OLANZAPINE
DESCRIPTION
ONZA (olanzapine) is a psychotropic agent that belongs to the thienobenzodiazepine class. The chemical designation is 2-methyl-4-(4-methyl-1-piperazinyl)-10 H -thieno[2,3- b ] [1,5]benzodiazepine. The molecular formula is C 17 H 20 N 4 S, which corresponds to a molecular weight of 312.44.
Olanzapine is a yellow crystalline solid, which is practically insoluble in water.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Olanzapine is a selective monoaminergic antagonist with high affinity binding to the following receptors: serotonin 5HT 2A/2C (K i =4 and 11 nM, respectively), dopamine D 1-4 (K i =11-31 nM), muscarinic M 1-5 (K i =1.9-25 nM), histamine H 1 (K i =7 nM), and adrenergic (alpha) 1 receptors (K i =19 nM). Olanzapine binds weakly to GABA A , BZD, and (beta) adrenergic receptors (K i > 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' efficacy in schizophrenia is mediated through a combination of dopamine and serotonin type 2 (5HT 2 ) 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 5HT 2 with similar receptor affinities may explain some of the other therapeutic and side effects of olanzapine. Olanzapine's antagonism of muscarinic M 1-5 receptors may explain its anticholinergic effects. Olanzapine's antagonism of histamine H 1 receptors may explain the somnolence observed with this drug. Olanzapine's antagonism of adrenergic (alpha) 1 receptors may explain the orthostatic hypotension observed with this drug.
Pharmacokinetics:
Olanzapine is well absorbed and reaches peak concentrations in approximately 6 hours following an oral dose. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Food does not affect the rate or extent of olanzapine absorption. Pharmacokinetic studies showed that ONZA tablets and ONZA ZYDIS (olanzapine orally disintegrating tablets) dosage forms of olanzapine are bioequivalent.
Olanzapine displays linear kinetics over the clinical dosing range. Its half-life ranges from 21 to 54 hours (5th to 95th percentile; mean of 30 hr), and apparent plasma clearance ranges from 12 to 47 L/hr (5th to 95th percentile; mean of 25 L/hr).
Administration of olanzapine once daily leads to steady-state concentrations in about one week that are approximately twice the concentrations after single doses. Plasma concentrations, half-life, and clearance of olanzapine may vary between individuals on the basis of smoking status, gender and age ( see Special Populations ).
Olanzapine is extensively distributed throughout the body, with a volume of distribution of approximately 1000 L. It is 93% bound to plasma proteins over the concentration range of 7 to 1100 ng/mL, binding primarily to albumin and (alpha) 1 -acid glycoprotein.
Metabolism and Elimination -- Following a single oral dose of 14 C labeled olanzapine, 7% of the dose of olanzapine was recovered in the urine as unchanged drug, indicating that olanzapine is highly metabolized. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. In the plasma, olanzapine accounted for only 12% of the AUC for total radioactivity, indicating significant exposure to metabolites. After multiple dosing, the major circulating metabolites were the 10-N-glucuronide, present at steady state at 44% of the concentration of olanzapine, and 4'-N-desmethyl olanzapine, present at steady state at 31% of the concentration of olanzapine. Both metabolites lack pharmacological activity at the concentrations observed.
Direct glucuronidation and cytochrome P450 (CYP) mediated oxidation are the primary metabolic pathways for olanzapine. In vitro studies suggest that CYPs 1A2 and 2D6, and the flavin-containing monooxygenase system are involved in olanzapine oxidation. CYP2D6 mediated oxidation appears to be a minor metabolic pathway in vivo, because the clearance of olanzapine is not reduced in subjects who are deficient in this enzyme.
Special Populations --
Renal Impairment--Because olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction alone is unlikely to have a major impact on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based upon the degree of renal impairment is not required. In addition, olanzapine is not removed by dialysis. The effect of renal impairment on metabolite elimination has not been studied.
Hepatic Impairment--Although the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects (n=6) with clinically significant (Childs Pugh Classification A and B) cirrhosis revealed little effect on the pharmacokinetics of olanzapine.
Age--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 ).
Gender--Clearance of olanzapine is approximately 30% lower in women than in men. There were, however, no apparent differences between men and women in effectiveness or adverse effects. Dosage modifications based on gender should not be needed.
Smoking Status--Olanzapine clearance is about 40% higher in smokers than in nonsmokers, although dosage modifications are not routinely recommended.
Race--No specific pharmacokinetic study was conducted to investigate the effects of race. A cross-study comparison between data obtained in Japan and data obtained in the US suggests that exposure to olanzapine may be about 2-fold greater in the Japanese when equivalent doses are administered. Clinical trial safety and efficacy data, however, did not suggest clinically significant differences among Caucasian patients, patients of African descent, and a third pooled category including Asian and Hispanic patients. Dosage modifications for race are, therefore, not recommended.
Combined Effects--The combined effects of age, smoking, and gender could lead to substantial pharmacokinetic differences in populations. The clearance in young smoking males, for example, may be 3 times higher than that in elderly nonsmoking females. Dosing modification may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine ( see DOSAGE AND ADMINISTRATION ).
Clinical Efficacy Data:
Schizophrenia
The efficacy of olanzapine in the management of the manifestations of psychotic disorders was established in 2 short-term (6-week) controlled trials of inpatients who met DSM III-R criteria for schizophrenia. A single haloperidol arm was included as a comparative treatment in one of the two trials, but this trial did not compare these two drugs on the full range of clinically relevant doses for both.
Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in psychosis. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual though content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiar with the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, two more recently developed but less well evaluated scales were employed; these included the 30-item Positive and Negative Symptoms Scale (PANSS), in which is embedded the 18 items of the BPRS, and the Scale for Assessing Negative Symptoms (SANS). The trial summaries below focus on the following outcomes: PANSS total and/or BPRS total; BPRS psychosis cluster; PANSS negative subscale or SANS; and CGI Severity. The results of the trials follow:
(1) In a 6-week, placebo-controlled trial (n=149) involving two fixed olanzapine doses of 1 and 10 mg/day (once daily schedule), olanzapine, at 10 mg/day (but not at 1 mg/day), was superior to placebo on the PANSS total score (also on the extracted BPRS total), on the BPRS psychosis cluster, on the PANSS Negative subscale, and on CGI Severity.
(2) In a 6-week, placebo-controlled trial (n=253) involving 3 fixed dose ranges of olanzapine (5.0±2.5 mg/day, 10.0±2.5 mg/day, and 15.0±2.5 mg/day) on a once daily schedule, the two highest olanzapine dose groups (actual mean doses of 12 and 16 mg/day, respectively) were superior to placebo on BPRS total score, BPRS psychosis cluster, and CGI severity score; the highest olanzapine dose group was superior to placebo on the SANS. There was no clear advantage for the high dose group over the medium dose group.
Examination of population subsets (race and gender) did not reveal any differential responsiveness on the basis of these subgroupings.
Bipolar Mania
The efficacy of olanzapine in the treatment of acute manic episodes was established in 2 short-term (one 3-week and one 4-week) placebo-controlled trials in patients who met the DSM-IV criteria for Bipolar I Disorder with manic or mixed episodes. These trials included patients with or without psychotic features and with or without a rapid-cycling course.
The primary rating instrument used for assessing manic symptoms in these trials was the Young Mania Rating Scale (Y-MRS), and 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology in a range from 0 (no manic features) to 60 (maximum score). The primary outcome in these trials was change from baseline in the Y-MRS total score. The results of the trials follow:
In one 3-week placebo-controlled trial (n=67) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 10 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score. In an identically designed trial conducted simultaneously with the first trial, olanzapine demonstrated a similar treatment difference, but possibly due to sample size and site variability, was not shown to be superior to placebo on this outcome.
In a 4-week placebo-controlled trial (n=115) which involved a dose range of olanzapine (5-20 mg/day, once daily, starting at 15 mg/day), olanzapine was superior to placebo in the reduction of Y-MRS total score.
INDICATIONS AND USAGE
Schizophrenia
ONZA is indicated for the management of the manifestations of psychotic disorders.
The efficacy of ONZA was established in short-term (6-week) controlled trials of schizophrenic inpatients ( see CLINICAL PHARMACOLOGY ).
The effectiveness of ONZA in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use ONZA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient ( see DOSAGE AND ADMINISTRATION ).
Bipolar Mania
ONZA is indicated for the short-term treatment of acute manic episodes associated with Bipolar I Disorder.
The efficacy of ONZA was established in two placebo-controlled trials (one 3-week and one 4-week) with patients meeting DSM-IV criteria for Bipolar I Disorder who currently displayed an acute manic or mixed episode with or without psychotic features ( see CLINCIAL PHARMACOLOGY ).
The effectiveness of ONZA for longer-term use, that is, for more than 4 weeks treatment of an acute episode, and for prophylactic use in mania, has not been systematically evaluated in controlled clinical trials. Therefore, physicians who elect to use ONZA for extended periods should periodically re-evaluate the long-term risks and benefits of the drug for the individual patient ( see DOSAGE AND ADMINISTRATION ).
CONTRAINDICATIONS
ONZA is contraindicated in patients with a known hypersensitivity to the product.
WARNINGS
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.
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.
PRECAUTIONS
General
Orthostatic Hypotension - - Olanzapine may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its (alpha) 1 -adrenergic antagonistic properties. Syncope was reported in 0.6% (15/2500) of olanzapine-treated patients in phase 2-3 studies. 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. 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 -- 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' 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 D 2 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 all 2500 patients in 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 preexisting 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' 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' 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' 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 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' 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 Orthostatic Hypotension ).
Information for Patients -- Physicians are advised to discuss the following issues with patients for whom they prescribe olanzapine:
Orthostatic Hypotension -- Patients should be advised of the risk of orthostatic hypotension, especially during the period of initial dose titration and in association with the use of concomitant drugs that may potentiate the orthostatic effect of olanzapine, e.g., diazepam or alcohol ( see Drug Interactions ).
Interference with Cognitive and Motor Performance - - Because 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.
Pregnancy -- Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy with olanzapine.
Nursing -- Patients should be advised not to breast-feed an infant if they are taking olanzapine.
Concomitant Medication -- Patients should be advised to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions.
Alcohol - - Patients should be advised to avoid alcohol while taking olanzapine.
Heat Exposure and Dehydration -- Patients should be advised regarding appropriate care in avoiding overheating and dehydration.
Phenylketonurics -- ONZA ZYDIS (olanzapine orally disintegrating tablets) contains phenylalanine (0.34 and 0.45 mg per 5 and 10 mg tablet, respectively).
Laboratory Tests -- Periodic assessment of transaminases is recommended in patients with significant hepatic disease ( see Transaminase Elevations ).
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.
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 (e.g., fluvoxamine) could potentially inhibit olanzapine elimination. Because olanzapine is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease olanzapine clearance.
Charcoal -- The administration of activated charcoal (1 g) reduced the C max and AUC of 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.
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. Thus, a clinically signficant pharmacokinetic interaction between olanzapine and valproate is unlikely.
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.
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, lithium, 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.
Carcinogenesis, Mutagenesis, Impairment of Fertility- -
Carcinogenesis -- Oral carcinogenicity studies were conducted in mice and rats. Olanzapine was administered to mice in two 78-week studies at doses of 3, 10, 30/20 mg/kg/day (equivalent to 0.8-5 times the maximum recommended human daily dose on a mg/m 2 basis) and 0.25, 2, 8 mg/kg/day (equivalent to 0.06-2 times the maximum recommended human daily dose on a mg/m 2 basis). Rats were dosed for 2 years at doses of 0.25, 1, 2.5, 4 mg/kg/day (males) and 0.25, 1, 4, 8 mg/kg/day (females) (equivalent to 0.13-2 and 0.13-4 times the maximum recommended human daily dose on a mg/m 2 basis, respectively). The incidence of liver hemangiomas and hemangiosarcomas was significantly increased in one mouse study in female mice dosed at 8 mg/kg/day (2 times the maximum recommended human daily dose on a mg/m 2 basis). These tumors were not increased in another mouse study in females dosed at 10 or 30/20 mg/kg/day (2-5 times the maximum recommended human daily dose on a mg/m 2 basis); in this study, there was a high incidence of early mortalities in males of the 30/20 mg/kg/day group. The incidence of mammary gland adenomas and adenocarcinomas was significantly increased in female mice dosed at >/=2 mg/kg/day and in female rats dosed at >/=4 mg/kg/day (0.5 and 2 times the maximum recommended human daily dose on a mg/m 2 basis, respectively). Antipsychotic drugs have been shown to chronically elevate prolactin levels in rodents. Serum prolactin levels were not measured during the olanzapine carcinogenicity studies; however, measurements during subchronic toxicity studies showed that olanzapine elevated serum prolactin levels up to 4-fold in rats at the same doses used in the carcinogenicity study. An increase in mammary gland neoplasms has been found in rodents after chronic administration of other antipsychotic drugs and is considered to be prolactin mediated. The relevance for human risk of the finding of prolactin mediated endocrine tumors in rodents is unknown ( see Hyperprolactinemia under PRECAUTIONS , General ).
Mutagenesis -- No evidence of mutagenic potential for olanzapine was found in the Ames reverse mutation test, in vivo micronucleus test in mice, the chromosomal aberration test in Chinese hamster ovary cells, unscheduled DNA synthesis test in rat hepatocytes, induction of forward mutation test in mouse lymphoma cells, or in vivo sister chromatid exchange test in bone marrow of Chinese hamsters.
Impairment of Fertility -- In a fertility and reproductive performance study in rats, male mating performance, but not fertility, was impaired at a dose of 22.4 mg/kg/day and female fertility was decreased at a dose of 3 mg/kg/day (11 and 1.5 times the maximum recommended human daily dose on a mg/m 2 basis, respectively). Discontinuance of olanzapine treatment reversed the effects on male mating performance. In female rats, the precoital period was increased and the mating index reduced at 5 mg/kg/day (2.5 times the maximum recommended human daily dose on a mg/m 2 basis). Diestrous was prolonged and estrous delayed at 1.1 mg/kg/day (0.6 times the maximum recommended human daily dose on a mg/m 2 basis); therefore olanzapine may produce a delay in ovulation.
Pregnancy--
Pregnancy Category C -- In 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 dose on a mg/m 2 basis, respectively) no evidence of teratogenicity was observed. In a rat teratology study, early resorptions and increased numbers of nonviable fetuses were observed at a dose of 18 mg/kg/day (9 times the maximum recommended human daily dose on a mg/m 2 basis). Gestation was prolonged at 10 mg/kg/day (5 times the maximum recommended human daily dose on a mg/m 2 basis). In a rabbit teratology study, fetal toxicity (manifested as increased resorptions and decreased fetal weight) occurred at a maternally toxic dose of 30 mg/kg/day (30 times the maximum recommended human daily dose on a mg/m 2 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 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' 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 ).
ADVERSE REACTIONS
The information below is derived from a clinical trial database for olanzapine consisting of 4189 patients with approximately 2665 patient-years of exposure. This database includes: (1) 2500 patients who participated in multiple-dose premarketing trials in schizophrenia and Alzheimer' disease representing approximately 1122 patient-years of exposure as of February 14, 1995; (2) 182 patients who participated in premarketing bipolar mania trials representing approximately 66 patient-years of exposure; (3) 191 patients who participated in a trial of patients having various psychiatric symptoms in association with Alzheimer' disease representing approximately 29 patient-years of exposure; and (4) 1316 patients from 43 additional clinical trials as of May 1, 1997.
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. However, this information is also generally applicable to bipolar mania.
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 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 which 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.
Incidence of Adverse Events in Short-Term, Placebo-Controlled Trials --The following findings are based on the short-term, placebo-controlled premarketing trials for schizophrenia and bipolar mania and a subsequent trial of patients having various psychiatric symptoms in association with Alzheimer' disease.
Adverse Events Associated with Discontinuation of Treatment in Short-Term, Placebo-Controlled Trials --Schizophrenia--Overall, there was no difference in the incidence of discontinuation due to adverse events (5% for olanzapine vs 6% for placebo). However, discontinuations due to increases in SGPT were considered to be drug related (2% for olanzapine vs 0% for placebo) ( see PRECAUTIONS ).
Bipolar Mania--Overall, there was no difference in the incidence of discontinuation due to adverse events (2% for olanzapine vs 2% for placebo).
Commonly Observed Adverse Events in Short-Term, Placebo-Controlled Trials --The most commonly observed adverse events associated with the use of olanzapine (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (olanzapine incidence at least twice that for placebo) were:
Common Treatment-Emergent Adverse Events
Associated with the Use of Olanzapine
in 6-Week Trials--SCHIZOPHRENIA Adverse Event Percentage of Patients
Reporting Event
Olanzapine Placebo
(N=248) (N=118)
Postural hypotension 5 2
Constipation 9 3
Weight gain 6 1
Dizziness 11 4
Personality disorder 18 4
Akathisia 5 1
1 Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.
Common Treatment-Emergent Adverse Events
Associated with the Use of Olanzapine in
3-Week and 4-Week Trials--BIPOLAR MANIA Adverse Event Percentage of Patients
Reporting Event
Olanzapine Placebo
(N=125) (N=129)
Asthenia 15 6
Dry Mouth 22 7
Constipation 11 5
Dyspepsia 11 5
Increased appetite 6 3
Somnolence 35 13
Dizziness 18 6
Tremor 6 3
Adverse Events Occurring at an Incidence of 2% or More Among Olanzapine-Treated Patients in Short-Term, Placebo-Controlled Trials --Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred in 2% or more of patients treated with olanzapine (doses >/=2.5 mg/day) and with incidence greater than placebo who participated in the acute phase of placebo-controlled trials.
Table 1
Treatment-Emergent Adverse Events: Incidence in
Short-Term, Placebo-Controlled Clinical Trials 1 Percentage of
Patients Reporting
Event
Body System/Adverse Event
Olanzapine Placebo
(N=532) (N=294)
Body as a Whole
Accidental Injury 12 8
Asthenia 10 9
Fever 6 2
Back pain 5 2
Chest pain 3 1
Cardiovascular System
Postural hypotension 3 1
Tachycardia 3 1
Hypertension 2 1
Digestive System
Dry mouth 9 5
Constipation 9 4
Dyspepsia 7 5
Vomiting 4 3
Increased appetite 3 2
Hemic and Lymphatic System
Ecchymosis 5 3
Metabolic and Nutritional Disorders
Weight gain 5 3
Peripheral edema 3 1
Musculoskeletal System
Extremity pain (other than joint) 5 3
Joint pain 5 3
Nervous System
Somnolence 29 13
Insomnia 12 11
Dizziness 11 4
Abnormal gait 6 1
Tremor 4 3
Akathisia 3 2
Hypertonia 3 2
Articulation impairment 2 1
Respiratory System
Rhinitis 7 6
Cough increased 6 3
Pharyngitis 4 3
Special Senses
Amblyopia 3 2
Urogenital System
Urinary incontinence 2 1
Urinary tract infection 2 1
1 Events reported by at least 2% of patients treated with olanzapine, except the following events which had an incidence equal to or less than placebo: abdominal pain, agitation, anorexia, anxiety, apathy, confusion, depression, diarrhea, dysmenorrhea 2 , hallucinations, headache, hostility, hyperkinesia, myalgia, nausea, nervousness, paranoid reaction, personality disorder 3 , rash, thinking abnormal, weight loss.
2 Denominator used was for females only (olanzapine, N=201; placebo, N=114).
3 Personality disorder is the COSTART term for designating non-aggressive objectionable behavior.
Additional Findings Observed in Clinical Trials --The following findings are based on clinical trials.
Dose Dependency of Adverse Events in Short-Term, Placebo-Controlled Trials --
Extrapyramidal Symptoms: The following table 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 doses with placebo in the treatment of schizophrenia.
TREATMENT-EMERGENT EXTRAPYRAMIDAL
SYMPTOMS ASSESSED BY RATING SCALES
INCIDENCE IN A FIXED DOSAGE RANGE,
PLACEBO-CONTROLLED CLINICAL
TRIAL--ACUTE PHASE *
Percentage Placebo Olanzapine Olanzapine Olanzapine
of Patients 5± 2.5 mg/day 10 ± 2.5 mg/day 15 ± 2.5 mg/day
Parkinsonism 1 15 14 12 14
Akathisia 2 23 16 19 27
* No statistically significant differences.
1 Percentage of patients with a Simpson-Angus Scale total score >3.
2 Percentage of patients with a Barnes Akathisia Scale global score >/=2.
The following table enumerates the percentage of patients with treatment-emergent extrapyramidal symptoms as assessed by spontaneously reported adverse events during acute therapy in the same controlled clinical trial comparing olanzapine at 3 fixed doses with placebo in the treatment of schizophrenia.