Olanzapine instructions for use. "Olanzapine": analogues, description of the drug, instructions for use

Release form:

Tablets from light yellow to yellow color, cylindrical, biconvex, engraved with "L" on one side.

Excipients: microcrystalline cellulose - 85.6 mg, lactose monohydrate - 17.2 mg, crospovidone - 1.1 mg, magnesium stearate - 1.1 mg.

Tablets from light yellow to yellow, cylindrical, biconvex, engraved with "FA20" on one side.

Excipients: microcrystalline cellulose - 171.3 mg, lactose monohydrate - 34.3 mg, crospovidone - 2.2 mg, magnesium stearate - 2.2 mg.

7 pcs. - cellular contour packings (4) - packs of cardboard.

Tablets light yellow to yellow, cylindrical, biconvex, engraved with "F20C" on one side.

Excipients: microcrystalline cellulose - 257 mg, lactose monohydrate - 51.6 mg, crospovidone - 3.2 mg, magnesium stearate - 3.2 mg.

7 pcs. - cellular contour packings (8) - packs of cardboard.

Tablets light yellow to yellow, cylindrical, biconvex, engraved "N30C" on one side.

Excipients: microcrystalline cellulose - 342.6 mg, lactose monohydrate - 68.8 mg, crospovidone - 4.3 mg, magnesium stearate - 4.3 mg.

7 pcs. - cellular contour packings (4) - packs of cardboard.

Pharmacotherapeutic group:

• Neurotropic agents

Pharmacological properties:

Pharmacodynamics

Antipsychotic drug (neuroleptic). It has an affinity for serotonin (5-HT 2A / 2C, 5-HT 3, 5-HT 6), dopamine (D 1, D 2, D 3, D 4, D 5), muscarinic (M 1-5), adrenergic (α 1) and histamine (H 1) receptors.

In vitro revealed antagonism to 5-HT, dopamine and cholinergic receptors. It has a more pronounced affinity and activity for serotonin 5-HT 2 receptors, in comparison with dopamine D 2 receptors.

Selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, has a slight effect on the striatal (A9) nerve pathways involved in the regulation motor functions. Reduces the conditioned protective reflex at lower doses than those that cause catalepsy.

Enhances the anti-anxiety effect during the "anxiolytic" test. Reliably reduces productive (including delirium, hallucinations) and negative symptoms.

Pharmacokinetics

Suction and distribution

Absorption is high, does not depend on food intake; the time to reach Cmax after oral administration is 5-8 hours. When taken in the dose range of 1-20 mg, plasma concentration changes linearly, in proportion to the dose.

At a plasma concentration of 7-1000 ng / ml, the connection with proteins is 93% (mainly with albumin and α 1-acid glycoprotein).

Metabolism

Metabolized in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which does not penetrate the BBB.

Isoenzymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine.

The main pharmacological activity of the drug is due to olanzapine, the activity of its metabolites is less pronounced.

breeding

Clearance - 26 l / h (12-47 l / h), T 1/2 - 33 h (21-54 h). Excreted by the kidneys - 57% (mainly in the form of metabolites).

Pharmacokinetics in special clinical situations

Non-smokers (clearance - 18.6 l / h, T 1/2 - 38.6 h), smokers (clearance - 27.7 l / h, T 1/2 - 30.4 h), women (clearance - 18.9 l / h, T 1/2 - 36.7 h), men (clearance - 27.3 l / h, T 1/2 - 32.3 h), patients 65 years and older (clearance - 17.5 l / h, T 1/2 -51.8 h), patients under the age of 65 years (clearance - 18.2 l / h, T 1/2 - 33.8 h).

Smokers with mild hepatic impairment have lower clearance than non-smokers without hepatic impairment.

Indications for use:

Schizophrenia in adults (exacerbation, maintenance and long-term anti-relapse therapy), psychotic disorders with productive (including delusions, hallucinations, automatisms) and / or negative (emotional flattening, decreased social activity, impoverishment of speech) symptoms and concomitant affective disorders;

Bipolar affective disorder in adults (monotherapy or in combination with lithium or valproic acid): acute manic or mixed episodes with / without psychotic manifestations and with / without rapid phase change;

Relapse of bipolar disorder (with the effectiveness of the drug in the treatment of the manic phase);

Depressive conditions associated with bipolar disorder (in combination with fluoxetine).

Regarding diseases:

• Bipolar disorder
• Depression
• Schizophrenia

Contraindications:

lactation period;

Children's age up to 18 years;

Hypersensitivity to the components of the drug.

FROM caution the drug should be prescribed for liver failure, prostatic hyperplasia, angle-closure glaucoma, epilepsy, myelosuppression (including leukopenia, neutropenia), myeloproliferative diseases, hypereosinophilic syndrome, paralytic intestinal obstruction, pregnancy.

Dosage and administration:

The drug is taken orally, regardless of food intake, at a dose of 5-20 mg / day.

At schizophrenia at adults the recommended starting dose is 10 mg/day.

At acute mania associated with bipolar disorder, at adults- 15 mg 1 time / day as monotherapy or 10 mg 1 time / day in combination with lithium preparations or valproic acid (maintenance therapy at the same dose).

At depression associated with bipolar disorder, at adults- 5 mg 1 time / day in combination with 20 mg fluoxetine (if necessary, changing the doses of drugs is allowed).

Elderly patients

Side effect:

Frequency of occurrence side effects defined as follows: very often (≥ 10%), often (≥ 1% and<10%), нечасто (≥ 0.1% и <1%), редко (≥ 0.01% и < 0.1%), очень редко (<0.01%).

In clinical studies, drowsiness and weight gain were very common; in 34% - hyperprolactinemia (mild and transient). Clinical manifestations of hyperprolactinemia were rare.

Often: dizziness, asthenia, akathisia, increased appetite, peripheral edema, orthostatic hypotension, dryness of the oral mucosa, constipation.

Rarely: transient, asymptomatic increase in the activity of ALT, ACT.

In isolated cases: an increase in plasma glucose levels of more than 200 mg / dl (suspected diabetes mellitus), 160 - 200 mg / dl (suspected hyperglycemia) in patients with an initial glucose concentration of less than 140 mg / dl.

There were cases of an increase in the level of triglycerides (by 20 mg / dl from the baseline), cholesterol (by 0.4 mg / dl from the baseline), asymptomatic eosinophilia (isolated cases).

In patients with psychosis associated with dementia: very often - a violation of gait and falling; often - urinary incontinence and pneumonia.

In patients with dopamine agonist-induced psychosis in Parkinson's disease: very often - increased symptoms of parkinsonism and hallucinations.

In patients with bipolar mania (receiving the drug in combination with lithium or valproic acid): very often - weight gain, dryness of the oral mucosa, increased appetite, tremor; often - a speech disorder.

The side effects observed in clinical studies and post-marketing experience are listed below.

From the side of the cardiovascular system: often - orthostatic hypotension; infrequently - bradycardia; very rarely - venous thromboembolism.

From the digestive system: often - constipation, dryness of the oral mucosa, increased appetite; rarely - hepatitis; very rarely - pancreatitis, jaundice.

From the side of metabolism: often - peripheral edema; very rarely - diabetic coma, diabetic ketoacidosis. hyperglycemia, hypercholesterolemia, hypertriglyceridemia.

From the musculoskeletal system: very rarely - rhabdomyolysis.

From the nervous system: very often - drowsiness; often - akathisia, dizziness, asthenia; rarely - convulsions.

From the side of the skin: rarely - rash.

From the genitourinary system: very rarely - priapism.

From the hematopoietic system: often - eosinophilia, rarely - leukopenia, very rarely - thrombocytopenia.

From the side of laboratory indicators: very often - hyperprolactinemia; often - increased activity of ALT, ACT, hyperglycemia; very rarely - hyperbilirubinemia, increased activity of alkaline phosphatase.

Others: very often - weight gain, infrequently - photosensitivity, very rarely - allergic reactions, withdrawal syndrome.

Overdose:

Symptoms: tachycardia, agitation / aggressiveness, articulation disorder, extrapyramidal disorders, impaired consciousness (from sedation to coma), delirium, convulsions, neuroleptic malignant syndrome, respiratory depression, aspiration, increase or decrease in blood pressure, arrhythmias, cardiac and respiratory arrest.

Treatment: gastric lavage, administration of activated charcoal, symptomatic treatment, maintenance of respiratory function.

Sympathomimetics (including epinephrine, dopamine), which are beta-adrenergic receptor agonists, should not be used (stimulation of these receptors may aggravate the decrease in blood pressure).

The minimum dose for acute fatal overdose was 450 mg, the maximum dose with a favorable outcome (survival) was 1500 mg.

Use during pregnancy and lactation:

With caution, the drug should be prescribed during pregnancy.

If necessary, the appointment of the drug during lactation, breastfeeding should be canceled.

Interaction with other drugs:

Inducers or inhibitors of the CYP 1A2 isoenzyme may alter the metabolism of olanzapine.

The clearance of olanzapine is increased in smoking patients and with the simultaneous use of carbamazepine (increased CYP1A2 activity).

Ethanol did not affect the pharmacokinetics of olanzapine at steady state, however, taking ethanol together with olanzapine may be accompanied by an increase in the pharmacological effects of olanzapine (sedation).

Activated charcoal reduces the bioavailability of olanzapine by up to 50-60%.

Fluoxetine (60 mg once or 60 mg daily for 8 days) increases Cmax of olanzapine by 16% and reduces clearance by 16%, which has no clinical significance (olanzapine dose adjustment is not required).

Fluvoxamine (an inhibitor of CYP 1A2), reducing the clearance of olanzapine, increases the Cmax of olanzapine in non-smoking women by 54% and 77% in smoking men, AUC - by 52% and 108%, respectively (an olanzapine dose reduction is necessary).

Olanzapine slightly inhibits the formation of valproic acid glucuronide (the main metabolic pathway). Valproic acid has little effect on the metabolism of olanzapine. A clinically significant pharmacokinetic interaction between olanzapine and valproic acid is unlikely.

Special instructions and precautions:

In the treatment of neuroleptics (including olanzapine), neuroleptic malignant syndrome may develop (hyperthermia, muscle rigidity, changes in mental status, vegetative disorders, including unstable pulse or blood pressure, tachycardia, cardiac arrhythmias, increased sweating; increased activity of CPK , myoglobinuria due to rhabdomyolysis, acute renal failure).

If clinical manifestations of neuroleptic malignant syndrome (including hyperthermia without other symptoms) are detected, olanzapine should be discontinued.

With the development of signs of tardive dyskinesia, a dose reduction or withdrawal of olanzapine is recommended. Symptoms of tardive dyskinesia may increase or manifest after discontinuation of the drug.

When taking olanzapine (in studies) in elderly patients with psychosis on the background of dementia, cerebrovascular disorders (stroke, transient ischemic attack), including deaths, were noted. These patients had previous risk factors (cerebrovascular disorders (history), transient ischemic attack, arterial hypertension, smoking), as well as concomitant diseases and/or medications associated with cerebrovascular disorders over time. Olanzapine is not recommended for the treatment of patients with dementia-related psychosis.

Special precautions are necessary when ALT and/or AST levels are elevated in patients with hepatic impairment or who are being treated with potentially hepatotoxic drugs. Patient monitoring and, if necessary, dose reduction is required.

There is a higher prevalence of diabetes mellitus in patients with schizophrenia. Very rarely, cases of hyperglycemia, development of diabetes mellitus or exacerbation of pre-existing diabetes mellitus, ketoacidosis and diabetic coma have been reported. A causal relationship between antipsychotics and these conditions has not been established. Clinical monitoring of patients with diabetes mellitus or risk factors for its development is recommended.

Olanzapine should be used with caution in patients with a history of epileptic seizures or in the presence of factors that lower the seizure threshold.

Olanzapine should be used with caution in patients with a decrease in the number of leukocytes and / or neutrophils, with signs of oppression or toxic impairment of bone marrow function under the influence of drugs (history), with suppression of bone marrow function due to concomitant disease, radio- or chemotherapy (in history); with hypereosinophilia or myeloproliferative disease.

The use of olanzapine in patients with clozapine-dependent neutropenia or agranulocytosis (history) was not accompanied by relapses of these disorders.

Olanzapine exhibits dopamine antagonism and, theoretically, can inhibit the action of levodopa and dopamine agonists.

Caution should be exercised when olanzapine is used in combination with other centrally acting drugs and ethanol.

Influence on the ability to drive vehicles and control mechanisms

During the treatment period, care must be taken when driving and engaging in potentially hazardous activities that require increased concentration of attention and speed of psychomotor reactions.

For impaired liver function

FROM caution the drug should be prescribed for liver failure.

Use in the elderly

Elderly patients, patients with risk factors (including severe chronic renal failure or moderate hepatic insufficiency), with a combination of risk factors (female sex, old age, non-smokers), in whom the metabolism of olanzapine may be slowed down, it is recommended to reduce the initial dose to 5 mg / day

Application in childhood

Contraindicated in children and adolescents under 18 years of age.

Storage conditions:

The drug should be stored dry, protected from light, out of the reach of children at a temperature not exceeding 25°C. Shelf life - 2 years.

Olanzapine is an antipsychotic (neuroleptic).

In preclinical studies, affinity for 5-HT 2A / 2C -, 5-HT 3 -, 5-HT 6 - serotonin receptors, D 1 -, D 2 -, D 3 -, D 4 -, D 5 - dopamine receptors, m-anticholinergic effects are due to the blockade of M 1-5 cholinergic receptors; also has an affinity for α 1 -adrenergic and H 1 -histamine receptors. Antagonism in relation to serotonin, dopamine and m-cholinergic receptors was revealed in animal experiments. In vivo and in vitro, olanzapine has a greater affinity and activity for serotonin 5-HT2 receptors than dopamine D2 receptors. According to electrophysiological studies, olanzapine selectively reduces the excitability of mesolimbic dopaminergic neurons, and at the same time has a slight effect on the striatal nerve pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned protective reflex (a test that characterizes antipsychotic activity) at doses lower than doses that cause catalepsy (a disorder that reflects an adverse effect on motor function). Unlike other neuroleptics, olanzapine enhances the anti-anxiety effect during the "anxiolytic" test.

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

With a single dose of 10 mg of olanzapine, positron emission tomography (PET) on healthy volunteers showed a greater affinity of olanzapine for 5 HT 2A than for D 2 -dopamine receptors. On the tomograms of patients with schizophrenia, it has been shown that in patients sensitive to treatment with olanzapine, the affinity for striatal D 2 receptors is comparable to the effect in patients sensitive to taking clozapine, and lower than in patients sensitive to treatment with other antipsychotic drugs and risperidone.

Clinical Efficiency

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

In patients with a manic or mixed episode of bipolar disorder, compared with placebo and the drug valproic acid (divalproate), high efficacy in reducing manic symptoms within 3 weeks has been shown. Comparable results of efficacy of olanzapine and haloperidol were observed in patients with symptomatic remission of mania and depression after 6-12 weeks.

In co-treatment of patients treated with lithium or valproic acid for at least 2 weeks, an additional 10 mg of olanzapine (co-therapy with lithium or valproic acid) resulted in a significant reduction in manic symptoms compared with lithium or valproic acid monotherapy for 6 weeks.

A 12-month study on the prevention of relapse of manic episodes in patients who achieved remission on olanzapine and were then randomized to receive olanzapine showed a statistically significant advantage over placebo in the primary endpoint of controlling the occurrence of relapse of bipolar disorder and in terms of preventing relapse of mania or relapse of depression. .

In a second 12-month manic relapse prevention study in patients who achieved remission on co-administration of olanzapine with lithium and then randomized to olanzapine monotherapy or lithium alone. The efficacy of olanzapine was not statistically significant compared with lithium for the main criterion for controlling relapse of bipolar disorder (olanzapine 30.0%, lithium 38.3%, p=0.055).

In an 18-month study of co-treatment of manic or mixed episodes in patients stabilized with olanzapine and mood-stabilizing drugs (lithium or valproic acid), long-term co-therapy with olanzapine with lithium or valproic acid was not statistically significant compared with monotherapy with lithium or valproic acid. acids in order to delay the onset of recurrence of bipolar disorder, determined by diagnostic signs.

Pharmacokinetics

After oral administration, olanzapine is well absorbed, Cmax in plasma is reached after 5-8 hours. Absorption of olanzapine does not depend on food intake. Studies with different doses in the range of 1-20 mg showed that the concentration of olanzapine in plasma changes linearly and proportionally to the dose.

Olanzapine is metabolized in the liver as a result of conjugation and oxidation processes. The main circulating metabolite is 10-N-glucuronide, which theoretically does not cross the blood-brain barrier. Isoenzymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl- and 2-hydroxymethylmetabolites 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 penetrate the blood-brain barrier.

In healthy volunteers after oral administration, the average T 1 / 2 was 33 hours (21-54 hours for 5-95%), and the average clearance of olanzapine from plasma was 26 l / h (12-47 l / h for 5-95%) .

The pharmacokinetic parameters of olanzapine vary depending on smoking, sex 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 inferior to the degree of differences in these indicators between individuals.

Pharmacokinetic parameters in adolescents (13-17 years old) and in adults are similar. According to clinical studies, exposure in adolescents is 27% higher than in adults. The difference in demographics between the adult and adolescent populations was that adolescents had fewer smokers and also had lower average body weights.

Significant differences between the mean values ​​of the half-life and plasma clearance of olanzapine in individuals with severely impaired renal function, compared with individuals with normal renal function, have not been established. About 57% of radiolabeled olanzapine is excreted in the urine, mainly as metabolites.

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

With a plasma concentration of olanzapine of 7-1000 ng / ml, its association with plasma proteins is about 93%. Olanzapine mainly binds to albumin and acidic α 1 -glycoprotein. In a study involving people of European, Japanese and Chinese origin, no differences in the pharmacokinetics of olanzapine associated with race were found. The activity of the CYP2D6 isoenzyme does not affect the metabolism of olanzapine.

Release form

Tablets from light yellow to yellow, round, biconvex, blotches of a darker color are allowed.

Excipients: lactose monohydrate - 50.6 mg, microcrystalline cellulose - 51.4 mg, pregelatinized starch - 51.4 mg, colloidal silicon dioxide - 0.8 mg, magnesium stearate - 0.8 mg.

10 pieces. - cellular contour packings (1) - packs of cardboard.
10 pieces. - cellular contour packings (2) - packs of cardboard.
10 pieces. - cellular contour packings (3) - packs of cardboard.
10 pieces. - cellular contour packings (4) - packs of cardboard.
10 pieces. - cellular contour packings (5) - packs of cardboard.

Dosage

inside. Olanzapine can be taken with or without food, as food does not affect the absorption of olanzapine.

Schizophrenia

The recommended starting 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 selected individually depending on the clinical condition of the patient. Increasing the dose above the standard daily dose (10 mg) is recommended only after an assessment of the clinical picture. When using the drug, it is necessary to regularly evaluate the need to continue therapy.

Bipolar disorder

For the treatment of a manic episode, the recommended starting 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 selected individually, depending on the clinical condition of the patient. Increasing the dose above the standard daily dose is recommended only after an assessment of the clinical picture and at intervals of at least 24 hours.

Maintenance therapy for bipolar disorder: Patients taking olanzapine for the treatment of a manic episode should continue maintenance therapy at the same dose. In patients in remission, the recommended starting dose of olanzapine is 10 mg once daily. In the future, the daily dose must be selected individually; depending on the clinical condition of the patient, ranging from 5 mg to 20 mg per day.

For the treatment of a depressive episode, olanzapine should be given in combination with fluoxetine once daily, in the evening, with or without food. As a rule, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. Antidepressant activity was confirmed with the use of olanzapine at a dose of 6-12 mg (average daily dose - 7.4 mg) and fluoxetine at a dose of 25-30 mg (average daily dose - 39.3 mg). If necessary, it is allowed to change the dose of both olanzapine and fluoxetine. When using the drug, it is necessary to regularly evaluate the need to continue therapy.

Treatment-resistant depression

Olanzapine should be given in combination with fluoxetine once daily, in the evening, with or without food. As a rule, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, it is allowed to change the dose of both olanzapine and fluoxetine. Antidepressant activity has been confirmed with olanzapine 6–12 mg and fluoxetine 25–30 mg. When using the drug, it is necessary to regularly evaluate the need to continue therapy.

General rules for choosing a daily dose for special groups of patients when taken orally

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

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

Overdose

Signs and symptoms of overdose

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

Other clinically significant effects of olanzapine overdose included delirium, convulsions, neuroleptic malignant syndrome, respiratory depression, aspiration, high and low blood pressure, arrhythmias (<2% случаев передозировки) и остановку сердца и дыхания. Минимальная доза при острой передозировке с летальным исходом составила 450 мг, максимальная доза при передозировке с благоприятным исходом (выживание) – 2 г.

Medical assistance for overdose

There is no specific antidote for olanzapine. Provoking vomiting is not recommended. Standard procedures for overdose (gastric lavage, activated charcoal) may be shown. Co-administration of activated charcoal and olanzapine has shown a decrease in oral bioavailability of olanzapine by up to 50-60%. Symptomatic treatment is indicated in accordance with the clinical condition and control of vital body functions, including correction of low blood pressure, circulatory disorders and maintenance of respiratory function. Do not use epinephrine, dopamine and other adrenomimetics, which are β-adrenergic agonists, since stimulation of these receptors can aggravate arterial hypotension.

Monitoring of cardiovascular activity is necessary to identify possible arrhythmias. The patient should be under continuous medical supervision until complete recovery.

Interaction

The metabolism of olanzapine may be altered by inhibitors or inducers of the cytochrome P450 isoenzyme, which exhibit specific activity against the CYP1A2 isoenzyme. The clearance of olanzapine is increased in smoking patients and in patients taking carbamazepine (due to an increase in the 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, mainly metabolized by the CYP1A2 isoenzyme, does not change.

In clinical studies, it has been shown that a single dose of olanzapine 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 (isoenzyme CYP3A4, CYP2C19). There were also no signs of drug interaction when using olanzapine in combination with lithium preparations or biperiden.

Against the background of the equilibrium concentration of olanzapine, no change in the pharmacokinetics of ethanol was noted. However, the use of ethanol together with olanzapine may be accompanied by an increase in the pharmacological effects of olanzapine, for example, sedation.

Fluoxetine (60 mg once or 60 mg daily for 8 days) causes an increase in the maximum concentration (C max) of olanzapine by an average of 16% and a decrease in the clearance of olanzapine by an average of 16%. The degree of influence of this factor is significantly inferior to the severity of individual differences in these indicators, so it is usually not recommended to change the dose of olanzapine when it is used in combination with fluoxetine.

Fluvoxamine, an inhibitor of the CYP1A2 isoenzyme, reduces the clearance of olanzapine. This results in a mean increase in Cmax of olanzapine with fluvoxamine by 54% in non-smoking women and 77% in smoking men, a mean increase in AUC (area under the concentration-time curve) of olanzapine by 52% and 108%, respectively. Low doses of olanzapine should be given to patients who are co-treated 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 has little effect on the metabolism of olanzapine in vitro. Therefore, a clinically significant pharmacokinetic interaction between olanzapine and valproic acid is unlikely.

Absorption of olanzapine is independent of food intake.

A single dose of aluminium- or magnesium-containing antacids or cimetidine did not interfere with oral bioavailability of olanzapine. The simultaneous use of activated charcoal and olanzapine reduced the bioavailability of the latter when administered orally to 50-60%.

Based on in vitro studies using human liver microsomes, olanzapine also showed a very low potential to inhibit the activity of the following cytochrome P450 isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A.

Side effects

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

table 2

Footnote comments for Table 2:

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

2) Summarized data from all clinical trials.

3) Registered spontaneous side effects in post-marketing studies.

4) In all groups of patients, regardless of body weight, there was a clinically significant increase in body weight.

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

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

5) With the abrupt withdrawal of olanzapine, symptoms such as increased sweating, insomnia, tremors, anxiety, nausea or vomiting were observed.

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

In patients treated with olanzapine, parkinsonism, akathisia, and dystonia were observed less frequently than in patients treated with titrated doses of haloperidol. Due to the lack of detailed information on the presence of acute and tardive dyskinesias in patients, it is currently impossible to conclude that olanzapine causes the development of tardive dyskinesias or other tardive extrapyramidal syndromes to a lesser extent.

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

8) An increase in glucose concentration from normal values ​​on an empty stomach was often observed (<5.56 ммоль/л) до повышенных (≥7 ммоль/л).

Change in glucose concentration from fasting borderline values ​​(≥5.56–<7 ммоль/л) до повышенных (≥7 ммоль/л) было очень частым.

9) An increase in cholesterol concentration from normal values ​​on an empty stomach was often observed (<5.17 ммоль/л) до повышенных (≥6.2 ммоль/л).

Change in cholesterol concentration from borderline values ​​on an empty stomach (≥5.17–<6.2 ммоль/л) до повышенных (≥6.2 ммоль/л) было очень частым.

10) An increase in the concentration of triglycerides from normal values ​​on an empty stomach was often observed (<1,69 ммоль/л) до повышенных (≥2.26 ммоль/л).

Change in triglyceride concentration from fasting borderline values ​​(≥1.69–<2.26 ммоль/л) до повышенных (≥2.26 ммоль/л) было очень частым.

11) In clinical studies of up to 12 weeks duration, plasma prolactin concentrations exceeded the upper limit of normal in approximately 30% of patients with normal baseline prolactin values. In most of these patients, the increase in prolactin concentration was moderate, and less than 2 times the upper limit of normal.

Undesirable effects in special groups of patients

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

Frequent (<10% и ≥1%) нежелательными эффектами при применении оланзапина у пожилых пациентов с психозом, связанным с деменцией, были недержание мочи и пневмония.

Pneumonia, fever, lethargy, erythema, visual hallucinations, and urinary incontinence have also been frequently observed.

In clinical studies in patients with psychosis induced by taking a drug (dopamine receptor agonist) in Parkinson's disease, an increase in the symptoms of parkinsonism was noted very often (≥10%) and at a higher frequency than in the placebo group. Hallucinations were also noted very often (≥10%) and at a higher frequency than in the placebo group.

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

Indications

• for the treatment of schizophrenia. Olanzapine is effective in maintaining clinical improvement in ongoing therapy in patients with schizophrenia who respond to initial treatment;
• for the treatment of a moderate to severe manic episode;
• to prevent relapse in patients with bipolar disorder, in whom it has been effective in the treatment of 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 to this episode). Olanzapine alone is not indicated for treatment-resistant depression.

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.

Application features

Use during 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 should inform their 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, whose symptoms may vary in severity and duration after birth. Agitation, arterial hyper- and hypotension, tremor, drowsiness, respiratory distress syndrome or eating disorder have been reported. Therefore, it is necessary to carefully monitor the condition of newborns.

In a study, olanzapine was found to pass into breast milk. The mean dose received by the child (mg/kg) at steady state in the mother was 1.8% of the maternal dose of olanzapine (mg/kg). Breast-feeding is not recommended during olanzapine therapy.

Application for violations of liver function

Application for violations of kidney function

Use in children

Use in elderly patients

special instructions

The risk of suicide attempt in patients with schizophrenia and type 1 bipolar disorder is due to these diseases themselves. In this regard, against the background of pharmacotherapy, careful monitoring of those patients who have a particularly high risk of suicide is required. When prescribing olanzapine, one should strive to minimize the number of tablets taken by the patient in order to reduce the risk of overdose.

Malignant neuroleptic syndrome

Neuroleptic Malignant Syndrome (NMS) (a potentially lethal symptom complex) can develop during treatment with any neuroleptics, including olanzapine. Clinical manifestations of neuroleptic malignant syndrome include a significant increase in body temperature, muscle rigidity, changes in mental status and autonomic disorders (unstable pulse or blood pressure, tachycardia, cardiac arrhythmias, increased sweating). Additional signs may include an increase in creatine phosphokinase activity, myoglobinuria (rhabdomyolysis) and acute renal failure. Clinical manifestations of neuroleptic malignant syndrome or a significant increase in body temperature without other symptoms of neuroleptic malignant syndrome require the abolition of all antipsychotics, including olanzapine.

Tardive dyskinesia

In comparative studies, treatment with olanzapine was significantly less frequently accompanied by the development of dyskinesias requiring medical correction than the use of typical and other atypical antipsychotics. However, the risk of tardive dyskinesia during long-term antipsychotic therapy should be taken into account. With the development of signs of tardive dyskinesia, dose adjustment of the antipsychotic is recommended. It should be borne in mind that when switching to olanzapine, the symptoms of tardive dyskinesia may develop as a result of the simultaneous cancellation of previous therapy. Over time, the intensity of these symptoms may increase, moreover, these symptoms may develop after cessation 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 trials, the incidence of deaths 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 with olanzapine treatment include age >80 years, sedation, concomitant use with benzodiazepines, or the presence of lung disease (eg, pneumonia with or without aspiration).

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

Parkinson's disease

The use of olanzapine in the treatment of psychosis induced by the use of dopamine receptor agonists in Parkinson's disease is not recommended. In clinical studies in patients with psychosis induced by taking a drug (dopamine receptor agonist) in Parkinson's disease, an increase in the symptoms of parkinsonism was noted very often (≥10%) and at a higher frequency than in the placebo group. Hallucinations were also noted very often (≥10%) and at a higher frequency than in the placebo group.

Liver dysfunction

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 (aspartate aminotransferase (ACT) and alanine aminotransferase (ALT)) in the blood serum. Rare cases of hepatitis have been reported. In addition, there have been isolated reports of cholestatic and mixed liver damage. Particular caution is required when increasing serum ACT and/or ALT activity in patients with hepatic impairment, with limited hepatic functional reserve, or in patients receiving treatment with potentially hepatotoxic drugs. In the event of an increase in the activity of ACT and (or) ALT during treatment with olanzapine, careful monitoring of the patient and, if necessary, dose reduction is required. With severe violations of liver function due to the intake of olanzapine, its use should be discontinued.

Hyperglycemia and diabetes

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

Change in lipid profile

In placebo-controlled studies, undesirable changes in the lipid spectrum were observed in patients treated with olanzapine. Clinical observation is recommended.

Development of the risk of sudden death

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

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

Cerebrovascular adverse events (eg, stroke, transient ischemic attack), including death, have been reported 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% vs. 0.4%, respectively).

All patients with cerebrovascular disease had prior risk factors for cerebrovascular adverse events (eg, previous cerebrovascular adverse event or transient ischemic attack, hypertension, smoking), as well as comorbidities and/or drug use temporally associated with cerebrovascular adverse events. phenomena.

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

convulsions

Olanzapine should be used with caution in patients with a history of seizures or those exposed to factors that lower the seizure threshold. Seizures have rarely been observed in these patients treated with olanzapine.

M-anticholinergic activity

In clinical studies, olanzapine therapy was rarely accompanied by adverse reactions due to the blockade of m-cholinergic receptors. However, clinical experience with olanzapine in patients with comorbidities is limited, so caution is advised when prescribing olanzapine to patients with clinically significant prostatic hyperplasia, paralytic ileus, angle-closure glaucoma, and similar conditions.

Blockade of dopamine receptors

Under in vitro conditions, olanzapine exhibits dopamine receptor antagonism and, like other antipsychotics (antipsychotics), can theoretically inhibit the action of levodopa and other dopamine receptor agonists.

Hematological changes

Olanzapine should be used with caution in patients with low levels of leukocytes and/or neutrophils in the blood; receiving drugs that can cause neutropenia; with oppression of bone marrow function due to a disease of radiation or chemotherapy; as well as in patients with eosinophilia and (or) myeloproliferative diseases. The development of neutropenia has been reported mainly when olanzapine is 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 relapse of these disorders. The development of neutropenia has been reported mainly with combination therapy with olanzapine and valproic acid.

QT interval

In clinical studies, clinically significant prolongation of the QT interval was observed infrequently (QT interval with Fridericium correction > 500 ms in patients with baseline QTcF<500 мс) у пациентов, получавших оланзапин, на фоне отсутствия значимых различий с плацебо по частоте возникновения нежелательных явлений со стороны сердца. Однако, так же как и при применении других антипсихотических средств, рекомендуется соблюдать осторожность при применении оланзапина в сочетании с препаратами, способными удлинять интервал QT, особенно у пациентов пожилого возраста, с врожденным удлинением интервала QT, хронической сердечной недостаточностью, гипертрофией миокарда, гипокалиемией и гипомагниемией.

Cancellation of therapy

In case of abrupt withdrawal of olanzapine, it is extremely rare (<0.01 %) сообщалось об остром развитии потливости, бессонницы, тремора, тревоги, тошноты и рвоты.

Thromboembolism

Rarely (<0,01 %) сообщалось о развитии венозной тромбоэмболии на фоне терапии оланзапином. Наличие причинно-следственной связи между приемом оланзапина и венозной тромбоэмболии не установлено. Однако учитывая, что у пациентов с шизофренией часто имеются приобретенные факторы риска венозной тромбоэмболии, требуется проводить совокупную оценку всех возможных факторов риска развития данного осложнения, в том числе иммобилизации пациентов, и принимать необходимые меры по профилактике.

General activity in relation to the central nervous system

Given the primary effect of olanzapine on the CNS, caution should be exercised when olanzapine is used in combination with other centrally acting drugs and alcohol.

Postural hypotension

Postural hypotension has been observed infrequently in clinical trials of olanzapine in the elderly. As with the use of other antipsychotics, in the case of the use of olanzapine in patients over 65 years of age, it is recommended to periodically monitor blood pressure.

Body mass

During treatment (up to 6 weeks) of the acute phase of schizophrenia, when in placebo-controlled trials of olanzapine, the percentage for patients who experienced weight gain ≥7% of baseline, the difference was statistically significant and amounted to 29% in those taking olanzapine, and only 3% in the placebo group. The average weight gain of these patients treated with olanzapine in the acute phase was 2.8 kg. Body mass index (BMI) was always clinically significantly increased in the study group. With long-term treatment of schizophrenia with olanzapine, weight gain averaged 5.4 kg, in 56% of patients in the test group, body weight increased by more than 7% from baseline. For patients who were on long-term therapy for bipolar disorder, the average weight gain was 3.8 kg, and the number of patients with a weight gain 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 levels of increase in prolactin concentration themselves were moderate. Identified clinical manifestations included: menstrual disorders (common), sexual dysfunction (in particular, erectile dysfunction (in men), decreased or loss of libido (in men and women), abnormal orgasm) and from the mammary glands (infrequently).

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic drugs. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease, requiring caution in these patients.

Body temperature regulation

Antipsychotic drugs are generally attributed to disrupting the body's ability to control core body temperature. Appropriate caution should be observed in patients who are taking olanzapine and are under conditions that increase core body temperature. For example, they perform vigorous exercise, are exposed to high ambient temperatures, are taking any drug with anticholinergic activity along with olanzapine, or are in conditions of dehydration (sweating profusely).

Children and adolescents under 18 years of age

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 conducted in adolescents 13-17 years of age, there was a greater increase in body weight and changes in lipid and prolactin concentrations than in similar studies in adults.

Influence on the ability to drive vehicles and other mechanisms

Patients taking olanzapine should be warned about the dangers associated with the operation of machinery, including a car, since olanzapine can cause drowsiness and dizziness.

Olanzapine is an antipsychotic drug that also has antimanic activity. It stabilizes mood, improves somatic functions in chronic mental disorders. The uniqueness of the drug lies in its wide pharmacological profile with respect to several receptor systems in the body. The use should be carefully monitored by a doctor - if necessary, he will adjust the dosage regimen.

Show all

Composition and form of release

The drug is available in the form of tablets. They are round, flat with beveled edges, yellow. The engraving corresponds to the concentration of the active substance. One tablet may contain olanzapine as an active substance in the amount of:

• 5 mg;
• 10 mg;
• 15 mg;
• 20 mg.

Auxiliary components are represented by aspartame, strawberry flavor, colloidal silicon dioxide, magnesium stearate and hydroxypropyl cellulose. In one package, 30 tablets are dispensed with instructions for the use of Olanzapine from the manufacturer.

Pharmacological properties

Olanzapine is a group of antipsychotic drugs. In preclinical trials, the drug showed a high degree of binding to serotonin, dopamine, cholinergic muscarinic, adrenergic and histamine receptors.

In an international study of schizophrenia and related disorders, olanzapine showed a statistically greater improvement than haloperidol.

In patients with manic or mixed episodes of bipolar disorder, olanzapine has been shown to be superior to sodium valproate in reducing manic symptoms within the first three weeks of use. In patients previously taking lithium preparations, a decrease in the symptoms of mania was noted with simultaneous treatment with olanzapine for as early as two weeks, while lithium monotherapy showed the same result in six weeks.



Pharmacokinetics

Tablets are taken orally if they are enteric-coated. There is also a form of the drug that dissolves in the mouth. Both types of release are equally effective.

The maximum concentration of the drug in blood plasma is reached 6 hours after application, the level of absorption does not depend on food intake. The metabolism of the drug takes place in the liver. The mean half-life varies by age and gender.

In healthy elderly patients, the mean half-life increased and clearance decreased compared to younger patients. In women, the half-life is slightly increased, and the clearance is reduced in comparison with men.

In patients with impaired renal function, no significant differences in elimination half-life were found. With pathologies of the liver, the clearance is reduced, and the half-life is lengthened.

The influence of sex, age and smoking on the clearance of olanzapine is insignificant in comparison with the general indicators among all patients.



Indications for use

Olanzapine is indicated for the treatment of schizophrenia. The drug has shown the effectiveness of maintenance dosages in long-term therapy in patients who have previously been successfully treated with olanzapine.

The use of the drug is indicated for the treatment of severe and moderate manic episodes, as well as for the prevention of recurrent attacks of bipolar disorders, which are accompanied by psychosis or without it.

Contraindications

It is forbidden to use Olanzapine with known individual hypersensitivity to the active ingredient or any other substance in the composition of the drug.

Before starting use, consultation with the attending physician is necessary.

Dosages

To prevent relapse in bipolar disorders, the initial dosage is 10 mg. If the patient is already taking olanzapine, it is recommended that the same dosage be used to prevent relapse.

If new depressive, manic or mixed attacks appear, treatment should be continued, but the doses should be adjusted by the attending physician. Additionally, mood-correcting drugs may be prescribed.

In the treatment of manic attacks, schizophrenia and in the prevention of bipolar disorders in adults, the daily dosage can range from 5 to 20 mg.

Elderly patients

Patients over 65 years of age can reduce the initial dosage to 5 mg per day if there are relevant clinical factors, for example, poor tolerance to higher dosages.

Liver and kidney dysfunction

In diseases of the kidneys and / or liver, it is advisable to reduce the initial dosage to 5 mg. It should be increased with caution and only after assessing the potential danger to the patient's body.

gender, smoking, age

Usually there is no need to adjust the dosage depending on sex and addiction to smoking. If one or more factors that slow down the metabolism of the drug are present, for example, female sex, advanced age, the initial dosage should be reduced.

children

Olanzapine should not be taken by children under 18 years of age, as there are no reliable data on its safety for this group of patients. Short-term studies have shown a significant increase in body weight and a change in blood prolactin levels in adolescents, in contrast to adults.

Mode of application

The action of Olanzapine is not associated with food intake, it does not affect the absorption of the drug. Cancellation of the drug should be carried out gradually. Orally dissolving tablets crumble easily, so they should be taken immediately after opening the blister. They can also be dissolved in water right before use.

Mouth-soluble tablets do not need to be swallowed with water. They have the same availability and absorption rate as olanzapine in the form of enteric tablets.

Overdose

Symptoms of an overdose of olanzapine include tachycardia, aggressiveness, extrapyramidal disturbances, and a decrease in the degree of consciousness. In severe cases, a coma is noted.

Other significant effects of an overdose:

• malignant neuroleptic syndrome;
• respiratory depression;
• cardiac arrhythmia;
• convulsions;
• jumps in blood pressure.

There are reports of death from an acute overdose of more than 0.45 g, however, there are data on surviving patients after an overdose of 2 g of olanzapine.

Treatment

The drug has no antidote. You can't induce vomiting. Standard measures are taken: gastric lavage, activated charcoal or silicon dioxide. Symptomatic therapy and monitoring of vital body functions are recommended.

Do not use epinephrine, dopamine or other drugs with beta-agonist effects, as they may worsen hypotension. Careful monitoring of the condition should be carried out until the patient fully recovers.

Adverse reactions

Side effects are dose-dependent and can be adjusted by dosage adjustment. Sometimes they go away on their own with the same dosage, but if the symptoms worsen, the treatment regimen should be reviewed or a different drug prescribed. Adverse reactions are presented by the frequency of reports about them. In parentheses, their number is indicated relative to the number of patients:

Organ System/Frequency	Very often (1/10)	Often (1/100)	Infrequently (≥ 1/1000)	Rare (1/10000 )
Hematopoietic and lymphatic systems		Decrease in the concentration of leukocytes and neutrophils		Thrombocytopenia
The immune system			Allergy
Metabolism and digestion	Weight gain	Increased levels of cholesterol, glucose, triglycerides, appetite	Exacerbation of diabetes mellitus with ketoacidosis	Hypothermia
	Drowsiness	Dizziness, tardive dyskinesia, parkinsonism	Epileptic seizures with a tendency to them, dystonia, dysarthria	Neuroleptic malignant syndrome, withdrawal syndrome
Mediastinal and thoracic organs			Nosebleeds
			Bradycardia, ECG changes	Tachycardia, ventricular fibrillation, sudden death syndrome
	hypotension		Venous thrombosis, pulmonary embolism
		Constipation, dry mouth	Bloating, flatulence	Pancreatitis
Hepatobiliary system		An increase in the level of hepatic transaminases ALT and AST in laboratory diagnostics	Increasing bilirubin levels	Cholestatic and mixed liver dysfunction, hepatitis
Skin covering		rashes	Alopecia, photosensitivity
Musculoskeletal system		Arthralgia
urinary system			Urinary incontinence, urinary retention
reproductive system		erectile dysfunction, decreased libido	Breast swelling, amenorrhea, galactorrhea, gynecomastia in men	Priapism
General disorders		Asthenia, fatigue, swelling

If any side effects are found, you should contact your doctor to correct the treatment regimen or prescribe other drugs similar in action to Olanzapine.

Long-term use

When treated for 48 weeks or more, adverse reactions may increase and manifest as:

• weight gain;
• changes in blood glucose levels;
• changes in cholesterol levels and liver transaminases.

In adults who completed a year of treatment, the rate of increase in blood glucose levels slowed six months after the end of therapy.

Side effects in separate groups

In elderly patients with dementia, olanzapine therapy has been associated with an increased risk of death and cerebrovascular events. Common undesirable effects in this group of patients: blurred gait, falls, dizziness. Pneumonia, fever, erythema, visual and auditory hallucinations were often noted.

In elderly patients with psychosis on the background of parkinsonism, there was a worsening of the course of Parkinson's disease and hallucinations. In combination therapy with lithium or sodium valproate preparations, an increase in body weight was observed.

During clinical trials, the following adverse reactions were noted:

• ataxia, dysarthria;
• withdrawal syndrome: vomiting, nausea, diarrhea;
• jaundice;
• allergic anaphylactic reactions;
• hives and itching;
• tremor of the limbs and speech disorders;
• hallucinations;
• gait disturbances.

Adverse reactions are more common in elderly patients, as well as in combined treatment with drugs based on lithium or sodium valproate.

Pregnant women

There are no clinical data on the use of the drug during pregnancy. Women should tell their doctor if they are or are planning to conceive during treatment with olanzapine. It is recommended to use the medicine only if the expected benefit outweighs the potential risk.

In very rare cases, tremors, drowsiness and hypertension have been reported in newborns whose mothers took the drug during the third trimester of pregnancy. Digestive disorders and respiratory distress syndrome have also been observed, so observation is necessary.

Lactation

The drug is able to penetrate into breast milk. And although its concentrations are only 1.5% of the dosage taken by the mother, it is recommended to stop breastfeeding for the period of treatment and transfer the child to artificial mixtures if therapy is necessary.

drug interaction

The pharmacokinetics of the drug may be affected by substances that inhibit or increase the activity of liver enzymes. Carbamazepine and fluvoxamine can lead to an increase in the concentration of olanzapine in the blood, as they inhibit the enzymes responsible for the metabolism of olanzapine. With simultaneous use, it is necessary to reduce the dosage of Olanzapine and monitor the patient's condition.

Reduced bioavailability

Activated charcoal reduces the bioavailability of the drug by half, so these drugs should be separated in time of administration with an interval of two hours. Fluoxetine or antacids do not affect the absorption of olanzapine.

The effect of olanzapine on other drugs

Olanzapine is able to reduce the effectiveness of dopamine agonists. No interactions were found with tricyclic antidepressants, theophylline, diazepam and warfarin.

Olanzapine did not show interaction with the parallel use of lithium or biperidone preparations, did not affect the concentration of valproate in the blood plasma.

Action on the CNS

Caution should be exercised in the use of the drug in patients who consume alcohol or drugs that exhibit sedative effects on the central nervous system.

Application features

The therapeutic effect can be achieved in the range from several days to weeks. During this period, patients require careful monitoring. Treatment should be continued even after the symptoms of psychotic disorders have disappeared.

Psychosis on the background of dementia

Olanzapine is not intended for the treatment of psychosis associated with dementia or behavioral disorders. This group of patients has an increased risk of death and stroke.

Sudden Death Syndrome is not dose related. Risk factors that increase mortality in this group of patients:

• elderly age;
• sedation;
• digestive disorders;
• respiratory disorders;
• the use of benzodiazepines.

In the same group, the risk of such side effects as short-term cerebrovascular accidents, stroke, including deaths, is increased.

Parkinson's disease

For the treatment of psychosis on the background of parkinsonism in an elderly group of patients, it is advisable to choose other drugs that are not based on the active substance olanzapine.

Malignant neuroleptic syndrome

This condition is potentially life-threatening and has been reported in rare cases following treatment with olanzapine. Symptomatic manifestations of the syndrome:

• overexertion, muscle hardness;
• change in mental state;
• irregular pulse and blood pressure;
• tachycardia;
• cardiac arrhythmia;
• increased sweating.

There is also acute renal failure. If the patient has symptoms of neuroleptic malignant syndrome, all antipsychotic drugs, including olanzapine, should be discontinued.

Diabetes

In rare cases, patients showed an increase in the concentration of glucose in the blood, an exacerbation of diabetes. These conditions may be associated with ketoacidosis and hyperglycemic coma. In some cases, deaths are possible. A risk factor is weight gain due to diabetes.

Constant monitoring of blood glucose levels is necessary in patients who suffer from diabetes mellitus or complain of symptoms characteristic of hyperglycemia.

Change in lipid levels

Undesirable changes in the concentration of lipids in the blood are possible. Patients on antipsychotic therapy should have ongoing laboratory testing of blood lipid levels.

The treatment of this condition is selected in accordance with which lipids are excessively elevated in the blood.

liver function

Often there is an increase in the concentration of hepatic transaminases, especially at the beginning of treatment. Caution should be exercised in those patients who already have such disorders in their medical history.

Vigilance is necessary if patients are simultaneously taking drugs that have a toxic effect on the liver. If hepatitis is diagnosed, treatment with olanzapine should be discontinued.

Neutropenia

Caution is needed in the treatment of patients who suffer from neutropenia, leukopenia or take drugs that provoke these conditions. It is also necessary to control if the patient has drug depression and toxic effects on bone tissue in the history of the disease.

When undergoing radiation or chemotherapy, with myeloproliferative syndrome, monitoring of the condition and a qualitative blood test are necessary.

Termination of treatment

With the sudden cancellation of Olanzapine, in rare cases, an abstinence syndrome develops. It is accompanied by symptoms such as indigestion, tremors of the limbs, insomnia and excessive sweating.

If these signs are found, it is necessary to return to the previous treatment regimen with Olanzapine and gradually reduce the dosage until it is completely canceled within two weeks.

Thromboembolism, effects on the central nervous system

The association between venous thromboembolism and olanzapine is rare. Since patients with schizophrenia often have risk factors for venous thromboembolism, measures should be taken to reduce the risk of thrombosis.

Caution must be exercised in the use of olanzapine with alcohol or drugs that act on the central nervous system.

Convulsions, dyskinesia

Olanzapine should be used with caution in patients with a history of convulsions or a reduced threshold for convulsions. The drug may be associated with a risk of tardive dyskinesia, especially with long-term treatment.

If symptoms of this pathology are detected in a patient taking olanzapine, the option of reducing the dosage or completely discontinuing the drug should be considered. Symptoms may increase temporarily, even after discontinuation of therapy.

Sudden cardiac arrest

The risk of sudden cardiac arrest is twice as high in patients taking antipsychotic drugs as compared to healthy volunteers. Sudden cardiac arrest has been rarely reported.

Olanzapine contains aspartame, which can be harmful to people with PKU.

Drug analogues

Analogues for the active substance:

• Adagio;
• Zalasta;
• Zyprexa;
• Zolaphren;
• Olanklein;
• Parnasan;
• Egolanza.

Analogues by pharmacological group and effect on the body:

• Azaleptin;
• Azapine;
• Azaleptol;
• Clozapine;
• Leponex;
• Hedonin;
• Quetipin;
• Quetixol.

When choosing an analogue, it is imperative to consult with your doctor so that he takes into account all the features of the course of the disease and prevents the development of side effects by prescribing an adequate treatment regimen.

Conclusion

Olanzapine is an effective antipsychotic drug. However, its use in an inadequate treatment regimen is associated with a high risk of severe side effects. To prevent them, you must consult a doctor and do not self-medicate.

Latin name: Olanzapine
ATX code: N05AH03
Active substance: Olanzapine (Olanzapine)
Manufacturer: ALSI Pharma AO (Russia)
Vacation from the pharmacy: on prescription
Storage conditions: up to 25 degrees
Best before date: 2 years.

Description, olanzapine tablets is an antipsychotic medicine (atypical antipsychotic). It has a psychopharmacological effect with an antidepressant effect. Antipsychotics have appeared in medicine relatively recently; previously, herbal preparations or intravenous administration of calcium and bromide were used in the treatment of psychosis.

Indications for use

• Schizophrenia
• Manic episodes of any degree
• Psychotic disorders on the background of affective disorders
• Therapy for resistant depression. In combination with fluoxetine.

Composition and forms of release

1 tablet contains 5 mg of the active substance of the same name. Additional substances: lactose - 50.6 mg, cellulose - 51.4 mg, starch - 51.4 mg, colloidal silicon dioxide - 0.8 mg, magnesium stearate - 0.8 mg, calcium stearate.

Tablets are yellow, round, biconvex.

10 tablets in a cell package, together with the instructions, are placed in a box.

Pharmacological properties

Neuroleptic Olanzapine - has an extensive therapeutic effect on the nervous system. As a result of the research, an analogy of olanzapine with serotonin 5-HT2A/C, 5HT3, 5HT6 was revealed; dopamine Dl, D2, D3, D4, D5; muscarinic M1-5; adrenergic αl and histamine III receptors.

Materials of electrophysiological studies have shown that olanzapine selectively weakens the irritability of mesolimbic (A10) dopaminergic neurons, imperceptibly affects the striatal (A9) nerve pathways involved in the regulation of motor functions.

Therapy with olanzapine reduces productive (delusions, hallucinations, suspicion) and negative (emotional and social autism) disorders, reduces aggressiveness and eliminates emotional experiences.

After use, it is absorbed and absorbed from the gastrointestinal tract. Absorption of the drug does not depend on food intake. Pharmacological activity occurs within 5-8 hours. The intensity of the drug in plasma varies linearly and according to the dose.

Olanzapine is metabolized in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide.

Method of application and dosage

Agonists are used to treat acute mania and prescribe 15 mg of the drug 1 time per day or 10 mg 1 time per day in combination with lithium preparations or with a dose of basic wolprenic acid.

Price: from 136 rubles.

With depression on the background of bipolar disorder, 1 time per day simultaneously with Fluoxetine at a dose of 20 mg.

For elderly patients and patients with risk factors (with chronic kidney or liver failure), the dose is 5 mg per day.

Contraindications: hypersensitivity to the components of the drug, age under 18, lactose intolerance.

Precautions: liver and kidney failure, epilepsy, convulsive syndrome, paralytic ileus, pregnancy, old age, taking with other drugs of central action.

Use in pregnancy and lactation: As a result of the lack of experience with the use of olanzapine during pregnancy, the drug is prescribed if the potential benefit to the mother significantly outweighs the potential risk to the fetus.

Side effects

Tendency to sleep, weight gain, increased appetite, dizziness, arterial hypotension, odor and dry mouth, swelling. If any of these symptoms worsen or side effects occur, tell your doctor immediately.

Overdose

It is expressed in excitation, tachycardia, aggressiveness, impaired consciousness, convulsions, arrhythmias, increased or decreased pressure, cardiac or respiratory arrest.

Interaction with other drugs

Ethanol enhances the inhibitory effect on the central nervous system.

Activated charcoal and antacids reduce absorption.

Carbamazepine accelerates clearance.

Fluvoxamine increases the level of olanzapine in the blood.

Analogues

Latin name: Zalasta

Active ingredient: Olanzapine (Olanzapine)

Producer: KRKA POLSKA, Sp.z.o.o (Poland)

Price: from 937 rubles

Ingredients: Olanzapine, cellactose, pregelatinized starch, colloidal anhydrous silica, corn starch, magnesium stearate.

Release form: Tablet.

Pharmacological action: Antipsychotic.

Indications for use: Therapy of schizophrenia and prevention of relapse in bipolar disorder.

Advantages: Zalasta is a drug with a pronounced antipsychotic effect, highly effective against both positive and negative symptoms. The effect of the drug in the treatment of exacerbations in patients with schizophrenia is better than that of traditional antipsychotics.

Flaws: causes a very strong appetite, which leads to rapid weight gain, drowsiness.

Latin name: Kventiax

Active ingredient: Quetiapine (Quetiapine)

Producer: KRKA-Rus, Russia

Price: from 1700 rubles

Ingredients: The active ingredient is quetiapine fumarate.

Release form: tablets.

Pharmacological action: antipsychotic.

Medicinal property: The positive therapeutic effect lasts more than 12 hours.

Indications for use: acute and chronic forms of psychosis (schizophrenia); manic episodes in bipolar disorder and panic attacks.

Pros:

The unique scheme of therapy with a gradual increase and then a decrease in the dose, gives the effectiveness of treatment in all cases. In comparison with other analogues, the use of this tool is accompanied by fewer side effects.

Minuses:

Due to the high cost of the drug, it is difficult to buy; disrupts metabolism.

Gross formula

Pharmacological group of the substance Olanzapine

Nosological classification (ICD-10)

CAS code

Characteristics of the substance Olanzapine

Atypical neuroleptic of the thienobenzodiazepine class. Yellow crystalline substance, practically insoluble in water.

Pharmacology

It has a high affinity for serotonin 5-HT 2A (dissociation constant K i = 4 nM) and 5-HT 2C (K i = 11 nM), dopamine D 1-4 (K i = 11-31 nM), muscarinic M 1- 5 (K i = 1.9-25 nM), histamine H 1 (K i = 7 nM) and alpha 1 -adrenergic receptors (K i = 19 nM). Weakly interacts with GABA A, benzodiazepine and beta-adrenergic receptors (K i more than 10 µM). In conditions in vitro and in vivo has a more pronounced affinity and activity for 5-HT 2 receptors in comparison with D 2 receptors. According to electrophysiological studies, it selectively lowers the excitability of mesolimbic dopaminergic neurons, has a slight effect on the striatal nerve pathways involved in the regulation of motor functions. Antipsychotic effect due to blockade of serotonin 5-HT 2 - and dopamine receptors, anticholinergic effects - blockade of M 1 -5-cholinergic receptors, drowsiness - influence on histamine H 1 -receptors, orthostatic hypotension - blockade of alpha 1 -adrenergic receptors.

Eliminates the productive symptoms of psychosis (delusions, hallucinations, thought disorders, hostility, suspicion), smoothes out negative symptoms (emotional and social autism, introversion, poverty of speech). It dulls the sharpness of emotional experiences, weakens the aggressiveness and impulsiveness of behavioral reactions, forms tolerance for the surrounding reality and reduces initiative. Stops excitement and corrects behavioral and mental disorders in patients with mental disorders. Reduces the conditioned protective reflex (a test that characterizes antipsychotic activity) at doses lower than doses that cause catalepsy. It is effective, especially at doses of 20-60 mg / day, in cases of schizophrenia refractory to therapy with typical antipsychotics: the effect gradually develops by the end of 2 months of treatment and then rapidly increases, reaching a maximum by the end of 4 months of therapy. There is evidence of efficacy in depressive-delusional syndrome. Causes hyperprolactinemia (with prolonged use), extrapyramidal disorders (rarely, mainly when using high doses), weight gain (450 g / week or more), which may persist after treatment is stopped.

Well absorbed from the gastrointestinal tract, food intake does not affect the speed and completeness of absorption. Bioavailability is reduced by 40% due to the effect of "first pass" through the liver. Cmax is achieved after 5-8 hours. Steady-state concentration is reached after 1 week of daily intake and is twice the plasma concentration after a single dose. Plasma concentration in the dose range of 1-20 mg varies linearly and is proportional to the dose. Plasma protein binding - 93% (mainly with albumin and alpha 1-acid glycoprotein). Passes through histohematic barriers, including the BBB. The volume of distribution is about 1000 liters. Biotransformed in the liver with the participation of isoenzymes CYP1A2 and CYP2D6 and flavin-containing monooxygenases to 10-N-glucuronide (44%) and 4-N-desmethylolanzapine (31%). Both metabolites are pharmacologically inactive at plasma concentrations generated over the therapeutic dose range of olanzapine. Slightly affects cytochrome P450 enzymes (the risk of unwanted pharmacokinetic interactions with other drugs is negligible). T 1/2 depends on age and is 49-55 hours in patients over 65 years old, 29-39 hours younger than 65 years old. Plasma clearance is 12-47 l / h (average 25 l / h) and decreases by 1, 5 times in people over 65 years of age (compared to young people), 30% in women (compared to men), 40% in non-smokers (compared to smokers) and with impaired liver function. It is excreted by the kidneys (57%, unchanged - 7%) and intestines (30%). Not excreted by dialysis (due to the large volume of distribution and the high degree of binding to plasma proteins).

Carcinogenicity studies in mice and rats treated with olanzapine at doses 0.13-5 times the MRHD for 78 weeks to 2 years have shown an increase in the incidence of hemangioma and hemangiosarcoma of the liver (2-5 times the MRHD), adenoma and breast adenocarcinomas (0.5-2 MRDC) associated with hyperprolactinemia. Reversible neutro- and lymphopenia, hemolytic anemia, and a decrease in the rate of weight gain were noted. No mutagenic properties were found. Impaired fertility in male and female rats was detected at 11- and 1.5-fold excess of MRH, respectively. In female rats and rabbits treated during pregnancy with olanzapine at doses 9 and 30 times, respectively, higher than the MRDC, teratogenic properties were not detected. Early resorption of fetuses, a decrease in body weight and an increase in the number of non-viable fetuses were noted; duration of pregnancy was prolonged at a 5-fold excess of MRHD. It is excreted in the breast milk of rats (there is no data on excretion in human milk).

The use of the substance Olanzapine

Schizophrenia and other psychotic disorders with severe productive and negative symptoms, affective disorders (treatment of exacerbations, maintenance and long-term anti-relapse therapy), acute manic or mixed seizures in bipolar affective disorder with / without psychotic manifestations, with / without rapid phase change.

Contraindications

Hypersensitivity, breastfeeding.

Application restrictions

Renal and / or liver failure, benign prostatic hypertrophy, history of seizures, Parkinson's disease, cerebrovascular disorders, Alzheimer's disease, diabetes mellitus, eosinophilia, myeloproliferative diseases, paralytic ileus, angle-closure glaucoma, concomitant use of drugs that lengthen the QT interval (especially in old age), dehydration, hypovolemia, history of myocardial infarction, heart failure, breast cancer, incl. history, pregnancy, age up to 18 years (safety and efficacy not established).

Use during pregnancy and lactation

During pregnancy - with caution, comparing the intended benefit to the mother and the potential risk to the fetus.

At the time of treatment should stop breastfeeding.

Side effects of olanzapine

From the nervous system and sensory organs: dizziness, headache, migraine, weakness, asthenia, drowsiness, insomnia, anxiety, hostility, agitation, euphoria, amnesia, depersonalization, phobia, obsessive-compulsive symptoms, neuralgia, facial nerve paresis, hypoesthesia, extrapyramidal disorders, incl. tardive dyskinesia, ataxia, neck stiffness, muscle twitching, tremor, akathisia, dysarthria, stuttering, syncope, delirium, suicidal tendencies, stupor, coma, subarachnoid hemorrhage, stroke, nystagmus, diplopia, mydriasis, pigment deposition in the lens, cataract, xerophthalmia, hemorrhages in the eye, disturbance of accommodation, amblyopia, glaucoma, corneal damage, eye pain, keratoconjunctivitis, blepharitis, noise and pain in the ears, deafness, impaired taste sensations.

From the side of the cardiovascular system and blood (hematopoiesis, hemostasis): orthostatic hypotension, tachy- and bradycardia, palpitations, ventricular premature beats, ECG changes, cardiac arrest, cyanosis, vasodilation, transient leuko- and neutropenia, eosinophilia, leukocytosis, thrombocytopenia, hemorrhagic syndrome.

From the respiratory system: rhinitis, pharyngitis, laryngitis, voice change, increased cough, dyspnea, apnea, bronchial asthma, hyperventilation.

From the digestive tract: increased appetite up to bulimia, thirst, dry mouth, increased salivation, aphthous stomatitis, gingivitis, glossitis, dysphagia, belching, esophagitis, nausea, vomiting, gastritis, gastroenteritis, enteritis, melena, rectal bleeding, constipation, flatulence, fecal incontinence, transient increase in the activity of hepatic transaminases, gamma-glutamyl transpeptidase and creatine phosphokinase, hepatitis.

From the side of metabolism: hyperprolactinemia, increase (rarely decrease) in body weight, diabetes mellitus, hyperglycemia, diabetic ketoacidosis, diabetic coma, goiter.

From the genitourinary system: dysuria (including polyuria), hematuria, pyuria, albuminuria, urinary incontinence, urinary tract infections, cystitis, decreased libido, impotence, ejaculation disorders, priapism, gynecomastia, galactorrhea, pain in the mammary glands, uterine fibrosis, premenstrual syndrome, meno- and metrorrhagia, amenorrhea.

From the musculoskeletal system: arthritis, arthralgia, bursitis, myasthenia gravis, myopathy, calf muscle cramps, bone pain.

From the side of the skin: photosensitivity, alopecia, hirsutism, dry skin, eczema, seborrhea, contact dermatitis, skin ulcers, discoloration of the skin, maculopapular rash.

Allergic reactions: hives.

Others: fever, chills, flu-like syndrome, lymphadenopathy, chest or abdominal pain, peripheral edema, withdrawal syndrome, abuse possible.

Interaction

Activated charcoal (1 g) reduces C max and AUC by 60%. A single dose of cimetidine (800 mg) or aluminum- and magnesium-containing antacids does not affect the bioavailability of olanzapine. Carbamazepine (400 mg/day) increases clearance by 50%. Activity inducing drugs CYP1A2 and glucuronyl transferase (omeprazole, rifampicin, etc.), increase the excretion of olanzapine; inhibitors CYP1A2(fluvoxamine, etc.) reduce it. Fluoxetine (60 mg once or 60 mg daily for 8 days) increases Cmax of olanzapine by 16% and reduces its clearance by 16%. Clinical trials have shown that a single administration of olanzapine during therapy with imipramine, desipramine, warfarin, theophylline or diazepam was not accompanied by suppression of the metabolism of these drugs. There were no signs of drug interaction when combined with lithium or biperiden. Against the background of the equilibrium concentration of olanzapine, no changes in the pharmacokinetics of ethanol were noted; when taken simultaneously, it is possible to increase the pharmacological effects of olanzapine, in particular the sedative effect. When taken simultaneously with diazepam, ethanol and antihypertensive agents, the risk of developing orthostatic hypotension increases. Enhances the effect of anticholinergics. Weakens the effect of levodopa and other dopamine receptor agonists. The likelihood of an increase in the level of hepatic transaminases increases when taken simultaneously with hepatotoxic drugs. A clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely.

Overdose

Symptoms: nausea, aspiration, agitation, aggressiveness, drowsiness, speech confusion, extrapyramidal disorders, respiratory failure (depression of the respiratory center), arterial hyper- or hypotension, tachycardia, arrhythmia, cardiac and respiratory arrest, impaired consciousness, CNS depression (from sedation to coma ), delirium, convulsions, neuroleptic malignant syndrome. The minimum dose for acute overdose with a fatal outcome was 450 mg, the maximum dose for overdose with a favorable outcome (survival) was 1500 mg.

Treatment: gastric lavage (artificially inducing vomiting is not recommended), taking activated charcoal, laxatives, ECG monitoring, maintaining vital functions, mechanical ventilation. There is no specific antidote. Dialysis is ineffective. If necessary, vasopressor therapy should avoid prescribing dopamine, epinephrine and other sympathomimetics (increased hypotension due to the summation of the effects of beta-agonists and alpha-adrenergic blocking action of olanzapine).

Routes of administration

inside.

Olanzapine Substance Precautions

With a combination of factors that slow down the metabolism of olanzapine (female patients, senile age, non-smokers), a reduced dosage should be used. Careful monitoring of patients with suicidal tendencies is required, especially at the beginning of treatment. During treatment, the activity of hepatic transaminases should be regularly monitored, especially in patients with impaired liver function. It is prescribed with caution to drivers of vehicles and people whose activities require an increased concentration of attention and speed of psychomotor reactions. During the treatment period, alcohol intake is excluded. If symptoms of neuroleptic malignant syndrome appear (fever, muscle tension, akinesia, tachycardia, leukocytosis, increased creatine phosphokinase), immediate withdrawal of the drug is necessary. Given the possibility of developing akathisia, when motor restlessness, restlessness, and a constant desire to move appear during treatment, it is necessary to reduce the dose and prescribe antiparkinsonian drugs.