Instructions Zolafren film-coated tablets 10 mg blister No. 30
Composition
active ingredient: 1 tablet contains 5 mg or 10 mg of olanzapine;
excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate; shell: hydroxypropylmethylcellulose (hypromellose), polyethylene glycol (Macrogol) 400, dye Yellow No.6 Al-Lake (E 110), titanium dioxide (E 171), iron oxide yellow (E 172), lactose monohydrate.
Dosage form
Film-coated tablets.
Main physicochemical properties: 5 mg tablets: beige, film-coated, biconvex tablets, with a score line on one side, 7 mm in diameter;
10 mg tablets: beige, film-coated, biconvex tablets, 7 mm in diameter.
Pharmacotherapeutic group
Antipsychotics. ATX code N05A H03.
Pharmacological properties
Pharmacodynamics.
Olanzapine is an antipsychotic, antimanic, mood-stabilizing drug with a broad spectrum of pharmacological actions mediated by a variety of receptors. Binding has been demonstrated to serotonin 5-HT2A/2C, 5-HT3, 5-HT6 receptors, dopamine D1, D2, D3, D4, D5 receptors, muscarinic M1–M5 receptors, a1-adrenergic receptor, and histamine H1 receptor. In behavioral studies in animals treated with olanzapine, olanzapine has been shown to antagonize both serotonin 5-HT, dopamine, and cholinergic receptors. Olanzapine has a higher level of binding to serotonin 5-HT2 receptors than to dopamine D2 receptors in both in vitro and in vivo models. Electrophysiological studies have shown that olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, while showing little effect on striatal (A9) pathways involved in motor function. Olanzapine inhibits the conditioned avoidance reflex, which indicates its antipsychotic activity at doses lower than those that cause catalepsy, which is a sign of motor side effects. Unlike some other antipsychotic drugs, olanzapine increases responses to stimuli in an anxiolytic test.
A single dose of 10 mg olanzapine was found to have higher binding to 5-HT2A receptors than to dopamine D2 receptors in volunteers using positron emission tomography (PET). In addition, analysis of single-photon emission computed tomography (SPECT) images of patients with schizophrenia showed that olanzapine-responsive patients had lower binding to striatal D2 receptors than other antipsychotic-responsive and risperidone-responsive patients, and comparable to clozapine-responsive patients.
Clinical efficacy.
In two of two placebo-controlled and two of three comparator-controlled studies involving over 2,900 patients with schizophrenia with positive and negative symptoms, olanzapine showed statistically significant improvements in patients' condition.
In an international double-blind comparative study of 1,484 patients with schizophrenia, schizoaffective disorder, and related disorders of varying severity associated with depressive symptoms (16.6 points on the Montgomery-Asberg Depression Scale), a prospective secondary analysis of baseline to end-of-life mood changes showed a statistically significant improvement (p = 0.001) after olanzapine treatment (–6.0) compared with haloperidol treatment (–3.1).
In patients with manic or mixed episodes in bipolar disorder, olanzapine was superior to placebo and divalproex in reducing manic symptoms over 3 weeks. Olanzapine was comparable to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks of treatment. In a study, olanzapine 10 mg added to lithium or valproate for 2 weeks resulted in a significant reduction in manic symptoms compared with lithium or valproate alone after 6 weeks.
In a 12-month study of the prevention of recurrence of manic episodes in patients who achieved remission with olanzapine and were then randomized to receive olanzapine or placebo, olanzapine demonstrated a statistically significant advantage over placebo on the endpoint of recurrence of bipolar disorder. Olanzapine also demonstrated a statistically significant advantage over placebo in preventing recurrence of mania or recurrence of depression.
In an 18-month study of patients stabilized with olanzapine as adjunctive treatment for manic or mixed episodes, lithium or valproate were used as mood stabilizers. There was no statistically significant advantage over lithium or valproate monotherapy in delaying relapse of bipolar disorder defined by syndromic (diagnostic) criteria.
Children.
Experience in adolescents (aged 13 to 17 years) is limited. There are data on the efficacy of short-term treatment of schizophrenia (6 weeks) and mania associated with bipolar disorders (3 weeks) in less than 200 adolescents. The initial dose of olanzapine was 2.5 mg and was increased up to 20 mg/day. During treatment with olanzapine, body weight in adolescents increased significantly compared with adults. In adolescents, increases in fasting total cholesterol, low-density lipoprotein cholesterol, triglycerides and prolactin were observed (see sections “Special instructions for use”, “Adverse reactions”) compared with adults. There are no controlled data on the maintenance of effect or long-term safety (see sections “Special instructions for use”, “Adverse reactions”). Information on long-term safety is mainly limited to data from open-label, uncontrolled studies.
Pharmacokinetics.
Absorption.
The drug is well absorbed after oral administration, with Cmax in plasma reached after 5–8 hours. Food intake does not affect the absorption of olanzapine. The absolute bioavailability of olanzapine when administered orally compared to intravenous administration has not been established.
Distribution.
The extent of binding of olanzapine to plasma proteins was approximately 93% over a concentration range of 7 ng/mL to 1000 ng/mL. Olanzapine binds primarily to albumin and α1-acid glycoprotein.
Biotransformation.
Olanzapine is metabolized in the liver by conjugation and oxidation. The major circulating metabolite is the 10-N-glucuronide, which does not cross the blood-brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, which have shown significantly less pharmacological activity in vivo than olanzapine in animal studies. The major pharmacological activity is due to the parent olanzapine.
Breeding.
After oral administration, the mean elimination half-life of olanzapine in volunteers varied depending on age and gender.
In healthy elderly volunteers (65 years of age and older), the mean elimination half-life was longer (51.8 vs. 33.8 hours) and plasma clearance was reduced (17.5 vs. 18.2 l/h) compared to younger volunteers. The pharmacokinetic variability observed in elderly volunteers is within the range of younger volunteers. In 44 schizophrenic patients >65 years of age, dosing from 5 to 20 mg/day was not associated with any distinctive adverse event profile.
In women, the mean half-life was longer (36.7 vs. 32.3 hours) and plasma clearance was reduced (18.9 vs. 27.3 L/h) compared to men. However, the safety profile of olanzapine (5–20 mg) was comparable in women (N = 467) and men (N = 869).
Patients with renal failure.
In patients with renal impairment (creatinine clearance < 10 mL/min) compared to healthy volunteers, there was no significant difference in mean elimination half-life (37.7 vs. 32.4 hours) or plasma clearance (21.2 vs. 25.0 L/h). Studies have shown that approximately 57% of radiolabeled olanzapine is present in the urine, primarily as metabolites.
Liver dysfunction.
A small study of the effect of hepatic impairment in 6 subjects with clinically significant cirrhosis (Child-Pugh class A (n = 5) and B (n = 1)) found little effect on the pharmacokinetics of oral olanzapine (single dose 2.5–7.5 mg): subjects with mild to moderate hepatic dysfunction had slightly increased systemic clearance and a faster half-life compared with subjects without hepatic dysfunction (n = 3). More subjects with cirrhosis were smokers (4/6; 67%) than subjects without hepatic dysfunction (0/3; 0%).
Patients who smoke.
In non-smokers compared to smokers (men and women), the mean half-life was longer (38.6 vs. 30.4 hours) and plasma clearance was reduced (18.6 vs. 27.7 L/h).
Olanzapine plasma clearance is lower in elderly patients compared to young patients, in women compared to men, and in non-smokers compared to smokers. However, factors such as age, gender, and smoking status may have little effect on olanzapine plasma clearance and half-life compared to the variability in these parameters between individuals.
In studies involving Japanese and Chinese patients, no differences in the pharmacokinetics of olanzapine were found between the three populations.
Children.
Adolescents (ages 13 to 17 years): The pharmacokinetics of olanzapine are similar in adolescents and adults. In clinical trials, the mean exposure to olanzapine was approximately 27% higher in adolescents. Demographic differences between adolescents and adults include lower mean body weight and fewer smokers among adolescent patients. These factors likely contribute to the higher mean exposure to olanzapine observed in adolescents.
Preclinical safety data
Signs of oral toxicity in rodents were typical of potent neuroleptic compounds: hypoactivity, coma, tremors, clonic convulsions, salivation, and decreased weight gain. Median lethal doses were approximately 210 mg/kg (mice) and 175 mg/kg (rats). Dogs tolerated single oral doses of up to 100 mg/kg without fatal outcome. Clinical signs included sedation, ataxia, tremors, tachycardia, labored breathing, miosis, and anorexia. In monkeys, single oral doses of up to 100 mg/kg resulted in prostration, and higher doses resulted in semi-coma.
Repeated dose toxicity
In studies of up to 3 months (in mice) and up to 1 year (in rats and dogs), the predominant effects were central nervous system (CNS) depression, anticholinergic effects, and peripheral hematological disorders. Tolerance to CNS depression was observed. Growth parameters were reduced at high doses. Reversible effects consistent with elevated prolactin levels in rats included decreased ovarian and uterine weights and morphological changes in the vaginal epithelium and mammary gland.
Hematological toxicity
Effects on hematological parameters were observed in each species, including a dose-dependent decrease in circulating leukocytes in mice and a nonspecific decrease in circulating leukocytes in rats; however, there was no evidence of bone marrow cytotoxicity. Reversible neutropenia, thrombocytopenia, or anemia developed in a few dogs receiving 8 or 10 mg/kg/day (total olanzapine exposure [AUC] 12-15 times greater than in humans receiving a 12 mg dose). There were no adverse effects on progenitor and proliferating cells in the bone marrow in cytopenic dogs.
Reproductive toxicity
Olanzapine was not teratogenic. Sedation affected mating performance in male rats. Doses of 1.1 mg/kg (3 times the maximum human dose) affected the estrous cycle in rats, and doses of 3 mg/kg (9 times the maximum human dose) affected reproductive parameters. Intrauterine growth retardation and a transient decrease in the activity level of the offspring were observed in the offspring of rats treated with olanzapine.
Mutagenicity
Olanzapine was not mutagenic or clastogenic in a full range of standard tests, including bacterial mutation tests and in vitro and in vivo mammalian tests.
Carcinogenicity
Based on the results of studies in mice and rats, it was concluded that olanzapine is not carcinogenic.
Indication
Olanzapine is indicated for the treatment of schizophrenia.
Olanzapine is effective in maintaining the achieved clinical effect during long-term therapy in patients who have responded to initial therapy.
Olanzapine is indicated for the treatment of moderate to severe manic episodes.
Olanzapine is indicated for the prevention of recurrent attacks in patients with bipolar disorder who have responded to olanzapine treatment of mania.
Contraindication
Hypersensitivity to the active substance or to the excipients of the drug; known risk of angle-closure glaucoma.
Interaction with other medicinal products and other types of interactions
Drug interaction studies have only been conducted in adults.
Substances that potentially affect olanzapine.
Since olanzapine is metabolized by the CYP1A2 isoenzyme, substances that specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
CYP1A2 inducers.
The metabolism of olanzapine may be induced by smoking and the use of carbamazepine, which results in decreased olanzapine concentrations. A slight to moderate increase in olanzapine clearance has been observed. Clinical findings are limited, but clinical monitoring and, if necessary, an increase in the olanzapine dose is recommended (see section 4.2).
CYP1A2 inhibitors.
Fluoxamine, a specific CYP1A2 inhibitor, significantly reduces the metabolism of olanzapine. This results in a mean increase in Cmax after fluoxamine of 54% in non-smoking women and 77% in smoking men. The mean increase in olanzapine AUC is 52% and 108%, respectively. Patients taking fluoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin, should be given reduced doses of olanzapine. A reduction in the dose of olanzapine should be considered if treatment with a CYP1A2 inhibitor is initiated.
Reduced bioavailability.
Activated charcoal reduced the oral bioavailability of olanzapine by 50–60% and should be administered 2 hours before or 2 hours after olanzapine.
Fluoxetine (a CYP2D6 inhibitor), a single dose of antacids containing aluminum and magnesium, or cimetidine did not significantly affect the pharmacokinetics of olanzapine.
Effects of olanzapine on other drugs.
Olanzapine did not inhibit the major CYP 450 isoenzymes (e.g. 1A2, 2D6, 2C9, 2C19, 3A4) in vitro. Therefore, no specific interactions are expected, as confirmed by in vivo studies, where no inhibition of olanzapine metabolism was observed with the following active substances: tricyclic antidepressants (primarily represented by the CYP2D6 isoenzyme), warfarin (CYP2C9), theophylline (CYP 1A2) or diazepam (CYP 3A4 and 2C19).
No interactions of olanzapine were observed when administered with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not reveal the need for valproate dose adjustment when co-administered with olanzapine.
General CNS activity
Olanzapine should be used with caution in patients taking ethanol or drugs that may cause central nervous system (CNS) depression.
Concomitant use of olanzapine with antiparkinsonian drugs is not recommended in patients with Parkinson's disease and dementia (see section "Special warnings and precautions for use").
QTc interval.
Caution should be exercised when prescribing olanzapine with other drugs that may increase the QTc interval (see section "Special warnings and precautions for use").
CYP 2D6 inhibitors: Fluoxetine (60 mg once daily or 60 mg daily for 8 days) caused a mean increase in olanzapine Cmax by 16% and a mean decrease in olanzapine clearance by 16%. The magnitude of these effects is small compared to the interindividual variability, so dosage adjustments are not usually recommended.
The ability of olanzapine to interact with other drugs.
Antihypertensives: Olanzapine, due to its potential to lower blood pressure, may enhance the effects of certain antihypertensives.
Levodopa and dopamine agonists: Olanzapine may antagonize the effects of levodopa and dopamine agonists.
Imipramine: Single doses of olanzapine did not affect the pharmacokinetics of imipramine or its active metabolite desipramine.
Application features
During treatment with antipsychotics, clinical improvement may take from a few days to a few weeks. During this period, patients should be closely monitored.
Psychosis associated with dementia and/or behavioral disorders.
Olanzapine is not indicated for the treatment of psychosis associated with dementia and/or behavioral disturbances and is not recommended for use in these patients due to an increased risk of mortality and cerebrovascular events. In placebo-controlled clinical trials (6-12 weeks duration) in elderly patients (mean age 78 years) with psychosis associated with dementia and/or behavioral disturbances, the rate of death was 2-fold higher in patients treated with olanzapine than in patients treated with placebo (3.5% vs. 1.5%, respectively). The higher mortality was not related to the dose of olanzapine (mean daily dose 4.4 mg) or the duration of treatment. Risk factors for increased mortality include age 65 years or older, dysphagia, sedation, malnutrition and dehydration, pulmonary conditions (pneumonia, with or without aspiration), and concomitant use of benzodiazepines. However, mortality was higher with olanzapine than with placebo, regardless of risk factors.
Cerebrovascular adverse reactions (stroke, transient ischemic attack), including fatal outcomes, were observed in clinical trials. The incidence of cerebrovascular adverse reactions was 3-fold higher in patients treated with olanzapine than in patients treated with placebo (1.3% vs. 0.4%). All patients treated with olanzapine or placebo who experienced cerebrovascular adverse reactions had risk factors. Age ≥75 years and vascular/mixed dementia were identified as risk factors for cerebrovascular adverse reactions with olanzapine. The efficacy of olanzapine has not been established in these trials.
Neuroleptic malignant syndrome. Neuroleptic malignant syndrome (NMS) is a potentially fatal symptom complex associated with antipsychotic drugs. Rare cases of NMS have been reported with olanzapine. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, loss of consciousness, and symptoms of cardiac instability (irregular pulse or blood pressure changes, tachycardia, increased sweating, and cardiac arrhythmia). Additional features may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of NMS or the presence of hyperthermia without clinical manifestations of NMS require immediate discontinuation of all antipsychotic drugs, including olanzapine.
Hyperglycemia and diabetes mellitus: Hyperglycemia and development of diabetes mellitus or worsening of pre-existing diabetes mellitus associated with ketoacidosis or diabetic coma, as well as fatal cases, have been reported uncommonly. Pre-existing weight gain has occasionally been reported, which may be a risk factor.
Appropriate clinical monitoring is recommended for patients with diabetes mellitus and those at risk for diabetes mellitus, including measuring blood glucose levels at baseline, after 12 weeks, and annually thereafter. Patients treated with antipsychotics, including olanzapine, should be monitored for signs of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus and those at risk for diabetes should be monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at baseline, after 4 weeks, after 8 weeks, and after 12 weeks, and quarterly thereafter.
Anticholinergic activity: Clinical trials have shown a low incidence of anticholinergic events. However, due to limited clinical experience with olanzapine in patients with comorbid conditions, caution should be exercised when prescribing olanzapine to patients with prostatic hypertrophy, paralytic ileus, or similar conditions.
Liver function tests. Transient, asymptomatic elevations of the hepatic transaminases alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have been commonly observed with olanzapine, especially early in treatment. Olanzapine should be used with caution in patients with elevated ALT and/or AST, signs and symptoms of liver dysfunction, conditions associated with hepatic insufficiency, and patients receiving potentially hepatotoxic drugs. Olanzapine should be discontinued if hepatitis (including hepatocellular, cholestatic, or mixed liver injury) occurs.
Neutropenia: Olanzapine should be used with caution in patients with low white blood cell and/or neutrophil counts from any cause, in patients receiving medications that may cause neutropenia, in patients with a history of drug-induced bone marrow suppression/toxicity, in patients with bone marrow suppression due to underlying disease, radiation or chemotherapy, and in patients with hypereosinophilia and myeloproliferative disease. Neutropenia is a common adverse event when valproate is used concomitantly with olanzapine.
Discontinuation of therapy: Acute symptoms, including excessive sweating, insomnia, tremor, irritability, nausea, or vomiting, have been reported rarely (≥ 0.01% - < 0.1%) upon abrupt discontinuation of therapy.
QT interval: Clinically significant prolongation of the QTc interval (QTcF [Friederick-corrected] ≥ 500 milliseconds [ms] at any time after baseline was uncommon in patients with a QTcF < 500 msec at baseline, ranging from 0.1% to < 1%). There were no significant differences in the incidence of cardiac adverse events compared to placebo. However, caution should be exercised when olanzapine is coadministered with other drugs that prolong the QTc interval, especially in the elderly, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, or low potassium or magnesium levels.
Thromboembolism: Venous thromboembolism has been reported uncommonly (≥ 0.1% - < 1%) with olanzapine treatment. A causal relationship between olanzapine treatment and the development of venous thromboembolism has not been established. However, given that patients with schizophrenia are often predisposed to thromboembolism, all possible risk factors, such as immobilization of the patient, should be considered and all necessary precautions taken.
Seizures. Olanzapine should be used with caution in patients with a history of seizures or in the presence of factors that lower the seizure threshold. Seizures have been reported uncommonly with olanzapine. In most of these cases, patients had a history of seizures or were at increased risk of seizures.
Tardive Dyskinesia: In clinical trials of 1 year or less duration, olanzapine was associated with a statistically significant reduction in the incidence of treatment-emergent dyskinesia. Because of the increased risk of tardive dyskinesia with long-term use of antipsychotic drugs, appropriate dose reduction or discontinuation of the drug is recommended if a patient develops signs or symptoms of tardive dyskinesia. These symptoms may worsen over time or even reappear after treatment is discontinued.
Orthostatic hypotension: Orthostatic hypotension has been reported uncommonly in elderly patients in clinical trials. As with other antipsychotics, periodic monitoring of blood pressure is recommended in patients aged 65 years and older when olanzapine is used.
Sudden Cardiac Death: Cases of sudden cardiac death have been reported in postmarketing experience. In a retrospective observational cohort study, the risk of sudden cardiac death was approximately twofold increased in patients treated with olanzapine compared with patients not taking antipsychotics. The risk with olanzapine is consistent with that with the atypical antipsychotics included in the pooled analysis.
Lactose. The drug contains lactose, so it should not be prescribed to patients with hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.
Dopaminergic antagonism: Olanzapine exhibits dopamine antagonism in vitro and theoretically may antagonize the effects of levodopa and dopamine agonists, as do other antipsychotics.
Glucose: In clinical trials (up to 52 weeks), olanzapine produced greater changes in glucose levels compared to placebo. The difference in changes between olanzapine and placebo was greater in patients with a history of glucose dysregulation (including patients with diabetes or patients with hyperglycemia). These patients had significantly greater increases in HbA1c compared to placebo.
The percentage of patients whose glucose levels changed from normal or borderline to high has been steadily increasing.
In analyses of patients who underwent 9–12 months of olanzapine therapy, elevated blood glucose levels were reduced after 6 months.
Lipid changes. Undesirable changes in lipid levels may occur in patients treated with olanzapine. Lipid changes should be managed appropriately in patients with dyslipidemia and in patients with risk factors for lipid disorders. Patients treated with antipsychotics, including olanzapine, should have their blood lipid levels monitored regularly, for example at the start of treatment, after 12 weeks, and every 5 years thereafter.
In clinical trials lasting more than 12 weeks, patients taking olanzapine had increases in total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides compared to placebo.
Significant increases in lipid levels (total cholesterol, low-density lipoprotein, triglycerides) were observed more frequently in patients without a history of lipid disorders.
There were no statistically significant differences in increases in high-density lipoprotein (HDL) between patients taking olanzapine and patients taking placebo.
The proportion of patients who changed from normal or borderline to high total cholesterol, low-density lipoprotein, or triglyceride levels, or from normal or borderline to low high-density lipoprotein levels, was greater in long-term studies (at least 48 weeks) than in short-term studies. In patients who received 12 months of therapy, total cholesterol levels did not increase after 4 to 6 months.
Suicide: The potential for suicide attempts is common in both schizophrenia and bipolar I disorder, and patients at high risk of suicide who are treated with olanzapine should be carefully monitored. To reduce the risk of overdose, olanzapine should be prescribed in tablet form in small doses sufficient to achieve the desired therapeutic effect.
Olanzapine monotherapy in adults. In an analysis of 13 placebo-controlled clinical trials, patients treated with olanzapine experienced a mean weight gain of 2.6 kg compared with a mean weight loss of 0.3 kg in the placebo group at a median of 6 weeks; 22.2% of patients treated with olanzapine experienced a weight gain of at least 7% of their baseline weight compared with 3% of placebo patients at a median of 8 weeks; and 4.2% of patients experienced a weight gain of at least 15% of their baseline weight compared with 0.3% of placebo patients at a median of 12 weeks. Clinically significant weight gain was observed in all patient categories by BMI (body mass index). Discontinuation of therapy due to weight gain occurred in 0.2% of patients treated with olanzapine compared to 0% of patients in the placebo group.
In long-term clinical trials (at least 48 weeks), the mean weight gain in patients was 5.6 kg (median duration of treatment 573 days; N = 2021). The proportion of patients who gained at least 7%, 15%, or 25% of their baseline weight during long-term olanzapine treatment was 64%, 32%, and 12%, respectively. Discontinuation of therapy due to weight gain occurred in 0.4% of patients treated with olanzapine for at least 48 weeks.
Dysphagia. Esophageal motility disorders and dyspnea have been associated with antipsychotic use. Aspiration pneumonia has been a common cause of morbidity and mortality in patients with Alzheimer's disease. Olanzapine is not approved for the treatment of patients with Alzheimer's disease.
Body temperature regulation: Impairment of the body's ability to lower its temperature has been observed with antipsychotic drugs. This should be considered when prescribing olanzapine to patients who are in conditions that may lead to an increase in body temperature, such as strenuous exercise, exposure to extreme temperatures, concomitant use of drugs with anticholinergic activity, or dehydration.
Use in patients with comorbid conditions. Clinical experience with olanzapine in patients with certain medical conditions is limited. Olanzapine increases muscarinic receptor affinity in vitro. In premarketing clinical studies, olanzapine was associated with constipation, dry mouth, tachycardia, and other adverse events possibly related to cholinergic antagonism. Such adverse reactions have infrequently required discontinuation of olanzapine therapy, but olanzapine should be used with caution in patients with clinically significant prostatic hypertrophy, narrow-angle glaucoma, a history of paralytic ileus, or related conditions caused by cholinergic antagonism that may be exacerbated by olanzapine. In 5 placebo-controlled trials of olanzapine in elderly patients with dementia-related psychosis (n = 1184), the following treatment-related adverse reactions were observed with an incidence of at least 2% that was significantly greater than that in placebo-treated patients: fall, somnolence, peripheral edema, gait disturbance, urinary incontinence, lethargy, weight gain, asthenia, pyrexia, pneumonia, dry mouth, and visual hallucinations. The rate of discontinuation due to adverse events was higher in the olanzapine group compared to placebo (13% vs. 7%). Elderly patients with dementia-related psychosis treated with olanzapine had a higher mortality rate compared to placebo. Olanzapine is not indicated for the treatment of elderly patients with dementia-related psychosis. Olanzapine has not been used in sufficient numbers in patients with recent myocardial infarction or unstable heart disease. Patients with the above diagnoses were excluded from premarketing clinical trials. Olanzapine should be used with caution in patients with cardiac disease due to the risk of orthostatic hypotension.
Laboratory tests: It is recommended to monitor fasting glucose and lipid profile at the beginning of treatment and periodically during treatment.
Hyperprolactinemia. Like other agents with dopamine D2 receptor antagonist properties, olanzapine increases blood prolactin levels, and this increase is sustained with prolonged use. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in decreased pituitary gonadotropin secretion. This in turn may inhibit reproductive function by impairing gonadal spermatogenesis in both males and females. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating agents. Long-term hyperprolactinemia
