General: During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored during this period. When using olanzapine in combination with fluoxetine, lithium or valproate, also refer to their individual product literature for additional information.
Neuroleptic Malignant Syndrome (NMS): There have been reports of NMS, a potentially fatal symptom complex, in association with administration of antipsychotic drugs, including olanzapine. Clinical manifestations include 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 kinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. Careful monitoring of patients is necessary since recurrences of NMS have been reported.
Weight Gain: Potential consequences of weight gain should be considered before starting olanzapine. As with all antipsychotics, patients receiving olanzapine should receive regular monitoring of weight.
Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been associated with the use of antipsychotic agents. Exercise caution when giving olanzapine to 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).
Potential for Cognitive and Motor Impairment: Since olanzapine has the potential to cause somnolence and impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that olanzapine therapy does not affect them adversely.
Cardiovascular Effects: Orthostatic Hypotension: Patients receiving oral olanzapine therapy are reported to develop orthostatic hypotension associated with dizziness, tachycardia, and/or syncope, particularly at the initiation of treatment. The risk of orthostatic hypotension and syncope may be minimized by initiating therapy with a dose of 5 mg orally once a day. If hypotension occurs, a more gradual titration to the target dose should be considered.
Olanzapine should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medications) where the occurrence of syncope, or hypotension and/or bradycardia might put the patient at increased medical risk.
Sudden Cardiac Death: Retrospective observational study showed patients treated with atypical antipsychotics, including olanzapine, or typical antipsychotics had a similar dose-related increase of presumed sudden cardiac death compared to non-users of antipsychotics, with almost twice the risk than that for non-users. In postmarketing reports with olanzapine, the event of sudden cardiac death has been reported very rarely.
Cerebrovascular Effects: Cerebrovascular adverse events such as stroke and transient ischemic attack, including fatalities, were reported in elderly patients with dementia-related psychosis taking olanzapine.
QT Interval: As with other antipsychotics, caution should be exercised when olanzapine is prescribed with medicines known to increase QTC interval, especially in the elderly, in patients with congenital long QT syndrome, congestive heart failure, heart hypertrophy, hypokalemia or hypomagnesemia. Clinically meaningful QTC prolongations were uncommon in patients treated with olanzapine.
Endocrine and Metabolic Effects: Hyperglycemia and Diabetes Mellitus: Physicians should consider the risks and benefits when prescribing olanzapine to patients with an established diagnosis of diabetes mellitus, or having borderline increased blood glucose level (fasting 100 to 126 mg/dL, nonfasting 140 to 200 mg/dL). Patients should have baseline and periodic monitoring of blood glucose and body weight.
There have been reports of severe hyperglycemia, sometimes associated with ketoacidosis, hyperosmolar coma, or death, in patients receiving certain atypical antipsychotic agents including olanzapine. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. While relative risk estimates are inconsistent, the association between atypical antipsychotics and increases in glucose levels appears to fall on a continuum and olanzapine appears to have a greater association than some other atypical antipsychotics.
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 was resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control.
Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, olanzapine elevates prolactin levels and a modest elevation persists during chronic administration. Elevations associated with olanzapine treatment are generally mild, and may decline during continued administration.
Hyperprolactinemia may suppress hypothalamic gonadotropin-releasing hormone (GnRH), resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Premenopausal women should be questioned on menstrual irregularities and those who experience secondary amenorrhea for longer than six months duration while taking olanzapine, should be appropriately investigated and offered appropriate therapy.
Hyperlipidemia: Undesirable alterations in lipids have been observed with olanzapine use. Treatment-emergent clinically significant changes in fasting lipids were observed in patients with or without evidence of dyslipidemia at baseline. Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using olanzapine, is recommended.
Clinically significant and sometimes very high (> 500 mg/dL) elevations in triglyceride levels have been observed with olanzapine use. Modest mean increases in total cholesterol have also been seen with olanzapine use.
Hematologic Effects: Leukopenia, Neutropenia, and Agranulocytosis: Events of leukopenia/neutropenia temporally related to antipsychotic agents, including olanzapine have been reported. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of olanzapine should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1,000/mm3) should discontinue olanzapine and have their WBC followed until recovery.
Hepatic Effects: Transient, asymptomatic elevations of hepatic aminotransferases, alanine transaminase (ALT), aspartate aminotransferase (AST) have been reported commonly, particularly in early treatment. Caution should be exercised and follow-up organized in patients with: elevated ALT and/or AST, signs and symptoms of hepatic impairment, pre-existing conditions associated with limited hepatic functional reserve, and who are being treated with potentially hepatotoxic medicines. Olanzapine treatment should be discontinued in cases where hepatitis (including hepatocellular, cholestatic or mixed liver injury) has been diagnosed.
Nervous System Effects: 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, patients are likely to develop the syndrome at the inception of antipsychotic treatment. 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 drug products administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief periods at low doses or may even arise after discontinuation of treatment.
Comparator studies of one year or less duration showed that olanzapine was associated with a statistically lower incidence of treatment emergent dyskinesia. However, the risk of tardive dyskinesia increases with long-term exposure and thus, if signs or symptoms of tardive dyskinesia appear in a patient on olanzapine, a dose reduction or drug discontinuation should be considered. These symptoms can temporally deteriorate or even arise after discontinuation of treatment. Some patients may require treatment with olanzapine despite the presence of the syndrome.
Seizures: Olanzapine should be used cautiously in patients who have a history of seizures or are subject to factors which may lower the seizure threshold (e.g., Alzheimer's dementia). Conditions that lower the seizure threshold may be more prevalent in a population of ≥ 65 years old. Seizures have been reported to occur rarely in such patients when treated with olanzapine.
Suicide: The possibility of a suicide attempt is inherent in schizophrenia and in bipolar disorder. 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.
Respiratory Effects: Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic use. Olanzapine and other antipsychotic agents should be used cautiously in patients at risk for aspiration pneumonia. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.
Use in Patients with Concomitant Illness: Since clinical experience with olanzapine in patients with concomitant illness is limited, caution is advised when prescribing in patients with prostatic hypertrophy, narrow-angle glaucoma, or a history of paralytic ileus or related conditions because of the anticholinergic effects of olanzapine. It should also be used with caution in patients with hepatic impairment, or a history of blood dyscrasias, bone marrow depression, or myeloproliferative disease.
Use in Children: Pediatric (< 18 years old): When deciding among the alternative treatments available for adolescents, clinicians should consider the increased potential (in adolescents as compared with adults) for weight gain and hyperlipidemia. Clinicians should consider the potential long-term risks when prescribing to adolescents, and in many cases this may lead them to consider prescribing other drugs first in adolescents.
The safety and efficacy of olanzapine in children <13 years old have not been established.
The safety and efficacy of olanzapine and fluoxetine in combination in children >10 years old have not been established.
Use in Elderly: Geriatric (≥ 65 years old): Exercise caution 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 Pharmacology: Pharmacokinetics under Actions, Dosage & Administration for Special Populations and Precautions).