Olanzapine (Tablets, Lyophilisate) Instructions for Use

ATC Code

N05AH03 (Olanzapine)

Active Substance

Olanzapine (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Antipsychotic agent (neuroleptic)

Pharmacological Action

Olanzapine is an antipsychotic agent (neuroleptic).

Preclinical studies have established affinity for 5-HT_2A/2C, 5-HT₃, 5-HT₆ serotonin receptors, D₁, D₂, D₃, D₄, D₅ dopamine receptors; anticholinergic effects are due to blockade of M_1-5 cholinergic receptors; it also has affinity for α₁-adrenergic and H₁ histamine receptors. Animal experiments revealed antagonism towards serotonin, dopamine, and cholinergic receptors. In vivo and in vitro, Olanzapine has a more pronounced affinity and activity for 5-HT₂ serotonin receptors compared to D₂ dopamine receptors.

According to electrophysiological studies, Olanzapine selectively reduces the excitability of mesolimbic dopaminergic neurons, while having a minor effect on striatal pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned avoidance response (a test characterizing antipsychotic activity) at doses lower than those causing catalepsy (a disorder reflecting an adverse effect on motor function). Unlike other neuroleptics, Olanzapine enhances the anti-anxiety effect in the “anxiolytic” test.

Olanzapine provides a statistically significant response for both positive (delusions, hallucinations, etc.) and negative disorders.

After a single 10 mg dose of olanzapine, positron emission tomography (PET) in healthy volunteers established a greater affinity of olanzapine for 5-HT_2A receptors than for D₂ dopamine receptors. Tomograms of patients with schizophrenia showed that in patients responsive to olanzapine treatment, the affinity for striatal D₂ receptors is comparable to the effect in patients responsive to clozapine and lower than in patients responsive to treatment with other antipsychotic drugs and risperidone.

Clinical Efficacy

In an international, double-blind, comparative study of patients with schizophrenia, schizoaffective, or similar disorders with varying severity of depressive symptoms (mean baseline value 16.6 on the Montgomery-Asberg Depression Rating Scale), a prospective secondary analysis of the mood scale from baseline to endpoint control showed a statistically significant (p=0.001) improvement with olanzapine (-6.0) compared to haloperidol (-3.1).

In patients with a manic or mixed episode of bipolar disorder, high efficacy in reducing manic symptoms over 3 weeks was demonstrated compared to placebo and valproic acid (divalproate). Comparable efficacy results for olanzapine and haloperidol were observed in patients with symptomatic remission of mania and depression after 6-12 weeks.

In co-therapy for patients taking lithium or valproic acid for at least 2 weeks, the additional administration of 10 mg olanzapine (co-therapy with lithium or valproic acid) led to a significant reduction in manic symptoms compared to monotherapy with lithium or valproic acid over 6 weeks.

In a 12-month study on the prevention of relapse of manic episodes in patients who achieved remission with olanzapine and were then randomized to the Olanzapine group, a statistically significant advantage over placebo was established for the primary control criterion of recurrence of bipolar disorder and in terms of preventing relapse of mania or relapse of depression.

In a second 12-month study on the prevention of relapse of manic episodes in patients who achieved remission with combined olanzapine and lithium, and then randomized to olanzapine monotherapy or lithium. The efficacy of olanzapine was statistically insignificant compared to lithium for the primary control criterion of bipolar disorder recurrence (Olanzapine 30.0%, lithium 38.3%, p=0.055).

In an 18-month co-therapy study of manic or mixed episodes in patients stabilized with olanzapine and mood-stabilizing drugs (lithium or valproic acid), long-term combined therapy with olanzapine and lithium or valproic acid was statistically insignificant compared to monotherapy with lithium or valproic acid for delaying the emergence of bipolar disorder recurrence, defined by diagnostic criteria.

Pharmacokinetics

After oral administration, Olanzapine is well absorbed, with C_max in plasma reached within 5-8 hours. The absorption of olanzapine is not dependent on food intake. Studies with different doses in the range of 1-20 mg have shown that the plasma concentration of olanzapine changes linearly and proportionally to the dose.

Olanzapine is metabolized in the liver through conjugation and oxidation processes. The main circulating metabolite is 10-N-glucuronide, which theoretically does not cross the blood-brain barrier. CYP1A2 and CYP2D6 isoenzymes are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Both metabolites in animal studies had significantly less pronounced pharmacological activity in vivo than Olanzapine. The main pharmacological activity of the drug is due to the parent compound – olanzapine, which has the ability to cross the blood-brain barrier.

In healthy volunteers after oral administration, the mean T_1/2 was 33 hours (21-54 hours for 5-95%), and the mean plasma clearance of olanzapine was 26 L/h (12-47 L/h for 5-95%).

The pharmacokinetic parameters of olanzapine vary depending on smoking, gender, and age (see Table 1).

Table 1

However, the degree of change in half-life and clearance under the influence of each of these factors is significantly less than the degree of variation of these parameters between individuals.

Pharmacokinetic parameters in adolescents (13-17 years) and adults are similar. According to clinical studies, the exposure in adolescents is 27% higher than in adults. The difference in demographic parameters between the adult and adolescent populations was that there were fewer smokers among adolescents, and lower average body weight indicators were noted.

No significant differences were found between the mean values of half-life and plasma clearance of olanzapine in individuals with severe renal impairment compared to individuals with normal renal function. Approximately 57% of radiolabeled olanzapine is excreted in the urine, mainly as metabolites.

In smoking individuals with mild hepatic impairment, the clearance of olanzapine is lower than in non-smokers without hepatic impairment.

At plasma concentrations of olanzapine from 7-1000 ng/mL, its binding to plasma proteins is about 93%. Olanzapine mainly binds to albumin and α₁-acid glycoprotein. In a study involving individuals of European, Japanese, and Chinese origin, no differences in the pharmacokinetics of olanzapine related to race were found. The activity of the CYP2D6 isoenzyme does not affect the metabolism of olanzapine.

Indications

• For the treatment of schizophrenia. Olanzapine is effective for maintaining clinical improvement within the framework of ongoing therapy for patients with schizophrenia who responded to initial treatment;
• For the treatment of moderate to severe manic episode;
• For preventing recurrence in patients with bipolar disorder in whom it has been effective in treating the manic phase;
• Treatment-resistant depression. In combination with fluoxetine, Olanzapine is indicated for the treatment of treatment-resistant depression in adult patients (major depressive episodes with a history of ineffective use of two antidepressants at a dose and duration of therapy adequate for this episode). Olanzapine monotherapy is not indicated for the treatment of treatment-resistant depression.

ICD codes

Dosage Regimen

Tablets

Orally. Olanzapine can be taken regardless of meals, as food does not affect the absorption of olanzapine.

Schizophrenia

The recommended initial dose of olanzapine is 10 mg once daily. Therapeutic doses of olanzapine range from 5 mg to 20 mg per day. The daily dose must be individually adjusted depending on the patient’s clinical condition. Increasing the dose above the standard daily dose (10 mg) is recommended only after assessing the clinical picture. When using the drug, the need for continued therapy should be regularly assessed.

Bipolar Disorder

For the treatment of a manic episode, the recommended initial dose of olanzapine is 15 mg once daily as monotherapy or 10 mg once daily in combination with lithium or valproic acid. Therapeutic doses of olanzapine range from 5 mg to 20 mg per day. The daily dose must be individually adjusted depending on the patient’s clinical condition. Increasing the dose above the standard daily dose is recommended only after assessing the clinical picture and at intervals of at least 24 hours.

Maintenance therapy for bipolar disorder: patients who took Olanzapine for the treatment of a manic episode should continue maintenance therapy at the same dose. For patients in remission, the recommended initial dose of olanzapine is 10 mg once daily. Subsequently, the daily dose must be individually adjusted; depending on the patient’s clinical condition, within the range of 5 mg to 20 mg per day.

For the treatment of a depressive episode, Olanzapine should be prescribed in combination with fluoxetine once a day, in the evening, regardless of meals. Typically, the initial dose is 5 mg olanzapine and 20 mg fluoxetine. Antidepressant activity has been confirmed with olanzapine at a dose of 6-12 mg (mean daily dose 7.4 mg) and fluoxetine at a dose of 25-30 mg (mean daily dose 39.3 mg). If necessary, adjustment of the dose of both olanzapine and fluoxetine is allowed. When using the drug, the need for continued therapy should be regularly assessed.

Treatment-Resistant Depression

Olanzapine should be prescribed in combination with fluoxetine once a day, in the evening, regardless of meals. Typically, the initial dose is 5 mg olanzapine and 20 mg fluoxetine. If necessary, adjustment of the dose of both olanzapine and fluoxetine is allowed. Antidepressant activity has been confirmed with olanzapine at a dose of 6-12 mg and fluoxetine at a dose of 25-30 mg. When using the drug, the need for continued therapy should be regularly assessed.

General Rules for Selecting the Daily Dose for Special Patient Groups for Oral Administration

A reduction of the initial dose to 5 mg per day is recommended for elderly patients or patients with other clinical risk factors, including severe renal impairment or moderate hepatic impairment. A reduction of the initial dose to 5 mg may be recommended for patients with a combination of factors (female gender, elderly age, and non-smoking status) that may reduce the metabolism of olanzapine (see Table 1).

The use of olanzapine has not been studied in persons under 13 years of age.

Lyophilisate

The initial dose is 10-15 mg/day. The daily dose must be individually adjusted depending on the patient’s clinical condition. Therapeutic doses are 5-20 mg/day. Increasing the dose above the standard dose, which is (depending on the indication) 10-15 mg/day, is recommended only after an appropriate clinical examination of the patient. The dose should be increased gradually, with intervals of at least 24 hours.

For elderly patients, as well as in cases of severe renal impairment or moderate hepatic impairment, the initial dose is 5 mg/day.

A reduction of the initial dose is recommended for patients with a combination of factors (female patients, elderly age, non-smokers) where a slowdown in olanzapine metabolism is possible.

Adverse Reactions

The table below (see Table 2) summarizes the main adverse effects and their frequency, recorded during clinical trials and/or in the post-marketing period.

Table 2

Comments on footnotes for Table 2

1) Data accumulated during placebo-controlled clinical trials conducted for the indication “Schizophrenia, acute phase”.

2) Pooled data accumulated during all clinical trials.

3) Spontaneously reported adverse effects in post-marketing studies.

4) Clinically significant weight gain was observed in all patient groups, regardless of body weight.

Weight gain of 7% or more from the mean value after a short course of treatment (mean duration – 47 days) was observed very often (22.2%), an increase of 15% or more was frequent (4.2%), and an increase of 25% or more was infrequent (0.8%).

In patients receiving long-term treatment (at least 48 weeks), an increase of ≥7, ≥15 and ≥25% was very common (64.4; 31.7 and 12.3%, respectively).

5) Symptoms such as increased sweating, insomnia, tremor, anxiety, nausea or vomiting were observed upon abrupt withdrawal of olanzapine.

6) In clinical studies, cases of parkinsonism and dystonia in patients taking Olanzapine were frequent, but the difference with the placebo group was not statistically significant.

Parkinsonism, akathisia, and dystonia were observed less frequently in patients taking Olanzapine than in patients receiving titrated doses of haloperidol. Due to the lack of detailed information on the history of acute and tardive dyskinesias in patients, it is currently not possible to conclude that Olanzapine is less likely to cause tardive dyskinesia or other tardive extrapyramidal syndromes.

7) Seizures mainly in patients with a history of seizures or with risk factors for seizures.

8) An increase in glucose concentration from normal fasting values (<5.56 mmol/L) to elevated values (≥7 mmol/L) was frequently observed.

A change in glucose concentration from borderline fasting values (≥5.56-<7 mmol/L) to elevated values (≥7 mmol/L) was very common.

9) An increase in cholesterol concentration from normal fasting values (<5.17 mmol/L) to elevated values (≥6.2 mmol/L) was frequently observed.

A change in cholesterol concentration from borderline fasting values (≥5.17-<6.2 mmol/L) to elevated values (≥6.2 mmol/L) was very common.

10) An increase in triglyceride concentration from normal fasting values (<1.69 mmol/L) to elevated values (≥2.26 mmol/L) was frequently observed.

A change in triglyceride concentration from borderline fasting values (≥1.69-<2.26 mmol/L) to elevated values (≥2.26 mmol/L) was very common.

11) In clinical trials lasting up to 12 weeks, plasma prolactin concentration exceeded the upper limit of normal in approximately 30% of patients with normal baseline prolactin levels. In the majority of such patients, the increase in prolactin concentration was moderate, and less than 2 times the upper limit of normal.

Adverse effects in special patient groups

A very common (≥10%) adverse effect of olanzapine in clinical studies in patients with psychosis associated with dementia was gait disturbance and falls.

Frequent (<10% and ≥1%) adverse effects of olanzapine in elderly patients with psychosis associated with dementia were urinary incontinence and pneumonia.

Pneumonia, pyrexia, lethargy, erythema, visual hallucinations, and urinary incontinence were also frequently observed.

In clinical studies in patients with drug-induced psychosis (dopamine receptor agonist) in Parkinson’s disease, worsening of parkinsonism symptoms was very common (≥10%) and occurred more frequently than in the placebo group. Hallucinations were also very common (≥10%) and occurred more frequently than in the placebo group.

In patients with bipolar mania receiving Olanzapine in combination with lithium or valproic acid preparations, very common (≥10%) adverse effects were weight gain, dry mouth, increased appetite, tremor, and frequent (<10% and ≥1%) speech disorder.

Contraindications

• Hypersensitivity to any of the components of the drug;
• Contraindicated in persons under 18 years of age;
• Lactase deficiency;
• Lactose intolerance;
• Glucose-galactose malabsorption.

Use in Pregnancy and Lactation

Due to insufficient experience with the use of olanzapine during pregnancy, the drug should be prescribed during pregnancy only if the potential benefit to the patient significantly outweighs the potential risk to the fetus. Patients should be warned that if pregnancy occurs or is planned during treatment with olanzapine, they must inform their attending physician.

Newborns whose mothers took antipsychotics (including Olanzapine) during the third trimester of pregnancy are at risk of adverse reactions, including extrapyramidal disorders and/or withdrawal syndrome, the symptoms of which may vary in severity and duration after birth. Agitation, arterial hyper- and hypotension, tremor, drowsiness, respiratory distress syndrome, or feeding disorder have been reported. Therefore, newborns should be carefully monitored.

A study found that Olanzapine passes into breast milk. The average dose received by the infant (mg/kg) at maternal steady-state concentration was 1.8% of the maternal olanzapine dose (mg/kg). Breastfeeding is not recommended during olanzapine therapy.

Use in Hepatic Impairment

A reduction of the initial dose to 5 mg per day is recommended for patients with other clinical risk factors, including moderate hepatic impairment.

Use in Renal Impairment

A reduction of the initial dose to 5 mg per day is recommended for patients with other clinical risk factors, including severe renal impairment.

Pediatric Use

Contraindicated in persons under 18 years of age

Geriatric Use

A reduction of the initial dose to 5 mg per day is recommended for elderly patients.

Special Precautions

Suicide

The risk of suicide attempt in patients with schizophrenia and bipolar I disorder is inherent to these diseases themselves. In this regard, careful monitoring of patients at particularly high risk of suicide is required during pharmacotherapy. When prescribing olanzapine, the number of tablets taken by the patient should be minimized to reduce the risk of overdose.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) (a potentially lethal symptom complex) can develop during treatment with any antipsychotics, including Olanzapine. Clinical manifestations of neuroleptic malignant syndrome include significant hyperthermia, muscle rigidity, altered mental status, and autonomic instability (unstable pulse or blood pressure, tachycardia, cardiac arrhythmias, increased sweating). Additional signs may include increased creatine phosphokinase activity, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of neuroleptic malignant syndrome or significant hyperthermia without other symptoms of neuroleptic malignant syndrome require discontinuation of all antipsychotics, including Olanzapine.

Tardive dyskinesia

In comparative studies, treatment with olanzapine was associated with a significantly lower incidence of dyskinesias requiring drug correction than the use of typical and other atypical antipsychotics. However, the risk of tardive dyskinesia with long-term antipsychotic therapy should be considered. If signs of tardive dyskinesia develop, adjustment of the antipsychotic dose is recommended. It should be taken into account that when switching to Olanzapine, symptoms of tardive dyskinesia may develop due to the abrupt discontinuation of previous therapy. Over time, the intensity of these symptoms may increase; moreover, these symptoms may develop after discontinuation of therapy.

Experience in elderly patients with psychosis associated with dementia

The efficacy of olanzapine in elderly patients with psychosis associated with dementia has not been established. In this category of patients in placebo-controlled clinical studies, the mortality rate in the olanzapine group was higher than in the placebo group (3.5% vs. 1.5%, respectively). Risk factors that may predispose this group of patients to higher mortality when treated with olanzapine include age >80 years, sedation, concomitant use of benzodiazepines, or the presence of pulmonary pathology (e.g., pneumonia with or without aspiration).

There is insufficient data to establish differences in the incidence of cerebrovascular events and/or mortality (compared to placebo) and in risk factors in this group of patients taking oral olanzapine and receiving intramuscular injections.

Parkinson’s disease

The use of olanzapine is not recommended for the treatment of psychosis induced by dopamine receptor agonists in Parkinson’s disease. In clinical studies in patients with drug-induced psychosis (dopamine receptor agonist) in Parkinson’s disease, worsening of parkinsonism symptoms was very common (≥10%) and occurred more frequently than in the placebo group. Hallucinations were also very common (≥10%) and occurred more frequently than in the placebo group.

Hepatic function disorders

In some cases, taking olanzapine, usually in the early stages of therapy, was accompanied by a transient, asymptomatic increase in the activity of “liver” transaminases (AST and ALT) in the blood serum. Rare cases of hepatitis have been reported. In addition, isolated reports of cholestatic and mixed liver injury have been received. Particular caution is necessary in case of increased AST and/or ALT activity in the blood serum in patients with hepatic insufficiency, with limited hepatic functional reserve, or in patients receiving treatment with potentially hepatotoxic drugs. If AST and/or ALT activity increases during olanzapine treatment, careful monitoring of the patient is required and, if necessary, dose reduction. In case of severe liver dysfunction caused by olanzapine, its use should be discontinued.

Hyperglycemia and diabetes mellitus

There is a higher prevalence of diabetes mellitus in patients with schizophrenia. As with the use of some other antipsychotic drugs, cases of hyperglycemia, decompensation of diabetes mellitus, in some cases accompanied by ketoacidosis and diabetic coma, including fatal outcomes, have been rarely reported. Careful clinical monitoring of patients with diabetes mellitus and patients with risk factors for developing diabetes mellitus is recommended.

Changes in lipid profile

In placebo-controlled studies, undesirable changes in the lipid spectrum were observed in patients receiving Olanzapine. Clinical monitoring is recommended.

Development of risk of sudden death

Clinical experience with any antipsychotics, including Olanzapine, has revealed a similar, dose-dependent, two-fold increase in the risk of death from acute heart failure compared to cases of death from acute heart failure in patients who did not use antipsychotics.

Cerebrovascular adverse events, including stroke, in elderly patients with dementia

Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in studies of olanzapine in elderly patients with psychosis associated with dementia. In placebo-controlled studies, the incidence of cerebrovascular adverse events was higher in the olanzapine group compared to the placebo group (1.3% vs. 0.4%, respectively).

All patients with cerebrovascular events had pre-existing risk factors for cerebrovascular adverse events (e.g., a previous history of cerebrovascular adverse event or transient ischemic attack, arterial hypertension, smoking), as well as concomitant diseases and/or medication use temporally associated with the cerebrovascular adverse events.

Olanzapine is not indicated for the treatment of patients with psychosis associated with dementia.

Seizures

Olanzapine should be used with caution in patients with a history of seizures or those exposed to factors that lower the seizure threshold. Seizures were rarely observed in such patients during treatment with olanzapine.

Anticholinergic activity

During clinical trials, olanzapine therapy was rarely accompanied by adverse reactions due to blockade of muscarinic cholinergic receptors. However, clinical experience with olanzapine in patients with comorbid conditions is limited, so caution is recommended when prescribing olanzapine to patients with clinically significant prostatic hyperplasia, paralytic ileus, narrow-angle glaucoma, and similar conditions.

Dopamine receptor blockade

In vitro, Olanzapine exhibits antagonism at dopamine receptors and, like other antipsychotic agents (neuroleptics), may theoretically suppress the effect of levodopa and other dopamine receptor agonists.

Hematological changes

Olanzapine should be used with caution in patients with low white blood cell and/or neutrophil counts; receiving drugs that can cause neutropenia; with bone marrow depression caused by disease, radiation or chemotherapy; as well as in patients with eosinophilia and/or myeloproliferative diseases. Reports of neutropenia have occurred mainly when olanzapine was combined with valproate.

In clinical studies, the use of olanzapine in patients with a history of clozapine-dependent neutropenia or agranulocytosis was not accompanied by recurrence of these disorders. Reports of neutropenia have occurred mainly during combination therapy with olanzapine and valproic acid.

QT interval

In clinical studies, clinically significant QT interval prolongation (Fridericia-corrected QT interval [QTcF] >500 ms in patients with baseline QTcF <500 ms) was infrequently observed in patients receiving Olanzapine, with no significant differences compared to placebo in the incidence of cardiac adverse events. However, as with the use of other antipsychotic agents, caution is recommended when using olanzapine in combination with drugs that can prolong the QT interval, especially in elderly patients, patients with congenital long QT syndrome, chronic heart failure, myocardial hypertrophy, hypokalemia, and hypomagnesemia.

Treatment discontinuation

In case of abrupt withdrawal of olanzapine, acute development of sweating, insomnia, tremor, anxiety, nausea and vomiting was very rarely reported (<0.01 %).

Thromboembolism

Venous thromboembolism has been very rarely reported (<0.01 %) during olanzapine therapy. A causal relationship between olanzapine use and venous thromboembolism has not been established. However, given that patients with schizophrenia often have acquired risk factors for venous thromboembolism, a comprehensive assessment of all possible risk factors for this complication, including patient immobilization, should be carried out and necessary preventive measures should be taken.

General Activity on the Central Nervous System

Considering the primary action of olanzapine on the CNS, caution should be exercised when using olanzapine in combination with other centrally acting drugs and alcohol.

Postural Hypotension

Postural hypotension was infrequently observed in clinical studies of olanzapine in the elderly. As with other antipsychotic agents, when using olanzapine in patients over 65 years of age, periodic blood pressure monitoring is recommended.

Body Weight

During treatment (up to 6 weeks) of the acute phase of schizophrenia, in placebo-controlled trials of olanzapine, the percentage of patients who experienced weight gain ≥7% from baseline was statistically significantly different: 29% in the Olanzapine group versus only 3% in the placebo group. The average weight gain for these patients taking Olanzapine in the acute phase was 2.8 kg. The Body Mass Index (BMI) always increased clinically significantly in the study group. During long-term therapy for schizophrenia with olanzapine, the average weight gain was 5.4 kg, and in 56% of patients in the test group, body weight increased by more than 7% from baseline. For patients who underwent long-term therapy for bipolar disorder, the average weight gain was 3.8 kg, and the number of patients with a weight increase of more than 7% was 31%.

Hyperprolactinemia

In controlled clinical trials (no more than 12 weeks), an increase in blood prolactin levels was found in 30% of patients in the test group and 10.5% in the placebo (control) group. The actual increases in prolactin concentration were moderate. Identified clinical manifestations included: menstrual disturbances (frequent), sexual function disorders (specifically, erectile dysfunction (in men), decreased or loss of libido (in men and women), abnormal orgasm) and breast-related issues (infrequent).

Dysphagia

The occurrence of impaired esophageal motility and aspiration is associated with the use of antipsychotic medications. Aspiration pneumonia is a common cause of morbidity and mortality in patients with severe Alzheimer’s disease, requiring caution regarding such patients.

Body Temperature Regulation

Antipsychotic drugs in general are attributed with impairing the body’s ability to control core body temperature. Appropriate caution should be exercised by patients who are taking Olanzapine and are in conditions that promote an increase in core body temperature. For example, performing vigorous physical exercise, being exposed to high ambient temperatures, taking any medication with anticholinergic activity concomitantly with olanzapine, or being in a state of dehydration (profuse sweating).

Children and Adolescents Under 18 Years

Olanzapine is not recommended for use in children and adolescents under 18 years of age due to a lack of sufficient data on efficacy and safety. In short-term studies conducted in adolescents aged 13-17 years, a more significant increase in body weight and changes in lipid and prolactin concentrations were noted compared to similar studies in adults.

Effect on Ability to Drive and Operate Machinery

Patients taking Olanzapine should be warned about the hazards associated with operating machinery, including motor vehicles, as Olanzapine may cause drowsiness and dizziness.

Overdose

Signs and Symptoms of Overdose

Very common (frequency ≥10%) symptoms of olanzapine overdose were tachycardia, agitation/aggression, dysarthria, various extrapyramidal disorders, and disturbances of consciousness of varying severity (from sedation to coma).

Other clinically significant consequences of olanzapine overdose included delirium, seizures, neuroleptic malignant syndrome, respiratory depression, aspiration, increased and decreased blood pressure, arrhythmias (<2% of overdose cases), and cardiac and respiratory arrest. The minimum dose in an acute fatal overdose was 450 mg, and the maximum dose in an overdose with a favorable outcome (survival) was 2 g.

Medical Care for Overdose

There is no specific antidote for olanzapine. Induction of vomiting is not recommended. Standard procedures for overdose (gastric lavage, administration of activated charcoal) may be indicated. Concomitant administration of activated charcoal and olanzapine has been shown to reduce the oral bioavailability of olanzapine by up to 50-60%. Symptomatic treatment according to the clinical condition and monitoring of vital functions are indicated, including correction of reduced blood pressure, circulatory disorders, and maintenance of respiratory function. Epinephrine, dopamine, and other adrenomimetics that are β-adrenoceptor agonists should not be used, as stimulation of these receptors may worsen arterial hypotension.

Monitoring of cardiovascular function is necessary to detect possible arrhythmias. The patient should be under continuous medical supervision until full recovery.

Drug Interactions

The metabolism of olanzapine may be altered by inhibitors or inducers of the cytochrome P450 isoenzyme exhibiting specific activity towards the CYP1A2 isoenzyme. Olanzapine clearance is increased in smoking patients and in patients taking carbamazepine (due to increased activity of the CYP1A2 isoenzyme). Potential inhibitors of the CYP1A2 isoenzyme may reduce the clearance of olanzapine. Olanzapine is not a potential inhibitor of the CYP1A2 isoenzyme; therefore, when taking olanzapine, the pharmacokinetics of drugs such as theophylline, which are mainly metabolized by the CYP1A2 isoenzyme, are not altered.

Clinical studies have shown that a single dose of olanzapine administered during therapy with the following drugs was not accompanied by suppression of the metabolism of these drugs: imipramine or its metabolite desipramine (CYP2D6, CYP3A, CYP1A2 isoenzymes), warfarin (CYP2C19 isoenzyme), theophylline (CYP1A2 isoenzyme), or diazepam (CYP3A4, CYP2C19 isoenzymes). No signs of drug interaction were also identified when olanzapine was used in combination with lithium preparations or biperiden.

Against the background of steady-state concentrations of olanzapine, no changes in the pharmacokinetics of ethanol were noted. However, taking ethanol together with olanzapine may be accompanied by an enhancement of the pharmacological effects of olanzapine, for example, sedative effects.

Fluoxetine (60 mg single dose or 60 mg daily for 8 days) causes an average increase in the maximum concentration (C_max) of olanzapine by 16% and a decrease in the clearance of olanzapine by an average of 16%. The extent of this factor’s influence is significantly less than the severity of individual variations in these parameters, so a change in the dose of olanzapine is usually not recommended when used in combination with fluoxetine.

Fluvoxamine, an inhibitor of the CYP1A2 isoenzyme, reduces the clearance of olanzapine. This results in an average increase in C_max of olanzapine when fluvoxamine is administered by 54% in non-smoking women and 77% in smoking men, and an average increase in AUC (area under the concentration-time curve) of olanzapine by 52% and 108%, respectively. Lower doses of olanzapine should be prescribed to patients who are concurrently receiving treatment with fluvoxamine.

In vitro studies using human liver microsomes have shown that Olanzapine slightly inhibits the formation of valproic acid glucuronide (the main metabolic pathway of valproic acid). Valproic acid also slightly affects the metabolism of olanzapine in vitro. Therefore, a clinically significant pharmacokinetic interaction between olanzapine and valproic acid is unlikely.

The absorption of olanzapine is not dependent on food intake.

A single dose of aluminum- or magnesium-containing antacids or cimetidine did not impair the oral bioavailability of olanzapine. Concurrent use of activated charcoal and olanzapine reduced the oral bioavailability of the latter by up to 50-60%.

According to in vitro studies using human liver microsomes, Olanzapine also demonstrated an extremely low potential for inhibiting the activity of the following cytochrome P450 isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

Storage Conditions

Store in a light-protected place at a temperature not exceeding 30°C (86°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.