Zypreza (Olanzapine)

ZYPREXA®

Lilly

Olanzapine

Antipsychotic

Action And Clinical Pharmacology: Pharmacodynamics: Olanzapine, a thienobenzodiazepine, is an antipsychotic agent, displaying high receptor affinity binding in vitro at serotonin 5-HT2A/C (Ki=4 and 11 nM, respectively), dopamine D1, D2, D3, D4 (Ki=11 to 31 nM), muscarinic M1-5 (Ki=1.9 to 2.5 nM), adrenergic a1(Ki=19 nM), and histamine H1 (Ki=7 nM) receptors. In a behavioral 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.

Pharmacokinetics: Olanzapine is well absorbed after oral administration, reaching peak plasma concentrations within 5 to 8 hours. The absorption is not affected by food. 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 M). 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 7 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/hour (5th to 95th percentile).

The plasma protein binding of olanzapine was about 93% over the concentration range of about 7 to about 1 000 ng/mL. Olanzapine is bound predominantly to albumin and a1-acid glycoprotein. Olanzapine is metabolized in the liver by conjugative and oxidative pathways. A mass balance study showed that approximately 57% of radiolabeled olanzapine appeared in urine, principally as metabolites. The major circulating metabolite is the 10-N-glucuronide, which is pharmacologically inactive and does not pass the blood brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, respectively. These metabolites do not produce behavioral activity in the rat at doses 4 to 16 times greater than active doses of olanzapine.

In vitro microsomal studies show that olanzapine is a weak inhibitor of CYP1A2 (Ki=36 M), CYP2D6 (Ki=89 M), and CYP3A4 (Ki=490 M). Based upon these Ki values, little inhibition of these cytochrome P450 enzymes is expected in vivo at concentrations below 5 M (roughly 1 500 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 M). Olanzapine is thus not likely to cause clinically important pharmacokinetic drug-drug interactions mediated through the metabolic routes outlined above (see Precautions, Drug Interactions).

Special Populations: In a single dose study involving 24 healthy subjects the mean elimination half-life of olanzapine was prolonged in elderly subjects compared with nonelderly subjects, as shown in Table I.

Large scale population pharmacokinetic analyses show that the plasma clearance of olanzapine is lower in elderly versus young subjects, in females versus males, and in nonsmokers versus smokers. However, the overall variability between individuals is larger than the magnitude of impact of the individual factors of age, gender or smoking, on olanzapine clearance and half-life.

The pharmacokinetic characteristics of olanzapine (5 mg single dose) were not substantially different in patients with severe renal impairment and in normal subjects. Multiple-dose studies in patients with renal failure, however, have not been performed.

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

No specific pharmacokinetic study was conducted to investigate ethnicity effects, but a review of the clinical pharmacology studies identified no important differences in the disposition of olanzapine in Caucasian subjects versus subjects of African descent.

Clinical Trials: The efficacy of olanzapine in the reduction of and maintenance of the reduction of the manifestations of schizophrenia and related psychotic disorders was established in 3 well-controlled clinical trials of psychotic inpatients who, at entry, met the DSM-III-R criteria for schizophrenia (most with a course at entry of “chronic with acute exacerbation”) and 1 well-controlled clinical trial of psychotic inpatients and outpatients who, at entry, met the DSM-III-R criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. The results of the trials follow:

A 6-week, placebo-controlled trial (N=335) compared 3 fixed dosage ranges of olanzapine (5±2.5, 10±2.5, and 15±2.5 mg/day once daily), 1 dosage range of haloperidol (15±5 mg/day on a b.i.d. schedule), and placebo. The 2 higher dosage ranges of olanzapine were statistically significantly superior to placebo on the Brief Psychiatric Rating Scale (BPRS) total, the Clinical Global Impressions – Severity of Illness (CGI-S) scale, and the BPRS positive psychosis cluster. The highest dosage range of olanzapine was statistically significantly superior to placebo and to haloperidol on the Scale for the Assessment of Negative Symptoms (SANS). Efficacy of olanzapine generally increased with dose. The 5±2.5 mg/day dosage range of olanzapine was numerically, but not statistically significantly superior to placebo on BPRS total and other assessments of overall psychopathology.

A 6-week, placebo-controlled trial (N=152) compared 2 fixed doses of olanzapine (1 or 10 mg/day once daily) and placebo; olanzapine, 10 mg/day, was statistically significantly superior to placebo on the BPRS total, the BPRS positive psychosis cluster, the CGI-S scale, the Positive and Negative Syndrome Scale (PANSS) total, the PANSS positive subscale, and the PANSS negative subscale. Olanzapine, 1 mg/day, appeared to be a no-effect dose with no difference, clinically or statistically, from placebo on any assessment of psychopathology.

A 6-week, dose comparison trial (N=431) compared 3 fixed dosage ranges of olanzapine (5±2.5, 10±2.5 and 15±2.5 mg/day once daily), olanzapine (1 mg/day once daily), and haloperidol (15±5 mg/day on a b.i.d. schedule). There were no statistically significant differences between groups on efficacy measures except for the highest dosage range of olanzapine, which was statistically significantly superior to olanzapine, 1 mg, on the BPRS positive psychosis cluster, PANSS positive subscale, and the CGI-S scale.

A 6-week comparator-controlled trial (N=1 996, 2:1 randomization, olanzapine:haloperidol) compared 1 dosage range of olanzapine (5 to 20 mg/day once daily) and 1 dosage range of haloperidol (5 to 20 mg/day once daily). The acute mean modal doses (for those patients with at least 3 weeks of treatment) were 13.2 mg/day for olanzapine and 11.8 mg/day for haloperidol. Olanzapine was statistically significantly superior to haloperidol on the BPRS total, the BPRS negative psychosis cluster, the PANSS negative subscale, and the CGI-S scale. Olanzapine was also statistically significantly superior to haloperidol on the Montgomery-Asberg Depression Rating Scale (MADRS). The validity of this scale in patients with schizophrenia, however, is not established.

The effectiveness of olanzapine in long-term therapy, i.e., >6 weeks, was evaluated in 3 double-blind, controlled, extension maintenance trials (of acute trials 1, 3, and 4 above). Patients who showed adequate clinical improvement following double-blind acute therapy were allowed to continue on in a double-blind, long-term extension maintenance phase on their acute dosage regime. Long-term maintenance of treatment response (as defined by continued reduction in signs and symptoms sufficient to not require hospitalization for psychosis) was compared over time (894 olanzapine-treated patients; median length of treatment was 237 days). The percentage of patients maintaining treatment response over 1 year was compared. Olanzapine was statistically significantly superior to placebo in the 1 placebo-controlled trial and was comparable or statistically significantly superior to the active comparator in 3 of 3 active comparator-controlled trials.

While the efficacy of olanzapine at a dose of 5 mg/day was not statistically superior to placebo [see (1)], some individual patients receiving this dose had a good acute response, and were well maintained during a 1-year extension phase.

The above trials (including open-label extension) and an additional trial in geriatric patients with primary degenerative dementia of the Alzheimer’s type constitute the primary database (N=2 500 patients treated with olanzapine, corresponding to 1 122.2 patient-years; N=810 patients treated with haloperidol, corresponding to 193.0 patient-years; N=236 patients treated with placebo, corresponding to 27.1 patient-years).

Indications And Clinical Uses: For the acute and maintenance treatment of schizophrenia and related psychotic disorders. In controlled clinical trials, olanzapine was found to improve both positive and negative symptoms.

Olanzapine 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.

Contra-Indications: Patients with a known hypersensitivity to the drug or the excipients of the product.

Manufacturers’ Warnings In Clinical States: Neuroleptic Malignant Syndrome (NMS): In premarketing clinical trials there were no reported cases of NMS in patients receiving olanzapine. 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 creatinine phosphokinase, myoglobinuria (rhabdomyolysis) and acute renal failure.

The management of NMS should include immediate discontinuation of all antipsychotic drugs including olanzapine, 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 reintroduction of therapy should be very carefully considered, since recurrence of NMS has been reported.

Tardive Dyskinesia: Tardive dyskinesia (TD), a syndrome consisting of potentially irreversible involuntary dyskinetic movements, is associated with the use of antipsychotic drugs. TD 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 maintenance trials (894 olanzapine-treated patients; median olanzapine treatment, 237 days), olanzapine was associated with a statistically significantly lower incidence of treatment emergent dyskinesia compared to haloperidol.

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 drugs 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, olanzapine should be prescribed in a manner that is most likely to minimize the risk of tardive dyskinesia. As with any antipsychotic drug, olanzapine 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 olanzapine, drug discontinuation should be considered. However, some patients may benefit from continued treatment with olanzapine despite the presence of the syndrome.

Precautions: Lactose: Zyprexa tablets contain lactose.

Occupational Hazards: Potential Effect on Cognitive and Motor Performance: Because olanzapine may cause somnolence, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that olanzapine therapy does not affect them adversely.

Hypotension and Syncope: As with other drugs that have high alpha-1 adrenergic receptor blocking activity, olanzapine may induce orthostatic hypotension, tachycardia, dizziness, and sometimes syncope, especially at the initiation of treatment. In a clinical trial database of 2 500 patients treated with olanzapine, syncope was reported in 0.6% (15/2 500). The risk of orthostatic hypotension and syncope may be minimized by initiating therapy with 5 mg daily (see Dosage). A more gradual titration to the target dose should be considered if hypotension occurs. 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).

Seizures: Conventional neuroleptics are known to lower seizure threshold. In clinical trials, seizures have occurred in a small number (0.9%, 22/2 500) 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 who have a history of seizures or have conditions associated with seizure or have a lowered seizure threshold.

Transaminase Elevations: During premarketing clinical trials, therapy with olanzapine was associated with elevation of hepatic transaminases, primarily ALT. Within a clinical trial database of 2 280 olanzapine-treated patients, with baseline ALT levels £60 IU/L, 5.9% (134/2 280) had treatment-emergent ALT elevations to >120 IU/L, 1.9% (44/2 280) had elevations to >200 IU/L, and 0.2% (5/2 280) had elevations to >400 IU/L. No patients had values in excess of 700 IU/L. None of the olanzapine-treated patients who had elevated transaminase values manifested clinical symptomatology associated with liver impairment. The majority of transaminase elevations were seen during the first 6 weeks of treatment. Most elevations were transient (66%) while patients continued on olanzapine therapy, or falling (11%) at the last available measurement. Of the 134 olanzapine-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 olanzapine-treated patients with baseline ALT >90 IU/L, none experienced an elevation to >400 IU/L.

Precautions should be exercised when using olanzapine 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 olanzapine, 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 olanzapine therapy.

Hematologic Indices: In clinical trials, there were no data to suggest olanzapine adversely affected bone marrow function, even in patients with a history of clozapine-associated neutropenia or leukopenia. Olanzapine 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.

Hyperprolactinemia: As with other drugs that block dopamine D2, and/or serotonin 5-HT2 receptors, olanzapine may elevate prolactin levels. Elevations associated with olanzapine 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, olanzapine 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 olanzapine treatment in patients with pituitary tumors. 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.

Uric Acid: In the premarketing clinical trial database, olanzapine was associated with mild elevations of uric acid in some patients. However, only 1 olanzapine-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 olanzapine.

Weight Gain: Olanzapine was associated with weight gain during clinical trials. Patients treated at higher doses (15±2.5 mg/day) had the greatest mean weight gain. However, a categorization of patients at baseline on the basis of body mass index (BMI) revealed a significantly greater effect in patients with low BMI compared to normal or overweight patients. Using pooled data from patients treated with olanzapine over the dosage range of 5 to 20 mg/day, weight gain tended to level off at 6 to 8 months of treatment, with a mean gain of 5.4 kg.

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 tumor or intestinal obstruction.

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 of core temperature, e.g. exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

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.

Drug Interactions: Given the primary CNS effects of olanzapine, caution should be used when it is taken in combination with other centrally-acting drugs and alcohol. As it exhibits in vitro dopamine antagonism, olanzapine may antagonize the effects of levodopa and dopamine agonists. Because of its potential for inducing hypotension, olanzapine may enhance the effects of certain antihypertensive agents.

Potential for Other Drugs to Affect Olanzapine: The metabolism of olanzapine may be induced by concomitant smoking, or carbamazepine therapy. The concomitant administration of activated charcoal reduced the oral bioavailability of olanzapine by 50 to 60%. Single doses of antacid (aluminum, magnesium) or cimetidine did not affect the oral bioavailability of olanzapine. Agents that induce CYP1A2 such as omeprazole may increase clearance of olanzapine. Conversely, inhibitors of CYP1A2 (e.g., fluvoxamine) could potentially inhibit elimination of olanzapine. However, as olanzapine is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease olanzapine clearance.

Potential for Olanzapine to Affect Other Drugs: In clinical trials with single doses of olanzapine, no inhibition of the metabolism of imipramine/desipramine (P450-CYP2D6), warfarin (P450-CYP2C9), or diazepam (P450-CYP3A4) was evident. Olanzapine showed no interaction when coadministered with lithium. Also, in in vitro studies with human microsomes, olanzapine showed little potential to inhibit cytochromes P450-CYP1A2, -CYP2C9, -CYP2C19, -CYP2D6, and -CYP3A4 (see 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 olanzapine.

Pregnancy: 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 olanzapine. 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.

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

Lactation: Olanzapine was excreted in milk of treated rats during lactation. It is not known if olanzapine is excreted in human milk. Patients should be advised not to breast-feed an infant if they are taking olanzapine.

Geriatrics: The number of patients 65 years of age or over, with schizophrenia or related disorders, exposed to olanzapine, during clinical trials was limited (N=44). Caution should thus be exercised with the use of olanzapine 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).

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

Renal and Hepatic Impairment: Small single-dose clinical pharmacology studies (see Pharmacology, Special Populations) did not reveal any major alterations in olanzapine pharmacokinetics in subjects with renal or hepatic impairment. Given the limited clinical experience with olanzapine in patients with these conditions, caution should be exercised (see Dosage).

Patients with Other Concomitant Illness: Clinical experience with olanzapine in patients with concomitant illness is limited. Caution is thus advised when using olanzapine in patients with diseases or conditions that could affect the metabolism or the pharmacodynamic activity of olanzapine (see Pharmacology, Pharmacokinetics, and Dosage).

Olanzapine has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these conditions were excluded from premarketing clinical trials.

As olanzapine 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 intercranial hypertension exacerbated.

Adverse Reactions: 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. It is important to emphasize that although the events were reported during therapy, they were not necessarily caused by the therapy.

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 figures cited, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side effect incidence in the populations studied.

Commonly Observed Adverse Events in Placebo-Controlled Clinical Trials: The following treatment-emergent adverse events, derived from Table II, commonly occurred during acute therapy with olanzapine (incidence of at least 5%, and more than double the incidence observed with placebo): dizziness, constipation, ALT increased, weight gain, akathesia and postural hypotension.

Adverse Events Associated with Discontinuation: Short-Term, Placebo-Controlled Clinical Trials: There was no statistically significant difference in rates of discontinuation of olanzapine or placebo attributed to adverse events. Overall, 5% of olanzapine-treated patients discontinued treatment for adverse events compared with 6% of placebo-treated patients. Discontinuations due to ALT elevations, however, were considered to be drug related (2% for olanzapine versus 0% for placebo) (see Precautions).

Short-Term, Active-Controlled Clinical Trials: Of the 1 796 olanzapine-treated patients in comparative clinical trials with haloperidol, 98 (5%) discontinued treatment for adverse events compared with 66 of 810 (8%) haloperidol-treated patients.

Overall Integrated Safety Database: In a premarketing clinical trial database of 2 500 olanzapine-treated patients, 14.9% (372/2 500) discontinued for an adverse event. About half (183/372) of these discontinuations were associated with the underlying psychopathology. Other adverse events most commonly (incidence of 0.5 to 0.6%) reported as the reason for discontinuation among olanzapine-treated patients were: ALT increased, unintended pregnancy, creatinine phosphokinase increased, and convulsion.

Incidence of Adverse Events in Placebo-Controlled Clinical Trials: Table II enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred during acute therapy (up to 6 weeks) of schizophrenia in 1% or more of patients treated with olanzapine (doses ³2.5 mg/day) where the incidence in patients treated with olanzapine was greater than the incidence in placebo-treated patients.

Incidence of Weight Changes in Placebo-Controlled Clinical Trials: During acute therapy (up to 6 weeks) in controlled clinical trials comparing olanzapine with placebo in the treatment of schizophrenia, the percentages of patients with weight gain ³7% of baseline body weight at any time were 29% for olanzapine and 3% for placebo, which was a statistically significant difference. The average weight gain during acute therapy in patients treated with olanzapine was 2.8 kg. However, a categorization of patients at baseline on the basis of body mass index (BMI) revealed a significantly greater effect in patients with low BMI compared to normal or overweight patients. In long-term extension trials weight gain tended to level off after 6 to 8 months of treatment, with an average gain of 5.4 kg (see Precautions).

Incidence of Vital Sign Changes in Placebo-Controlled Clinical Trials: In placebo-controlled clinical trials, orthostatic hypotension (greater than 30 mm decrease in systolic blood pressure) occurred with an incidence of 5% in olanzapine-treated patients compared to 2% in placebo-treated patients (vital sign measurements collected only after 3 to 7 days of olanzapine treatment). Olanzapine was associated with a mean baseline to endpoint increase in heart rate of 2.4 beats per minute compared to no change among placebo-treated patients (see Precautions).

Incidence of Laboratory Changes in Placebo-Controlled Clinical Trials: Olanzapine is associated with asymptomatic increases in ALT, AST and GGT (see Precautions). Olanzapine is also associated with generally mild increases in serum prolactin, which usually decreases with continued drug treatment. Olanzapine is also associated with asymptomatic elevations of eosinophils and uric acid (see Precautions), and with decreases in serum bicarbonate.

Incidence of ECG Changes in Placebo-Controlled Clinical Trials: Between-group comparisons for pooled placebo-controlled trials revealed no statistically significant olanzapine/placebo differences in the proportions of patients experiencing potentially important changes in ECG parameters, including QT, QTc and PR intervals.

Dose-Dependent Adverse Events in Fixed-Dose Clinical Trials: Dose-relatedness of adverse events was assessed using data from a clinical trial with a fixed dosage range. Table III enumerates the treatment-emergent adverse events in which there was a statistically significantly increasing dose response in this clinical trial.

Incidence of Treatment-Emergent Extrapyramidal Symptoms in Placebo-Controlled Trials: Table IV enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by categorical analyses of formal rating scales during acute therapy in a controlled clinical trial comparing olanzapine at 3 fixed dosage ranges with placebo in the treatment of schizophrenia.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Experience with olanzapine in overdosage is limited. In clinical trials, 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 analyses or ECG. Vital signs were usually within normal limits following overdoses.

Based on animal data, the predicted symptoms would reflect an exaggeration of the drug’s known pharmacological actions. Symptoms may include somnolence, mydriasis, blurred vision, respiratory depression, hypotension, and possible extrapyramidal disturbances.

There is no specific antidote to olanzapine; therefore, appropriate supportive measures should be initiated. 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. The use of activated charcoal for overdose should be considered because the concomitant administration of activated charcoal was shown to reduce the oral bioavailability of olanzapine by 50 to 60%. Gastric lavage (after intubation, if patient is unconscious) may also be considered.

Hypotension and circulatory collapse should be treated with appropriate measures such as i.v. fluids and/or sympathomimetic agents such as norepinephrine (do not use epinephrine, dopamine or other sympathomimetic agents with beta-agonist activity since beta stimulation may worsen hypotension in the setting of alpha blockade induced by olanzapine). Cardiovascular monitoring should commence immediately and should include continuous ECG monitoring to detect possible arrhythmias.

Close medical supervision and monitoring should continue until the patient recovers.

Dosage And Administration: Adults: 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 olanzapine would not be achieved for approximately 1 week in the typical patient. When dosage adjustments are necessary, dose increments/decrements of 5 mg daily 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 to 20 mg/day was studied (see Pharmacology, Clinical Trials). The safety and efficacy of doses above 20 mg/day have not been evaluated.

Geriatrics or Debilitated Patients: In clinical trials, 44 patients with schizophrenia or related disorders, 65 years of age or over, were treated with olanzapine (5 to 20 mg daily) (see Precautions and Pharmacology, Special Populations). Given the limited experience with olanzapine in the elderly, and the higher incidence of concomitant illness and concomitant medication in this population, olanzapine 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 olanzapine (e.g., nonsmoking female patients), or who may be pharmacodynamically more sensitive to olanzapine. 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 Precautions and Pharmacology, Special Populations).

Maintenance Therapy: It is recommended that responding patients be continued on olanzapine 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 olanzapine, the effectiveness of maintenance treatment is well established for many other antipsychotic drugs.

Availability And Storage: 2.5 mg: Each white, round, film-coated tablet, imprinted in blue ink with “Lilly” and Identi-Code 4112, contains: olanzapine 2.5 mg. Nonmedicinal ingredients: carnauba wax, color mixture white (hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and polysorbate 80), crospovidone, FD&C Blue No. 2 Aluminum Lake, hydroxypropylcellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate and microcrystalline cellulose. Amber HDPE bottles of 60.

5 mg: Each white, round, film-coated tablet, imprinted in blue ink with “Lilly” and Identi-Code 4115, contains: olanzapine 5 mg. Nonmedicinal ingredients: carnauba wax, color mixture white (hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and polysorbate 80), crospovidone, FD&C Blue No. 2 Aluminum Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate and microcrystalline cellulose. Amber HDPE bottles of 60.

7.5 mg: Each white, round film-coated tablet, imprinted in blue ink with “Lilly” and Identi-code 4116, contains: olanzapine 7.5 mg. Nonmedicinal ingredients: carnauba wax, color mixture white (hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and polysorbate 80), crospovidone, FD&C Blue No. 2 Aluminum Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate and microcrystalline cellulose. Amber HDPE bottles of 60.

10 mg: Each white, round film-coated tablet, imprinted in blue ink with “Lilly” and Identi-Code 4117, contains: olanzapine 10 mg. Nonmedicinal ingredients: carnauba wax, color mixture white (hydroxypropyl methylcellulose, titanium dioxide, polyethylene glycol and polysorbate 80), crospovidone, FD&C Blue No. 2 Aluminum Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate and microcrystalline cellulose. Amber HDPE bottles of 60.

Store tablets at 20 to 25°C. Protect from light and moisture.

ZYPREXA® Lilly Olanzapine Antipsychotic

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