Zyprexa Zidis, 28 pcs., 5 mg, dispersible tablets

Pharmacological properties of the drug Zyprexa tablets

Olanzapine is an antipsychotic drug (neuroleptic) with a wide pharmacological spectrum of action due to its effect on a number of receptor systems. The affinity of olanzapine for serotonin 5-HT2A/C-, 5-HT3-, 5-HT6-, dopamine D1-, D2-, D3-, D4-, D5-, muscarinic M1-, M5-, α1-adrenergic and histamine H1 receptors. During experiments studying the effect of olanzapine on the behavior of animals, the presence of olanzapine antagonism in relation to both serotonin 5-HT and dopamine and cholinergic receptors was revealed. Under in vitro and in vivo , olanzapine has a more pronounced affinity and activity for serotonin 5-HT2 receptors compared to dopamine D2 receptors. According to electrophysiological studies, olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, and at the same time has a slight effect on striatal (A9) nerve pathways involved in the regulation of motor functions. Olanzapine inhibits the conditioned defense reflex, which indicates its antipsychotic activity at lower doses than at doses that cause catalepsy (a disorder reflecting side effects on motor function). Two placebo-controlled and two of three comparative controlled studies involving 2900 patients with schizophrenia showed that olanzapine provided a statistically significant reduction in both productive and negative disorders. Pharmacokinetics. After oral administration, olanzapine is well absorbed and its maximum plasma concentration is reached after 5–8 hours. The absorption of olanzapine does not depend on food intake. In clinical studies examining doses ranging from 1 to 20 mg, olanzapine plasma concentrations were shown to be linear and dose proportional. Olanzapine is metabolized in the liver as a result of conjugation and oxidation processes. The main circulating metabolite is 10-N-glucuronide, which does not cross the BBB. Cytochrome P450 isoenzymes CYP 1A2 and CYP 2D6 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Both metabolites had significantly less pharmacological activity than olanzapine in vivo The main pharmacological activity of the drug is due to the parent substance - olanzapine. After oral administration, the mean elimination half-life of olanzapine in healthy patients is 33 hours (range 21 to 54 hours for 5 and 95%), and the mean plasma clearance of olanzapine is 26 L/h (range 12 to 47 L/h for 5 and 95). %). The pharmacokinetics of olanzapine varies depending on gender, age and whether the patient smokes. The specified data is summarized in the table:

Therefore, smoking, gender and age may influence olanzapine clearance and half-life. The degree of influence of these factors is less pronounced than the interindividual differences in these indicators. In patients with minor renal impairment and practically healthy individuals, there is no significant difference between the average values ​​of the half-life and clearance of the drug. About 57% of olanzapine is excreted in the urine, mainly in the form of metabolites. In smokers with mild hepatic impairment, the clearance of olanzapine is lower than in non-smokers without hepatic impairment. At plasma concentrations from 7 to 1000 ng/ml, about 93% of olanzapine is bound to plasma proteins. Olanzapine binds primarily to albumin and α1-acid glycoprotein. There were no differences in the pharmacokinetics of olanzapine due to race. The CYP 2D6 isoform of cytochrome P450 does not affect the metabolism of olanzapine.

Zyprexa

Antipsychotic (neuroleptic). Has affinity for serotonin 5-HT2A/C-, 5-HT3-, 5-HT6 receptors; dopamine D1-, D2-, D3-, D4-, D5 receptors; M1-5 cholinergic receptors; α1-adrenergic receptors and histamine H1 receptors. Shows antagonism towards serotonin 5-HT, dopamine and cholinergic receptors.

Under in vitro and in vivo conditions, it has a more pronounced affinity and activity for serotonin 5-HT2 receptors compared to dopamine D2 receptors. According to electrophysiological studies, olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons and, at the same time, has a slight effect on striatal (A9) nerve pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned defense response (a test that measures antipsychotic activity) at lower doses than required to achieve catalepsy (a disorder that reflects side effects on motor function). Unlike other neuroleptics, olanzapine enhances the anti-anxiety effect during the anxiolytic test.

When using olanzapine, both productive (including delusions, hallucinations) and negative disorders decrease.

Pharmacokinetics

After oral administration, olanzapine is well absorbed from the gastrointestinal tract, Cmax in plasma is reached after 5-8 hours. Plasma concentrations of olanzapine have a linear dependence on the dose (ranging from 1 to 20 mg). Eating does not affect the absorption of olanzapine.

At plasma concentrations from 7 to 1000 ng/ml, binding to plasma proteins is about 93%.

Olanzapine is metabolized in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which theoretically does not cross the BBB. Isoenzymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Experimental studies in animals have shown that these metabolites have significantly less pronounced pharmacological activity in vivo than olanzapine. The main pharmacological activity is due to unchanged olanzapine.

The activity of the CYP2D6 isoenzyme does not affect the level of metabolism of olanzapine.

In healthy volunteers, after oral administration, the half-life of olanzapine is 33 hours (21-54 hours), and the average plasma clearance is 26 l/h (12-47 l/h).

About 57% of radiolabeled olanzapine is excreted in the urine, mainly as metabolites.

The pharmacokinetic parameters of olanzapine vary depending on gender, age, and the presence of smoking habits (table):

However, the degree of changes in T1/2 and plasma clearance under the influence of each of these factors is significantly inferior to the degree of individual differences in these indicators.

There were no significant differences between the mean values ​​of T1/2 and plasma clearance of olanzapine in patients with severely impaired renal function compared with individuals with normal renal function.

In smoking patients with minor hepatic impairment, the plasma clearance of olanzapine is lower than in non-smokers without such impairment.

Indications for use of Zyprexa tablets

Olanzapine is indicated for the treatment of exacerbations and as maintenance therapy for schizophrenia and other psychoses with severe positive (delusions, hallucinations, thought disorders, hostility and suspiciousness) and/or negative symptoms (for example, flattened affect, emotional and social isolation, poverty of speech). Olanzapine also reduces the severity of secondary mood symptoms commonly associated with schizophrenia and similar disorders. Olanzapine is effective in maintaining clinical improvement with long-term therapy in patients who respond to initial therapy. Olanzapine, as monotherapy or in combination with lithium or valproate, is indicated for the treatment of acute manic or mixed episodes in bipolar disorder, with or without psychotic features, as well as rapid cycling. Olanzapine is indicated to reduce the severity of manic, mixed or depressive episodes in bipolar disorders and prolong the interictal period. Olanzapine in combination with fluoxetine is indicated for the treatment of depressive episodes occurring in bipolar disorder.

Use of Zyprexa tablets

Schizophrenia and related disorders: The recommended starting dose of olanzapine is 10 mg once daily with or without food, as absorption of the drug is not affected by food. The dosage range for olanzapine is 5–20 mg per day. The daily dose should be determined based on an assessment of the clinical status. Increasing the recommended starting dose above 10 mg is possible only after a clinical examination. Acute mania in bipolar disorder: The recommended starting dose of olanzapine as monotherapy is 15 mg per day or 10 mg per day in combination with lithium or valproate. This dose is prescribed regardless of food intake, since food intake does not affect the absorption of the drug. The dosage range for olanzapine is 5–20 mg per day. The daily dose should be determined based on an assessment of the clinical status. An increase in the recommended starting dose is possible only after clinical evaluation and should be carried out sequentially at intervals of at least 24 hours. Maintenance therapy for bipolar disorder: In patients who received olanzapine for the treatment of acute mania, maintenance therapy for bipolar disorder should be continued at the same dose. For patients in remission, the recommended starting dose of olanzapine is 10 mg per day. The subsequent daily dose is determined based on clinical status in the range of 5–20 mg per day. Olanzapine is prescribed regardless of food intake, as it does not affect the absorption of the drug. Bipolar depression: Olanzapine in combination with fluoxetine is prescribed once daily with or without food, usually starting with 5 mg olanzapine and 20 mg fluoxetine. The effectiveness of olanzapine as an antidepressant was demonstrated in the dose range of 6–12 mg (mean daily dose 7.4 mg) and fluoxetine 25–50 mg (mean daily dose 39.3 mg) in two clinical studies. Dose adjustment, if necessary, can be carried out for each drug separately (olanzapine, fluoxetine). General data regarding oral use in certain populations: at a reduced initial daily dose of 2.5–5 mg, the drug can be prescribed to elderly patients or in the presence of other clinical factors. An initial dose of 5 mg is recommended in patients with severe renal or moderate hepatic impairment, as well as in patients with a combination of factors (female gender, older age, smoking) that may reduce the metabolism of olanzapine. The effect of olanzapine in patients under 18 years of age has not been studied.

Side effects of Zyprexa tablets

In clinical studies, the most common (≥10 % ) side effects associated with olanzapine were somnolence and weight gain. An increase in plasma prolactin concentrations was observed in 34% of patients taking olanzapine, but the increase was moderate and transient (the final value did not exceed the upper limits of normal and was statistically insignificantly different from that with placebo), and clinical manifestations of hyperprolactinemia (for example, gynecomastia, galactorrhea, enlarged mammary glands) were rarely noted. In most patients, normalization of prolactin levels occurred without discontinuation of the drug. Common (≤10% but ≥1%) adverse effects associated with olanzapine included dizziness, asthenia, akathisia, increased appetite, peripheral edema, orthostatic hypotension, dry mouth, and constipation. Occasionally, a transient asymptomatic increase in the activity of liver transaminases (ALAT and AST) and eosinophils was detected. In clinical studies of patients with a baseline plasma glucose level of ≤140 mg/dL, isolated cases of increased glucose levels of both ≥200 mg/dL (probable diabetes mellitus) and ≥160 mg/dL but ≤200 mg/dL (probable diabetes mellitus) were observed. hyperglycemia). Rarely (≤1% and ≥0.01%) side effects such as photosensitivity and bradycardia were noted. Very rarely (≤0.1%, but ≥0.01%) hepatitis, leukopenia, seizures, skin rash are possible; extremely rare (≤0.01%) - allergic reactions, withdrawal syndrome, venous thromboembolism, jaundice, pancreatitis, thrombocytopenia, diabetic ketoacidosis, diabetic coma, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, rhabdomyolysis, priapism, increased alkaline phosphatase and bilirubin. Adverse effects in selected populations In clinical trials, patients with drug-induced (dopamine agonist) psychosis associated with Parkinson's disease were significantly more likely to experience an increase in symptoms compared to placebo. Hallucinations were also reported very frequently compared to placebo. During clinical trials, the most common (≥10%) adverse effects associated with olanzapine in elderly patients with dementia-associated psychosis were gait disturbance and falls; common (≤10% but ≥1%) are urinary incontinence and pneumonia. Very common (≥10%) side effects in patients with bipolar disorder receiving olanzapine in combination with lithium or valproate were weight gain, dry mouth, increased appetite and tremor, common (10% but ≥1%) were also speech disorders.

Zyprexa®

Clinical improvement with antipsychotic treatment may take several days to several weeks and requires careful monitoring of the patient.

Suicide

The risk of suicide attempts in patients with schizophrenia and bipolar disorder type 1 is determined by these diseases themselves. In this regard, during pharmacotherapy, careful monitoring of those patients whose risk of suicide is especially high is required. When prescribing olanzapine, efforts should be made to minimize the number of tablets taken by the patient in order to reduce the risk of overdose.

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) can develop during treatment with any antipsychotic drug, including olanzapine. Clinical manifestations of neuroleptic malignant syndrome include significant increase in body temperature, muscle rigidity, changes in mental status and autonomic disturbances (unstable pulse or blood pressure, tachycardia, arrhythmias, increased sweating). Additional features may include increased creatine phosphokinase activity, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of neuroleptic malignant syndrome or a significant unexplained increase in body temperature without other symptoms of neuroleptic malignant syndrome require discontinuation of all antipsychotics, including olanzapine.

Tardive dyskinesia

In comparative studies lasting more than 6 weeks, treatment with olanzapine was significantly less likely to be accompanied by the development of dyskinesia requiring drug correction than the use of haloperidol. However, the increased risk of tardive dyskinesia should be taken into account with long-term therapy with antipsychotics. If signs of tardive dyskinesia develop, it is recommended to reduce the dose or discontinue olanzapine. Symptoms of tardive dyskinesia may increase or manifest after discontinuation of the drug.

Psychosis associated with dementia and/or conduct disorders

Olanzapine is not indicated for the treatment of psychosis associated with dementia and/or behavioral disorders and is not recommended for use in this group of patients due to the high mortality rate and risk of cerebrovascular accidents. In placebo-controlled studies (duration 6-12 weeks) in elderly patients (mean age 78 years) with psychosis associated with dementia and/or conduct problems, there was a two-fold higher incidence of death in patients in the olanzapine group compared with those in the olanzapine group. placebo group (3.5% and 1.5%, respectively). The higher mortality rate was not associated with the dose of olanzapine (mean dose 4.4 mg) or duration of treatment. Risk factors that may predispose this group of patients to higher mortality when treated with olanzapine include age ≥ 65 years, dysphagia, sedation, malnutrition (wasting), dehydration, concomitant use with benzodiazepines, or the presence of pulmonary pathology (eg, pneumonia with with or without aspiration).

Cerebrovascular adverse events (eg, stroke, transient ischemic attack), including deaths, were observed in the same studies of olanzapine in elderly patients. In placebo-controlled studies, there was a threefold higher incidence of cerebrovascular adverse events in patients in the olanzapine group compared with the placebo group (1.3% versus 0.4%, respectively). All patients with cerebrovascular disorders had previous risk factors for the development of cerebrovascular adverse events: age ≥75 years, vascular or mixed dementia, a previous case of cerebrovascular adverse event or transient ischemic attack, arterial hypertension, smoking, as well as concomitant diseases and/or medications, temporally associated with cerebrovascular adverse events. The effectiveness of olanzapine was not established in these studies.

Parkinson's disease

The use of olanzapine is not recommended in the treatment of psychosis induced by dopamine receptor agonists in Parkinson's disease.

In clinical trials in patients with drug-induced psychosis (dopamine receptor agonist) for Parkinson's disease, increased parkinsonian symptoms and hallucinations were very common (≥10%) and at a higher frequency than in the placebo group. Olanzapine was not superior to placebo in treating psychotic symptoms in patients with Parkinson's disease. In these clinical studies, patients were required to take antiparkinsonian drugs (dopamine agonists) at the lowest effective dose and continue to take them at the same dose throughout the study. The starting dose of olanzapine was 2.5 mg per day and could be increased to 15 mg per day as recommended by the physician.

Liver dysfunction

In some cases, taking olanzapine, usually in the early stages of therapy, was accompanied by a transient, asymptomatic increase in hepatic aminotransferases (aspartate aminotransferase and alanine aminotransferase) in the blood serum. Rare cases of hepatitis have been reported. In very rare cases, hepatic cholestasis and other associated liver damage have been observed. Particular caution is required when serum aspartate aminotransferase and/or alanine aminotransferase activity increases in patients with impaired liver function, with limited liver functional reserve, or in patients receiving treatment with potentially hepatotoxic drugs.

Hyperglycemia and diabetes mellitus

Patients with schizophrenia have a higher prevalence of diabetes. As with some other antipsychotic drugs, cases of hyperglycemia, diabetes, exacerbation of pre-existing diabetes, ketoacidosis and diabetic coma have been reported. Close clinical monitoring of patients with diabetes and patients with risk factors for developing diabetes is recommended according to the following guidelines: measurement of blood glucose concentrations at baseline, 12 weeks after starting olanzapine, and annually thereafter. Patients taking antipsychotic drugs, including Zyprexa®, should be monitored for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, weakness). Patients with diabetes mellitus or risk factors for diabetes mellitus require regular monitoring of blood glucose concentrations. Regular monitoring of body weight is necessary: ​​before starting treatment, 4, 8 and 12 weeks after starting olanzapine, and subsequently every 3 months.

Change in lipid profile

During placebo-controlled studies, undesirable lipid changes were observed in patients receiving olanzapine (see Adverse Reactions), especially in patients with dyslipidemia and in patients with risk factors for developing lipid disorders. Patients taking antipsychotic medications, including Zyprexa, should have their lipid profiles monitored regularly as recommended: before starting treatment, 12 weeks after starting olanzapine, and every 5 years thereafter.

Sudden cardiac death

Sudden deaths have been reported in post-marketing surveillance of olanzapine. A retrospective observational study found an approximately twofold increase in the risk of sudden death in the olanzapine group compared with the group of patients not receiving antipsychotics. In this study, these results for olanzapine were comparable to those for the other atypical antipsychotics included in the analysis. Spontaneous reports of sudden death during post-marketing surveillance have been rare.

Convulsions

Olanzapine should be used with caution in patients with a history of seizures or exposure to factors that lower the seizure threshold. Cases of seizures were uncommon in patients taking olanzapine, and in most of these cases, the patients had a history of seizures or risk factors for seizures.

Hematological changes

As with the use of other antipsychotics, caution should be exercised when treating patients with olanzapine with a low number of leukocytes and/or neutrophils in the peripheral blood due to various reasons; with signs of suppression or toxic impairment of bone marrow function under the influence of drugs in the anamnesis; with suppression of bone marrow function due to concomitant disease, radiotherapy or chemotherapy in history; with hypereosinophilia or myeloproliferative disease.

In clinical studies, the use of olanzapine in patients with a history of clozapine-dependent neutropenia or agranulocytosis was not accompanied by relapses of these disorders.

Cancellation of therapy

In case of immediate withdrawal of olanzapine, sudden development of sweating, insomnia, tremor, anxiety, nausea and vomiting was rarely (≥ 0.01% and < 0.1%) reported.

QT interval duration

In clinical studies, clinically significant prolongation of the QT interval (QT interval adjusted by Fridericius [QTcF] > 500 ms in patients with baseline QTcF < 500 ms) was observed infrequently (0.1% to 1%) in patients receiving olanzapine, while no significant differences with placebo in the incidence of adverse cardiac events. However, as with other antipsychotics, caution is recommended when prescribing olanzapine in combination with drugs that can prolong the QT interval, especially in elderly patients with congenital prolongation of the QT interval, congestive heart failure, myocardial hypertrophy, hypokalemia and hypomagnesemia .

General activity in relation to the central nervous system (CNS)

Given the primary action of olanzapine on the central nervous system, caution should be exercised when using olanzapine in combination with other centrally acting drugs and alcohol.

Postural hypotension

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

Thromboembolism

Infrequently (≥ 0.1% and < 1%) cases of a temporal association between the development of venous thromboembolism and olanzapine therapy have been reported. The presence of a cause-and-effect relationship between olanzapine and venous thromboembolism has not been established. However, given that patients with schizophrenia often have acquired risk factors for venous thromboembolism, it is necessary to conduct a cumulative assessment of all possible risk factors for the development of this complication, including immobilization of patients, and take the necessary preventive measures.

Lactose

Zyprexa® tablets contain lactose. Patients with rare hereditary galactose intolerance, lactase intolerance and glucose-galactose malabsorption should not take olanzapine.

Anticholinergic activity

Although olanzapine exhibited anticholinergic activity in in vitro studies, olanzapine therapy was rarely associated with anticholinergic side effects in clinical studies. However, clinical experience with olanzapine in patients with comorbidities is limited, and caution is recommended when prescribing olanzapine to patients with clinically significant prostatic hypertrophy, paralytic ileus, angle-closure glaucoma, and similar conditions.

Dopaminergic antagonism

In vitro

Olanzapine exhibits dopamine antagonism and, like other antipsychotics, may theoretically inhibit the effects of levodopa and dopamine agonists.

Special instructions for the use of Zyprexa tablets

Warning! Neuroleptic malignant syndrome (NMS) NMS, a potentially fatal syndrome complex, has been described with the use of antipsychotic drugs, including olanzapine. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, loss of consciousness and symptoms of instability of the cardiovascular system (irregular pulse or blood pressure, tachycardia, increased sweating and cardiac arrhythmia). Additional signs may include increased CPK activity, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of NMS, as well as the presence of high fever without other clinical manifestations of NMS, require immediate discontinuation of all antipsychotics, including olanzapine. Tardive dyskinesia Due to the high risk of developing tardive dyskinesia with long-term use of antipsychotic drugs, a concerted dose reduction or complete discontinuation of the drug is necessary if the patient develops signs or symptoms of tardive dyskinesia. Over time, these symptoms may worsen the patient's condition or even appear after treatment is stopped. The effectiveness and safety of olanzapine in elderly patients with psychosis due to dementia have not been established. Risk factors associated with increased mortality in the population of patients receiving olanzapine therapy include age ≥80 years, concomitant use of sedatives, benzodiazepines, or the presence of concomitant pulmonary pathology (for example, pneumonia with or without aspiration). Warning! Liver function indicators. When using olanzapine, transient asymptomatic increases in the activity of hepatic transaminases (ALT and AST) were sometimes noted, especially at the beginning of treatment. In rare cases, the development of hepatitis and very rare cases of cholestatic or mixed liver damage have been reported. If the activity of ALT and/or AST increases during treatment, it is necessary to monitor the patient's condition and consider the advisability of reducing the dose of the drug. Hyperglycemia and diabetes mellitus : There is a high prevalence of diabetes mellitus among patients with schizophrenia. As with other antipsychotic drugs, hyperglycemia, diabetes mellitus, worsening of existing diabetes mellitus, ketoacidosis, and diabetic coma occur very rarely. A cause-and-effect relationship between the use of antipsychotic drugs and the listed conditions has not been established. Appropriate clinical monitoring is recommended in patients with diabetes mellitus and patients with risk factors for developing diabetes mellitus. Seizures Olanzapine should be used with caution in patients with a history of seizures or who are sensitive to factors that lower the seizure threshold. Rare cases of seizures have been reported in such patients during treatment with olanzapine. Anticholinergic activity Clinical studies have demonstrated a low incidence of anticholinergic manifestations. However, clinical experience with olanzapine in patients with concomitant diseases is limited, so caution is recommended when prescribing the drug to patients with clinically significant prostatic hypertrophy, paralytic ileus and angle-closure glaucoma. Dopaminergic Antagonism Olanzapine in vitro and may theoretically antagonize the effects of levodopa and dopamine agonists, as do other antipsychotics. General effect on the central nervous system Given the predominant effect of olanzapine on the central nervous system, care must be taken when prescribing it in combination with other centrally acting drugs and avoid simultaneous use of alcohol. Use during pregnancy and lactation Existing experience with olanzapine treatment during pregnancy is limited; the drug should be prescribed only in cases where the expected benefit of therapy for the mother significantly outweighs the potential risk to the fetus. Isolated cases of tremor, hypertension (arterial hypertension), drowsiness and insomnia have been described in infants whose mothers took olanzapine in the last trimester of pregnancy. In a study of healthy women who were breastfeeding, olanzapine was detected in breast milk. Patients are advised to stop breastfeeding if they are taking olanzapine. Effect on the ability to drive vehicles and operate potentially dangerous machinery Since olanzapine can cause drowsiness and dizziness, patients should avoid potentially hazardous activities during treatment with the drug.

Lyophilisate for the preparation of solution for injection Zyprexa (Zyprexa)

Instructions for medical use of the drug

Description of pharmacological action

Being a ligand of serotonin (2A/2C, 3, 6), dopamine (D1-D5), m-cholino- (m1-m5), histamine H1- and alpha1-adrenergic receptors, it selectively affects the limbic system.

Indications for use

An acute form of schizophrenia and other psychoses, accompanied by pronounced positive (delusions, hallucinations, thought disorders, hostility, suspicion) and/or negative (blunted affect, emotional and social isolation, poor speech activity) symptoms. Secondary affective symptoms due to schizophrenia and related disorders.

Release form

lyophilisate for preparing a solution for intramuscular administration 10 mg; bottle (bottle) 5 ml, cardboard pack 1;

Pharmacodynamics

An antipsychotic drug (neuroleptic) with a wide pharmacological spectrum of influence on a number of receptor systems. Preclinical studies have established the affinity of olanzapine for serotonin 5HT2A/C-, 5HT3-, 5HT6 receptors, dopamine D1-, D2-, D3-, D4-, D5 receptors, muscarinic m1-5 cholinergic receptors, adrenergic α1 receptors and histamine H1 receptors. Experimental studies have revealed the presence of olanzapine antagonism towards serotonin 5HT receptors, dopamine and cholinergic receptors. In vivo and in vitro, olanzapine has greater affinity and activity for serotonin 5HT2 receptors compared to 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 striatal nerve pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned defense response (a test that characterizes antipsychotic activity) at doses lower than doses that cause catalepsy (a disorder reflecting side effects on motor function). Unlike other antipsychotics (neuroleptics), olanzapine enhances the anti-anxiety effect during the anxiolytic test. Two placebo-controlled and two of three comparative controlled studies involving 2900 patients with schizophrenia showed that olanzapine provides a statistically significant reduction in both productive (including delusions, hallucinations) and negative disorders.

Pharmacokinetics

Absorption After oral administration, olanzapine is well absorbed from the gastrointestinal tract, Cmax in plasma is reached after 5-8 hours. Plasma concentrations of olanzapine have a linear dependence on the dose (ranging from 1 to 20 mg). Eating does not affect the absorption of olanzapine. Distribution At plasma concentrations from 7 to 1000 ng/ml, binding to plasma proteins, mainly albumin and α1-acid glycoprotein, is about 93%. Metabolism Olanzapine is metabolized in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which theoretically does not cross the BBB. Cytochrome P450 isoenzymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Experimental studies in animals have shown that these metabolites have significantly less pronounced pharmacological activity in vivo than olanzapine. The main pharmacological activity of the drug is due to the parent substance - olanzapine. The activity of the cytochrome P450 isoenzyme CYP2D6 does not affect the level of metabolism of olanzapine. Elimination: In healthy volunteers, after oral administration, T1/2 of olanzapine is 33 hours (21 - 54 hours for 5-95%), and the average plasma clearance is 26 l/h (12 - 47 l/h for 5-95%). About 57% of radiolabeled olanzapine is excreted in the urine, mainly in the form of metabolites. Pharmacokinetics in special clinical situations The pharmacokinetic parameters of olanzapine vary depending on gender, age, and the presence of smoking addiction: Characteristics of patients T1/2 (h) Plasma clearance (l/h) Non-smokers 38.6 18.6 Smokers 30.4 27.7 Women 36.7 18.9 Men 32.3 27.3 Elderly (65 years and older) 51.8 17.5 Under 65 years 33.8 18.2 However, the degree of changes in T1/2 and clearance under the influence of each of these factors is significantly inferior to the degree of individual differences in these indicators. There were no significant differences between the mean values ​​of T1/2 and olanzapine clearance in patients with severely impaired renal function compared with individuals with normal renal function. In smoking patients with minor hepatic impairment, the clearance of olanzapine is lower than in non-smokers without such impairment. In a study involving subjects of European, Japanese and Chinese descent, there were no differences in the pharmacokinetics of olanzapine associated with race.

Use during pregnancy

During pregnancy - with caution, comparing the expected benefits for the mother and the potential risk for the fetus. FDA category of effect on the fetus is C. Breastfeeding should be discontinued during treatment.

Contraindications for use

Hypersensitivity, breastfeeding.

Side effects

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, stiff neck, 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, accommodation disturbance, amblyopia, glaucoma, corneal damage, eye pain, keratoconjunctivitis, blepharitis, noise and pain in the ears, deafness, impaired taste. From the cardiovascular system and blood (hematopoiesis, hemostasis): orthostatic hypotension, tachy- and bradycardia, palpitations, ventricular extrasystole, ECG changes, cardiac arrest, cyanosis, vasodilation, transient leuko- and neutropenia, eosinophilia, leukocytosis, thrombocytopenia, hemorrhagic syndrome. From the respiratory system: rhinitis, pharyngitis, laryngitis, change in voice, increased cough, dyspnea, apnea, bronchial asthma, hyperventilation. From the gastrointestinal 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 liver transaminases, gamma-glutamyl transpeptidase and creatine phosphokinase, hepatitis. From the metabolic side: 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, breast pain, fibrosis uterus, premenstrual syndrome, menopause and metrorrhagia, amenorrhea. From the musculoskeletal system: arthritis, arthralgia, bursitis, myasthenia gravis, myopathy, calf muscle cramps, bone pain. From the skin: photosensitivity, alopecia, hirsutism, dry skin, eczema, seborrhea, contact dermatitis, ulcerative skin lesions, skin discoloration, maculopapular rash. Allergic reactions: urticaria. Other: fever, chills, flu-like syndrome, lymphadenopathy, chest or abdominal pain, peripheral edema, withdrawal syndrome, abuse possible.

Directions for use and doses

For schizophrenia and similar psychotic disorders, the recommended initial dose of the drug is 10 mg 1 time / Zyprexa can be taken regardless of meals. Therapeutic doses range from 5-20 mg/day. The daily dose must be selected individually depending on the clinical condition of the patient. Increasing the dose above the standard dose of 10 mg/day is recommended only after appropriate clinical examination of the patient. For acute mania in bipolar disorder, the recommended initial dose of the drug is 15 mg 1 time. Therapeutic doses of olanzapine range from 5-20 mg. The daily dose must be selected individually depending on the clinical condition of the patient. Increasing the dose above the standard dose of 15 mg/day is recommended only after appropriate clinical examination of the patient. The dose should be increased gradually, at intervals of at least 24 hours. For elderly patients, as well as for severe renal failure or moderate liver failure, the drug is prescribed at an initial dose of 5 mg/ A reduction in the initial dose is recommended for patients with a combination of factors (female patients , old age, non-smokers), which may slow down the metabolism of olanzapine.

Overdose

Symptoms: very often (≥10%) - tachycardia, agitation/aggression, articulation disorder, various extrapyramidal disorders and disturbances of consciousness of varying severity (from sedation to coma). Other clinically significant effects of olanzapine overdose included delirium, seizures, neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (Treatment: There is no specific antidote for olanzapine. Artificial induction of vomiting is not recommended. Standard detoxification techniques are indicated (i.e. e. gastric lavage, intake of activated charcoal). Simultaneous intake of activated charcoal reduces the bioavailability of olanzapine when taken orally by 50-60%. Symptomatic treatment is indicated in accordance with the clinical condition and monitoring of the functions of vital organs, including treatment of arterial hypotension, vascular collapse and support respiratory function.Epinephrine, dopamine and other sympathomimetics, which are β-adrenergic receptor agonists, should not be used, since stimulation of the latter can aggravate arterial hypotension.

Interactions with other drugs

The metabolism of olanzapine may be altered by inhibitors or inducers of cytochrome P450 isoenzymes that exhibit specific activity against CYP1A2. The clearance of olanzapine increases in smoking patients and in patients taking carbamazepine (due to increased CYP1A2 activity). Known potential inhibitors of CYP1A2 may reduce the clearance of olanzapine. Olanzapine is not a potential inhibitor of CYP1A2 activity, therefore the pharmacokinetics of drugs such as theophylline, which are metabolized primarily by CYP1A2, are not altered when taking olanzapine. Clinical trials have shown that a single dose of olanzapine during therapy with the following drugs: imipramine or its metabolite desipramine (CYP2D6, CYP3A4, CYP1A2), warfarin (CYP2C19), theophylline (CYP1A2) or diazepam (CYP3A4, CYP2C19) was not accompanied by their suppression metabolism. There were also no signs of drug interactions when olanzapine was used in combination with lithium or biperiden. Against the background of steady-state concentrations of olanzapine, no changes in the pharmacokinetics of ethanol were observed. However, taking ethanol with olanzapine may be accompanied by increased pharmacological effects of olanzapine, such as sedation. A single dose of an aluminum- and magnesium-containing antacid or cimetidine does not affect the bioavailability of olanzapine when taken orally. Simultaneous administration of activated carbon reduces the bioavailability of olanzapine by 50-60%. Fluoxetine (60 mg once or 60 mg daily for 8 days) causes an average 16% increase in olanzapine Cmax and an average 16% decrease in olanzapine clearance. The degree of influence of fluoxetine is significantly lower than the severity of individual differences in these indicators, therefore it is usually not recommended to change the dose of olanzapine when prescribed in combination with fluoxetine. In vitro studies using human liver microsomes have shown that olanzapine slightly inhibits the formation of valproate glucuronide (the main pathway of valproate metabolism). Valproate also has little effect on the metabolism of olanzapine in vitro. Therefore, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely. Based on in vitro studies using human liver microsomes, olanzapine has very little potential to inhibit the activity of the following cytochrome P450 isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.

Precautions for use

When there are a combination of factors that slow down the metabolism of olanzapine (female patients, elderly patients, non-smokers), it should be used in a reduced dosage. Careful monitoring of patients with suicidal tendencies is required, especially at the beginning of treatment. During treatment, liver transaminase activity should be regularly monitored, especially in patients with impaired liver function. Prescribe with caution to vehicle drivers and people whose activities require increased concentration 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 discontinuation of the drug is necessary. Considering the possibility of developing akathisia, if motor restlessness, restlessness, and a constant desire to move appear during treatment, it is necessary to reduce the dose and prescribe antiparkinsonian drugs.

Special instructions for use

When using any antipsychotics, including olanzapine, the development of neuroleptic malignant syndrome, a potentially fatal symptom complex, is possible. Clinical manifestations of this syndrome include a significant increase in body temperature, muscle rigidity, changes in mental status and autonomic disorders (unstable pulse or blood pressure, tachycardia, cardiac arrhythmia, increased sweating). Additional features may include increased CPK levels, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of neuroleptic malignant syndrome or a significant increase in body temperature without other symptoms of this syndrome require discontinuation of all antipsychotics, including olanzapine. In comparative studies lasting more than 6 weeks, treatment with olanzapine was significantly less likely to be accompanied by the development of dyskinesia requiring drug correction than the use of haloperidol. However, the risk of tardive dyskinesia should be taken into account during long-term therapy with antipsychotics. If signs of tardive dyskinesia develop, it is recommended to reduce the dose or discontinue olanzapine. Symptoms of tardive dyskinesia may increase or manifest after discontinuation of the drug. The drug should be used with extreme caution when the activity of AST and ALT increases in patients with insufficiency of liver function, limited functional reserve of the liver, or in patients receiving treatment with potentially hepatotoxic drugs. If the activity of AST and/or ALT increases during treatment with olanzapine, careful monitoring of the patient is required and, if necessary, a dose reduction. Olanzapine should be used with caution in patients with a history of epileptic seizures or exposed to factors that lower the seizure threshold. In such patients, seizures were rarely observed during olanzapine treatment. The drug should be prescribed with caution to patients with a low number of leukocytes and/or neutrophils due to various reasons; with signs of suppression/toxic impairment of bone marrow function under the influence of drugs in the anamnesis; with suppression of bone marrow function due to concomitant disease, radiotherapy or chemotherapy in history; with hypereosinophilia or myeloproliferative disease. In clinical studies, the use of olanzapine in patients with a history of clozapine-dependent neutropenia or agranulocytosis was not accompanied by relapses of these disorders. In clinical studies, olanzapine therapy was rarely accompanied by side effects associated with the anticholinergic activity of the drug. However, clinical experience with olanzapine in patients with concomitant diseases is limited, so caution is recommended when prescribing olanzapine to patients with clinically significant prostatic hypertrophy, paralytic ileus, angle-closure glaucoma and similar conditions. In vitro, olanzapine exhibits dopamine antagonism and, like other antipsychotics, may theoretically inhibit the effects of levodopa and dopamine agonists. Given the nature of the drug's action on the central nervous system, olanzapine should be used with caution in combination with other centrally acting drugs and ethanol. Use in Pediatrics The safety and effectiveness of olanzapine in patients under 18 years of age have not been studied. Effects on the ability to drive and use machines Patients taking olanzapine should be careful when operating mechanical vehicles, including a car, as olanzapine may cause drowsiness.

Storage conditions

List B.: In a dark place, at a temperature of 15–30 °C. Do not freeze.

Best before date

36 months

ATX classification:

N Nervous system

N05 Psycholeptics

N05A Antipsychotic drugs

N05AH Derivatives of diazepine, thiazepine and oxazepine

N05AH03 Olanzapine

Drug interactions Zyprexa tablets

The metabolism of olanzapine may be influenced by inhibitors or inducers of cytochrome P450 isoforms, especially CYP 1A2. Smoking or concomitant administration of carbamazepine increases the clearance of olanzapine. Smoking and treatment with carbamazepine stimulate CYP 1A2 activity. Inhibitors of CYP1A2 activity may reduce the clearance of olanzapine. Olanzapine is a weak inhibitor of CYP1A2 activity; it does not alter the pharmacokinetics of theophylline, which is predominantly metabolized by CYP 1A2. Clinical studies have found that the use of olanzapine during therapy with the following drugs is not accompanied by inhibition of the metabolism of such drugs: imipramine or its metabolite desipramine (CYP 2D6, CYP 3A, CYP 1A2), warfarin (CYP 2C19), theophylline (CYP 1A2), diazepam ( CYP 3A4, CYP 2C19). There was no interaction of olanzapine when administered concomitantly with lithium salts or biperiden. When steady state concentrations were reached, olanzapine did not affect the pharmacokinetics of ethanol. However, when ethanol is used concomitantly with olanzapine, additive pharmacological effects, such as increased sedation, may occur. Single doses of cimetidine or aluminum/magnesium-containing antacids did not affect the oral bioavailability of olanzapine. Additional administration of activated charcoal reduced the oral bioavailability of olanzapine by 50–60%. Fluoxetine (60 mg as a single dose or 60 mg daily for 8 days) resulted in an average increase in the maximum concentration of olanzapine by 16% and an average decrease in olanzapine clearance by 16%. The variation of these factors is small compared to the overall individual variability, so dosage adjustments are usually not required. Fluvoxamine, a CYP1A2 inhibitor, reduces the clearance of olanzapine. This results in an average increase in fluvoxamine Cmax: 54% among non-smoking women and 77% among male smokers. The mean increase in olanzapine AUC was 52% and 108%, respectively. Patients taking fluvoxamine should have their dosage of olanzapine reduced. In vitro experiments with human liver microsomes revealed that olanzapine has a slight ability to suppress the process of glucuronidation of valproic acid (the main route of its metabolization). In addition, a negligible effect of valproate on the metabolism of olanzapine in vitro . Daily additional in vivo of 10 mg olanzapine for 2 weeks did not affect the steady-state plasma concentration of valproate. Therefore, when valproate and olanzapine are used in combination, no additional adjustment of the dose of valproate is required. With a single intramuscular injection of olanzapine at a dose of 5 mg 1 hour before the administration of 2 mg of lorazepam, the pharmacokinetics of these drugs did not change. However, the administration of this combination of drugs was accompanied by increased drowsiness, which is typical when each drug is administered separately. Olanzapine has antagonistic activity against α1-adrenergic receptors. The drug should be prescribed with caution to patients taking antihypertensive drugs. Because olanzapine is metabolized by CYP 1A2, substances that can stimulate or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.

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Overdose of Zyprexa tablets, symptoms and treatment

Symptoms: very common (≥10%) symptoms of olanzapine overdose are tachycardia, agitation/aggression, dysarthria, various extrapyramidal disorders and disturbances of consciousness of varying severity (from sedation to coma). Other clinically significant effects of olanzapine overdose included delirium, seizures, coma, potential for NMS, respiratory depression, aspiration, hypertension or hypotension, arrhythmias (≤2% of cases), and cardiopulmonary shock. The minimum dose for an acute overdose with a fatal outcome was 450 mg, the maximum for an overdose with a favorable outcome was 1500 mg. Treatment: there is no specific antidote. It is not recommended to prescribe drugs that cause vomiting. Gastric lavage and administration of activated charcoal are indicated (its use reduces the bioavailability of olanzapine when taken orally by 50–60%). Symptomatic treatment is recommended in accordance with the clinical condition and monitoring of vital organ functions, including the elimination of arterial hypotension, circulatory collapse and support of respiratory function. Dopamine, epinephrine and other sympathomimetics, which are β-adrenergic receptor agonists, should not be used, since β-adrenergic stimulation can aggravate the manifestations of arterial hypotension. Cardiac monitoring of the cardiovascular system is necessary for timely detection of possible arrhythmia. Careful medical observation should be carried out until the patient recovers.