patients with or without evidence of glucose dysregulation at baseline (see Adverse Reactions, Other Adverse Events Observed During Clinical Trials with Oral and Intramuscular Olanzapine Across All Indications, Glucose Changes).

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.

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.

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.

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.

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.

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.

Store tablets at 15-30°C. Protect from light and moisture.

Store ZYPREXA IntraMuscular (unconstituted) between 15-30°C.

Reconstituted ZYPREXA IntraMuscular may be stored at controlled room temperature 20-25°C [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.

Sensitive to light, keep tablets in the original package in a dry place at 15-30°C.

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.

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).

Plasma concentrations of orally administered olanzapine were linear and dose proportional in trials studying doses from 1 to 15 mg. The maximum plasma concentrations (C_max) 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 μM). In young healthy volunteers, after once-a-day repeated dosing, steady-state C_max 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 and Conditions). Data from pooled, single dose pharmacokinetic studies showed the half-life of olanzapine to range from 21 to 54 hours (5^th to 95^th percentile), and the apparent plasma clearance to range from 12 to 47 L/hr (5^th to 95^th 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 α₁-acid glycoprotein.

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

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.

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.

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.

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.

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 μM), CYP2D6 (Ki=89 μM), and CYP3A4 (Ki=490 μM). Based upon these Ki values, little inhibition of these cytochrome P-450 enzymes is expected in vivo at concentrations below 5 μM (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 μM). Olanzapine is thus not likely to cause clinically important pharmacokinetic drug-drug interactions mediated through the metabolic routes outlined above. (See Drug Interactions.)

Pharmacodynamic Properties: ZYPREXA (olanzapine), a thienobenzodiazepine, is an antipsychotic 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-HT_2A/C (Ki=4 and 11 nM, respectively), 5-HT₃, 5-HT₆, muscarinic M₁-M₅ (Ki=1.9-2.5 nM), adrenergic α₁ (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-HT_2A 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.

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.

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