Olanzapine
Hyperglycemia and diabetes mellitus
There is a higher prevalence of diabetes mellitus in patients with schizophrenia. There are very rare reports of the development of hyperglycemia and/or decompensation of diabetes mellitus, sometimes accompanied by the development of ketoacidosis or ketoacidotic coma, including reports of several fatal cases. In some cases, there was an increase in body weight preceding decompensation, which could become a predisposing factor. In patients with diabetes mellitus and risk factors for the development of this disease, regular clinical monitoring and monitoring of blood glucose concentrations is recommended.
Change in lipid concentration
During therapy with olanzapine, it is necessary to monitor plasma lipid concentrations in patients with dyslipidemia and in patients with risk factors for lipid metabolic disorders. Patients taking olanzapine therapy need to monitor their lipid profile. If lipid concentrations change, therapy adjustments are required.
Anticholinergic activity
In clinical studies, olanzapine therapy was rarely accompanied by adverse reactions due to blockade of M-cholinergic receptors. Because clinical experience with olanzapine in people with underlying medical conditions is limited, the drug should be used with caution in patients with clinically significant prostatic hyperplasia, paralytic ileus, angle-closure glaucoma, and similar conditions.
Use of olanzapine in patients with Parkinson's disease
Olanzapine is not recommended for the treatment of psychosis caused by dopaminomimetics in Parkinson's disease. Symptoms of parkinsonism and hallucinations increase. However, olanzapine was not superior to placebo in treating psychosis.
Dopaminergic antagonism
In vitro
Olanzapine exhibits dopamine receptor antagonism and, like other antipsychotics (neuroleptics), may theoretically inhibit the action of levodopa and other dopamine receptor agonists.
Experience with olanzapine in elderly patients with dementia-related psychosis. The effectiveness of olanzapine in elderly patients with dementia-related psychosis has not been established. In placebo-controlled clinical trials (lasting 6-12 weeks) in elderly patients (mean age 78 years) with psychosis and behavioral disturbances due to dementia, there was an increase in deaths in patients treated with olanzapine compared with placebo ( 3.5% versus 1.5% respectively). The increase in mortality was independent of the olanzapine dose or duration of therapy. Risk factors predisposing to increased mortality include: age over 75 years, dysphagia, sedation, malnutrition and dehydration, lung diseases (for example, pneumonia, including aspiration), concomitant use of benzodiazepines.
Cerebrovascular adverse events including stroke in elderly patients with dementia
Cerebrovascular adverse events (stroke, transient ischemic attack), including deaths, were observed in studies of olanzapine in elderly patients with psychosis associated with dementia. In placebo-controlled studies, there was a higher incidence of cerebrovascular adverse events in patients in the olanzapine group compared with the placebo group (1.3% versus 0.4%, respectively). All patients had previous risk factors for cerebrovascular adverse events (smoking, hypertension, previous cerebrovascular adverse event or transient ischemic attack), as well as concomitant diseases with medications temporally associated with cerebrovascular adverse events.
Postural hypotension
Postural hypotension was not frequently observed in elderly patients during clinical trials of olanzapine. As with other antipsychotic drugs, periodic monitoring of blood pressure is recommended in patients over 65 years of age.
QT interval
In clinical studies, clinically significant QT prolongation (QT interval correction [QTcF] ≥500 milliseconds in patients with baseline QTcF <500 msec) was rarely observed (0.1%-1%) in patients receiving olanzapine therapy for against the background of no significant differences with placebo in terms of associated cardiac events. However, as with other antipsychotic drugs, caution should be exercised when prescribing olanzapine concomitantly with drugs that can prolong the QT interval, especially in elderly patients, patients with long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia or hypomagnesemia. Electrocardiogram monitoring should be performed during olanzapine therapy.
Liver dysfunction
At the beginning of therapy, an asymptomatic increase in the activity of liver transaminases (ALT and AST) in the blood serum is often observed. Rare cases of hepatitis have been reported. In addition, there have been isolated reports of cholestatic and mixed liver damage. In patients with initially elevated serum AST and/or ALT levels, patients with liver failure and conditions that potentially limit liver function, and those taking hepatotoxic drugs, special caution should be exercised when prescribing olanzapine. If ALT and/or AST increase during drug therapy, medical monitoring of the patient and, possibly, a reduction in the dose of the drug are recommended. If hepatitis (including hepatocellular, cholestatic or mixed) is diagnosed, olanzapine should be discontinued.
Hematological changes
The drug should be used with caution in patients with leukopenia and/or neutropenia of any origin, myelosuppression of drug origin, as well as during radiation or chemotherapy, due to concomitant diseases, in patients with hypereosinophilic conditions or myeloproliferative diseases. Neutropenia was often observed with simultaneous use of olanzapine and valproic acid (see section "Side effects").
Neuroleptic malignant syndrome (NMS)
NMS is a potentially life-threatening condition associated with treatment with antipsychotic drugs (neuroleptics), incl. olanzapine. Clinical manifestations of NMS: fever, muscle rigidity, impaired consciousness, autonomic disorders (unstable pulse or labile blood pressure, tachycardia, increased sweating, arrhythmias).
Additional symptoms of NMS: increased CPK, myoglobinuria (against the background of rhabdomyolysis) and acute renal failure. If symptoms of NMS develop, as well as an increase in body temperature for no apparent reason, it is necessary to discontinue all antipsychotics, incl. olanzapine.
Convulsive syndrome
Olanzapine should be used cautiously in patients with a history of seizures or risk factors that lower the seizure threshold. Seizures were rarely reported while taking olanzapine.
Tardive dyskinesia
In comparative studies, olanzapine therapy was significantly less likely to be accompanied by the incidence of tardive dyskinesia requiring drug correction than the use of typical and other atypical antipsychotics. The risk of developing tardive dyskinesia increases with increasing duration of therapy. If signs of tardive dyskinesia develop in a patient taking olanzapine, dose adjustment is recommended. Symptoms of dyskinesia may temporarily increase after discontinuation of the drug.
General activity in relation to the central nervous system
Caution should be exercised when using olanzapine and other centrally acting drugs simultaneously and avoid alcohol consumption.
Thromboembolism
Cases of venous thromboembolism have been reported very rarely (less than 0.01%) when taking olanzapine. A cause-and-effect relationship between olanzapine therapy and venous thrombosis has not been established. Because patients with schizophrenia often have acquired risk factors for venous thrombosis, all possible other factors (eg, immobilization) should be identified and preventive measures taken.
Sudden death
Clinical experience with all antipsychotics, including olanzapine, has shown a similar dose-dependent increase in the risk of sudden death due to acute heart failure. In a retrospective observational cohort study, the risk of suspected sudden cardiac death in patients treated with olanzapine was increased approximately twofold compared with patients not using antipsychotics. In the study, the risk for olanzapine was comparable to the risk for the atypical antipsychotics included in the pooled analysis.
Long-term drug therapy
With long-term therapy with olanzapine (up to 12 months), in order to prevent relapses in patients with bipolar disorders, there was an increase in body weight of >7% from the original (in 39.9% of patients). With longer therapy (more than 48 weeks), clinically significant changes were observed - increases in body weight, glucose concentration, total cholesterol/LDL/HDL or triglycerides. In adult patients who completed a 9-12 month course of treatment, an increase in mean blood glucose concentration was observed after approximately 6 months. Patients with risk factors for the development of concomitant diseases who are on long-term therapy with olanzapine need to be monitored by a specialist during the entire course of therapy.
Withdrawal syndrome
When olanzapine is stopped abruptly, very rarely (less than 0.01%) the following symptoms may develop: sweating, insomnia, tremor, anxiety, nausea or vomiting. When discontinuing the drug, a gradual dose reduction is recommended.
Use in children
Olanzapine is not recommended for use in children and adolescents under 18 years of age due to the lack of sufficient data on efficacy and safety. In short-term studies in patients 13 to 17 years of age, more significant increases in body weight and changes in lipid and prolactin concentrations were reported than in similar studies in adults (see section "Side Effects").
OLANZAPINE
special instructions
Improvement in the patient's clinical condition with antipsychotic therapy can take from several days to several weeks; this period requires careful monitoring of the patient.
Suicide
Patients with schizophrenia and bipolar disorder type 1 may have a tendency to commit suicide; therefore, during pharmacotherapy, careful monitoring of patients at high risk of committing suicide is required. To reduce the risk of overdose, the minimum amount of drug needed to properly manage the patient should be prescribed.
Psychosis and/or behavioral disorders due to dementia
Olanzapine is not approved for the treatment of psychosis and/or behavioral disorders associated with dementia and is not recommended for use in this group of patients due to the increased mortality and risk of cerebrovascular complications. In placebo-controlled studies (6-12 weeks duration) in elderly patients (mean age 78 years) with psychosis and/or behavioral disturbances due to dementia, there was a two-fold increase in the incidence of death in patients receiving olanzapine compared with patients receiving olanzapine. from the placebo group (3.5 vs. 1.5%, respectively). The increased incidence of deaths was independent of the dose of olanzapine (mean daily dose 4.4 mg) and duration of treatment. Risk factors that may predispose to increased mortality in this patient population include age over 65 years, dysphagia, sedation, malnutrition and dehydration, pulmonary disease (eg, pneumonia, with or without aspiration), and concomitant use of benzodiazepines. However, the incidence of death was higher in patients receiving olanzapine compared with those receiving placebo, regardless of these risk factors.
The results of the same clinical studies indicate cerebrovascular adverse events (CVAEs, e.g. stroke, transient ischemic attack), including deaths. There was a threefold increase in the incidence of CVD events in patients receiving olanzapine compared with patients receiving placebo (1.3% vs. 0.4%, respectively). All patients receiving olanzapine and placebo who experienced cerebrovascular events had risk factors. Risk factors for CVD associated with olanzapine treatment include age over 75 years and vascular/mixed dementia. Olanzapine was not effective in these studies.
Parkinson's disease
The use of olanzapine for the treatment of psychosis caused by the use of dopamine receptor agonists in Parkinson's disease is not recommended. In clinical studies, worsening of parkinsonian symptoms and hallucinations was observed very often (and with a higher frequency than in the placebo group) (see section “Side effects”), the effectiveness of olanzapine for relieving psychotic symptoms was not greater than placebo. Inclusion criteria for these studies were: stable lowest effective dose of antiparkinsonian drugs (dopamine receptor agonist) and use of the same antiparkinsonian drugs and doses throughout the study. Olanzapine was started at 2.5 mg/day and increased at the discretion of the investigator to 15 mg/day.
Neuroleptic malignant syndrome (3NS)
NMS is a potentially lethal symptom complex caused by antipsychotic drugs. Rare cases of 3HC have also been reported with the use of olanzapine. Clinical manifestations of 3HC include hyperthermia, muscle rigidity, mental status changes, and autonomic disturbances (unstable pulse or blood pressure, tachycardia, increased sweating, and arrhythmias). Additional signs: increased creatine phosphokinase activity, myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops signs and symptoms of NMS or has an unexplained high fever without additional manifestations of NMS, all antipsychotic medications, including olanzapine, should be discontinued.
Hyperglycemia and diabetes mellitus
Hyperglycemia and/or the development or exacerbation of diabetes mellitus, sometimes accompanied by ketoacidosis or coma, have been reported infrequently, including several deaths (see section "Side effects"). In some cases, previous weight gain has been reported, which may be a predisposing factor. Appropriate clinical monitoring in accordance with current antipsychotic treatment guidelines, such as baseline blood glucose measurements, is recommended 12 weeks after initiation of olanzapine therapy and annually thereafter. Patients receiving any antipsychotic agents, including olanzapine, should be monitored for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for its development should be regularly monitored for worsening glycemic control. Body weight should be checked regularly, for example before, 4, 8 and 12 weeks after starting olanzapine, and quarterly thereafter.
Lipid disorders
In placebo-controlled studies, undesirable changes in the lipid profile were observed in patients receiving olanzapine (see section "Side effects"). Lipid disorders should be subject to appropriate clinical correction, especially in patients with dyslipidemia and patients with risk factors for the development of lipid disorders. Patients receiving any antipsychotic drugs, including olanzapine, should have their lipid profiles monitored regularly in accordance with current antipsychotic treatment guidelines, e.g., baseline measurements, 12 weeks after initiation of therapy and every 5 years thereafter.
Anticholinergic activity
Although olanzapine exhibited anticholinergic activity in vitro, the incidence of anticholinergic effects in clinical studies was low. However, clinical experience with the use of olanzapine in patients with concomitant diseases is limited, and caution should be exercised when prescribing the drug to patients with prostatic hypertrophy, paralytic ileus and similar conditions.
Liver dysfunction
Taking olanzapine was often, especially in the early stages of therapy, accompanied by a transient, asymptomatic increase in the activity of hepatic aminotransferases (AST and ALT). Patients with elevated ALT and/or AST levels, signs and symptoms of liver failure, conditions that cause decreased liver function reserve, or those using potentially hepatotoxic drugs should be treated with caution and follow-up. When a diagnosis of hepatitis is made (including hepatocellular, cholestatic and liver damage), treatment with olanzapine should be discontinued.
Neutropenia
Olanzapine should be used with caution in patients with low white blood cell and/or neutrophil counts, regardless of the cause; history of drug suppression/bone marrow toxicity, bone marrow suppression due to concomitant disease, radiation or chemotherapy; and in patients with hypereosinophilic conditions or myeloproliferative disease. Neutropenia has often been reported with concomitant use of olanzapine and valproic acid (see section "Side effects").
Cancellation of therapy
Sweating, insomnia, tremor, anxiety, nausea, and vomiting were reported rarely (≥0.01 and <0.1%) during abrupt discontinuation of olanzapine.
QT interval
In clinical studies, patients receiving olanzapine infrequently (0.1-1%) experienced clinically significant prolongation of the QT interval (QT interval with correction of Fridericius [QTcF] ≥500 ms from a baseline QTcF <500 ms) in the absence of significant differences with placebo in the incidence of adverse cardiac events. However, like other antipsychotics, caution should be exercised when prescribing olanzapine in combination with drugs that can prolong the QTc interval, especially in the elderly, patients with congenital long QT interval, chronic heart failure, myocardial hypertrophy, hypokalemia or hypomagnesemia.
Thromboembolism
Venous thromboembolism has been reported infrequently (≥0.1 and <1%) during olanzapine therapy. A cause-and-effect relationship between the use of olanzapine and venous thromboembolism has not been established. However, given that patients with schizophrenia often have acquired risk factors for the development of venous thromboembolism, it is necessary to identify all possible risk factors for VTE, for example, immobilization of patients, and take the necessary preventive measures.
General activity of the central nervous system
Given the major effects of olanzapine on the central nervous system, caution should be exercised when using olanzapine in combination with other centrally acting drugs and alcohol. Because olanzapine exhibits dopamine receptor antagonism in vitro, it may block the effects of direct and indirect dopamine receptor agonists.
Convulsions
Olanzapine should be used with caution in patients with a history of seizures or exposure to factors that lower the seizure threshold. Convulsions have been reported infrequently during treatment with olanzapine. In most cases, a history of seizures or risk factors for seizures were reported.
Tardive dyskinesia
In comparative studies lasting a year or less, treatment with olanzapine was statistically significantly less likely to be accompanied by the development of iatrogenic dyskinesia. However, the risk of tardive dyskinesia increases with long-term exposure, so if signs or symptoms of tardive dyskinesia occur in a patient receiving olanzapine, dosage reduction or discontinuation of olanzapine should be considered. After discontinuation of therapy, these symptoms may temporarily worsen or even reappear.
Postural hypotension
Postural hypotension was reported infrequently in clinical studies of olanzapine in elderly patients. As with other antipsychotics, periodic monitoring of blood pressure is recommended in patients over 65 years of age.
Sudden cardiac death
According to post-marketing experience with olanzapine, cases of sudden cardiac death have been reported. In a retrospective observational cohort study, the risk of suspected sudden cardiac death in patients receiving olanzapine was approximately twice as high as in patients not receiving antipsychotics. The risk of olanzapine use in the study was comparable to that of the atypical antipsychotics included in the pooled analysis.
Children
Olanzapine is not recommended for use in children and adolescents. In studies in adolescents 13–17 years of age, various adverse reactions were reported, including weight gain, changes in metabolic parameters, and hyperprolactinemia. Long-term outcomes associated with these phenomena have not been studied and remain unknown (see sections "Side effects" and "Pharmacodynamics").
