Olanzapine - instructions for use, dose, side effects, contraindications

Excipients: calcium hydrophosphate 141.05 mg, 211.57 mg, 282.09 mg, microcrystalline cellulose 40.00 mg, 60.00 mg, 80.00 mg, sodium carboxymethyl starch (type A) 10.00 mg, 15.00 mg , 20.00 mg, magnesium stearate 2.00 mg, 3.00 mg, 4.00 mg.

Description:

Dosage 5 mg: round biconvex tablets of light yellow color with engraving "OPN"and" 5 "on one side and"bza" on the other side.

Dosage 7.5 mg: tocuff biconvex tablets of light yellow color with engraving "OPN"and" 7.5 "on one side and"bza" on the other side.

Dosage of 10 mg: tocuff biconvex tablets of light yellow color with engraving "OPN"and" 10 "on one side and"bza" on the other side.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.H.03 Olanzapine

Pharmacodynamics:

Olanzapine is an antipsychotic agent (neuroleptic) with a broad pharmacological spectrum of influence on a number of receptor systems. The affinity of olanzapine for serotonin 5-HT_{2A / 2C}, 5NT₃, 5NT₆, dopamine D₁, D₂, D₃, D₄, D₅, muscarinic M_1-5, adrenergic α₁ and histamine H₁receptors. The presence of olanzapine antagonism was revealed in relation to serotonin, dopamine and cholinergic receptors. Wherein olanzapine has a more pronounced affinity and activity with respect to serotonin 5HT₂ receptors, compared with dopamine D₂receptors. Olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, and at the same time has an insignificant effect on striatal (A9) neural pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned protective reflex (a test characterizing antipsychotic activity) at doses lower than the doses that cause catalepsy (a disorder reflecting a secondary effect on motor function). Olanzapine increases the anti-anxiety effect during the "anxiolytic" test.

According to clinical studies using positron emission tomography on healthy volunteers, with a single oral dose (10 mg) olanzapine had a higher occupation of 5-HT₂_A receptors than dopamine D₂receptors. A single-electron emission computed tomography study in patients with schizophrenia revealed that patients responding to olanzapine therapy had a lesser occupation of striatal D₂receptors than other patients responding to therapy with antipsychotic drugs and other antipsychotics.

Olanzapine provides statistically significant reduction as productive (delusions, hallucinations, etc.), and negative symptoms.

Pharmacokinetics:Absorption. Olanzapine has a high absorption, independent of food intake. Dispersible olanzapine tablets are bioequivalent to coated olanzapine tablets, and have a similar rate and degree of absorption. Can be used instead of coated tablets, with the same number and frequency. The time required to reach the maximum concentration of the drug in the blood plasma (TS_mOh) after oral administration - 5-8 hours. In studies with different doses in the range from 1 mg to 20 mg, it is shown that the concentrations of olanzapine in the plasma vary linearly and in proportion to the dose.

Distribution. The connection with serum proteins is 93% in the concentration range from 7 to 1000 ng / ml. Olanzapine binds mainly to albumin and α₁glycoprotein. Penetrates through gistogematicheskie barriers, incl. blood-brain barrier (BBB).

Metabolism. Olanzapine metabolized in the liver as a result of conjugation and oxidation. The main circulating metabolite is l0-N-glucuronide, which does not theoretically penetrate the blood-brain barrier. Isozymes CYP1A2 and CYP2D6 cytochrome P450 are involved in the formation of N-desmethyl- and 2-hydroxymethylmetabolites of olanzapine. Both metabolites in animal studies had significantly less pharmacological activity in vivothan olanzapine. The main pharmacological activity of the drug is due to the initial substance-olanzapine, which has the ability to penetrate through the histohematetic barriers, incl. blood-brain barrier. Isoenzyme activity CYP2D6 cytochrome P450 does not affect the level of metabolism of olanzapine.

Excretion. In healthy volunteers, after oral administration, the mean half-life 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%). For the half-life (T_1/2) and plasma clearance affects smoking, sex and age of the patient. Plasma clearance in women is lower than in men. It is excreted mostly by the kidneys (about 60%) in the form of metabolites.

The pharmacokinetic parameters of olanzapine vary depending on smoking, sex and age (see table):

Characteristics of patients	Half-life (hours)	Clearance in plasma (l / h)
Non-smokers	38,6	18,6
Smokers	30,4	27,7
Women	36,7	18,9
Men's	32,3	27,3
At the age of 65 years and over	51,8	17,5
Younger than 65 years	33,8	18,2

Nevertheless, the degree of influence of age, sex or smoking on clearance and T_1/2 olanzapine is insignificant in comparison with the individual variability of pharmacokinetics between individuals.

Pharmacokinetics in specific patient groups

Renal insufficiency

In patients with severe renal dysfunction, there were no significant differences between mean T_1/2 and clearance of olanzapine in blood plasma, compared with those with normal renal function

Liver failure

In patients with hepatic insufficiency and smoking, the clearance of olanzapine is lower than that of non-smokers, without compromising liver function.

In a study involving individuals of European, Japanese and Chinese origin, there are no differences in the pharmacokinetics of olanzapine associated with race.

Indications:

Schizophrenia. Olanzapine is indicated for the treatment of exacerbations, supporting and prolonged anti-relapse therapy of schizophrenic patients and other psychotic disorders with marked productive(delirium, hallucinations, automatisms, etc.) and / or negative (emotional flatness, decreased social activity, impoverishment of speech) symptomatology, as well as concomitant affective disorders.

Bipolar affective disorder. Olanzapine in the form of monotherapy or in combination with lithium or valproic acid preparations is indicated for the treatment of acute manic or mixed episodes in bipolar affective disorder with or without psychotic manifestations and with / without rapid phase change. Olanzapine It is indicated for the prevention of mania recurrence in patients with bipolar disorder, in whom olanzapine was effective in treating the manic phase.

In combination with fluoxetine olanzapine is indicated for the treatment of depressive conditions associated with bipolar disorder (and for the treatment of resistant depression in adult patients).

Contraindications:

- Hypersensitivity to olanzapine or other components of the drug;

- established risk of occlusive glaucoma;

- angle-closure glaucoma,

- children under 18 years of age (efficacy and safety not established).

Carefully:

Renal failure, hepatic insufficiency, prostatic hyperplasia, paralytic intestinal obstruction, epilepsy, history of convulsive syndrome, leukopenia and / or neutropenia of various genesis, myelosuppression of various genesis, incl. myeloproliferative diseases, hypereosinophilic syndrome, cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, congenital increase in the interval QT on an electrocardiogram (ECG) (increase in the corrected interval QT (QTc) on the ECG), or in the presence of conditions potentially capable of causing an increase in the interval QT (for example, simultaneous administration of drugs that extend the interval QT, congestive heart failure, hypokalemia, hypomagnesemia), elderly age, as well as simultaneous intake of other drugs of central action; immobilization.

Pregnancy and lactation:

Due to the limited experience of using the drug in pregnant women, olanzapine It should be used during pregnancy only if the expected benefit for the mother justifies the potential risk to the fetus.

In studies on rats, it was found that olanzapine does not have a carcinogenic and teratogenic effect and does not have mutagenic properties. However, it was found that olanzapine causes a delay in the development of the fetus. Temporarily reduces fertility in sexually mature individuals.

Women should be informed of the need to inform the doctor about the onset or planned pregnancy on the background of olanzapine therapy. In newborns whose mothers took antipsychotics in the third trimester of pregnancy, there is a risk of developing extrapyramidal disorders and / or withdrawal syndrome of varying severity and duration. There are isolated reports of tremors, arterial hypertension, lethargy and drowsiness in children born to mothers who took olanzapine in the third trimester of pregnancy. These children after birth should be under the supervision of a doctor.

In studies, it was found that olanzapine excreted in breast milk. The average dosage (mg / kg) received by a child when the mother's equilibrium concentration reached equilibrium was 1.8% of the mother's olanzapine dose (mg / kg).It is not recommended to breast-feed on the background of olanzapine therapy.

Dosing and Administration:

Inside, once a day because food does not affect the absorption of the drug, the drug tablets Olanzapine can be taken regardless of food intake. In case of cancellation, a gradual dose reduction is recommended.

Schizophrenia: the recommended initial dose of the drug is 10 mg per day.

Therapeutic doses of olanzapine are shown in the range from 5 mg to 20 mg per day. The daily dose must be selected individually depending on the clinical condition of the patient. An increase in the dose above the standard daily dose (10 mg) is recommended only after an appropriate clinical examination of the patient.

Episode of the Mania: the recommended initial dose of olanzapine is 15 mg once daily as monotherapy or 10 mg once daily in combination therapy with lithium or valproic acid.

Therapeutic doses of olanzapine are shown in the range from 5 mg to 20 mg per day. The daily dose must be selected individually, depending on the clinical condition of the patient. An increase in the dose above the standard daily dose is recommended only after an appropriate clinical examination of the patient.Increase the dose should be gradual, with intervals of at least 24 hours.

Prevention of relapse in bipolar disorder: the recommended initial dose of the drug in a state of remission of 10 mg per day. For patients already receiving the drug for the treatment of manic episodes, maintenance therapy is administered in the same doses.

Against the background of drug therapy Olanzapine In case of development of a new manic, mixed or depressive episode, if necessary, increase the dose of the drug with additional treatment of mood disorders, in accordance with clinical indications.

Supportive therapy for bipolar disorder. Patients receiving olanzapine for the treatment of acute mania, it is necessary to continue maintenance therapy at the same dose. In patients in remission, the recommended initial dose of olanzapine is 10 mg once daily. In the future, the daily dose should be selected individually, depending on the clinical state of the patient, ranging from 5 mg to 20 mg per day.

Olanzapine in combination with fluoxetine for the treatment of bipolar depression should be prescribed 1 time a day, in the evening, regardless of food intake.Typically, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. Antidepressant activity was confirmed with olanzapine at a dose of 6-12 mg (mean daily dose of 7.4 mg) and fluoxetine at a dose of 25-30 mg (mean daily dose of 39.3 mg). If necessary, you can change the dose of both olanzapine and fluoxetine.

Olanzapine in combination with fluoxetine for the treatment of resistant depression should be prescribed 1 time a day, in the evening, regardless of food intake. Typically, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, you can change the dosage of both olanzapine and fluoxetine. Antidepressant activity was confirmed with olanzapine in a dose of 6-12 mg and fluoxetine in a dose of 25-30 mg.

Special patient groups

In elderly patients a reduction in the initial dose (up to 5 mg per day) is usually not recommended, but it is possible in patients older than 65 years in the presence of risk factors (see section "Special instructions").

General rules for the choice of a daily oral dose for patients of special groups. Reduction of the initial dose to 5 mg per day is recommended for patients with clinical risk factors, including severe renal failure or moderate-grade liver failure.A reduction in the initial dose may be recommended for patients with a combination of factors (female, elderly, non-smokers) who can slow the metabolism of olanzapine.

Side effects:

The table below summarizes the main side effects and their frequency that were recorded during spontaneous reports, clinical trials and / or post-marketing periods. In each group, adverse reactions are presented in order of decreasing significance.

Often (≥10%)	Often (≥1 and <10%)	Infrequently (≥0,1 and <1%)	Frequency unknown (the frequency can not be determined from the available data)
Violations of the blood and lymphatic system
	Eosinophilia	Leukopenia Neutropenia	Thrombocytopenia
Immune system disorders
		Hypersensitivity
Disorders from the metabolism and nutrition
Weight gain¹	Increased cholesterol concentration^2,3 Increase in glucose concentration⁴ Increase in the concentration of triglycerides^2,5 Glucosuria Increased appetite	Development or decompensation of diabetes mellitus, sometimes accompanied by ketoacidosis and diabetic coma, including several deaths	Hypothermia
Disturbances from the nervous system
Drowsiness	Dizziness Akathisia⁶ Parkinsonism⁶ Dyskinesia⁶	Convulsions (against a background of a convulsive syndrome in the anamnesis or risk factors for their development) Amnesia Dysatria Dystonia (including the oculogic crisis)	Malignant neuroleptic syndrome Late dyskinesia Syndrome of "withdrawal" of the drug⁷
Heart Disease
		Bradycardia with or without collapse Elongation of the QTc interval on the ECG	Ventricular tachycardia / fibrillation Sudden death
Vascular disorders
Arterial hypotension (including orthostatic)		Thromboembolism (including pulmonary embolism and deep vein thrombosis)
Disorders from the digestive system
	Short-term, transient anticholinergic effects, incl. constipation and dry mouth	Bloating	Pancreatitis
Disturbance of the liver and bile ducts
	Asymptomatic, temporary increase in the level of "liver" transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT)), especially at the beginning of treatment		Hepatitis (including hepatocellular, cholestatic or mixed liver damage)
Disturbances from the skin and subcutaneous tissues
	Rash	The reaction of photosensitivity Alopecia
Disorders from the kidneys and urinary tract
		Urinary incontinence Delayed urination
Violations of the sides of the genital organs and breast
	erectile disfunction Reduction of libido in men and women	Amenorrhea Increase of mammary glands in women Galactorrhea in women Gynecomastia and enlargement of mammary glands in men
Musculoskeletal system disorders
	Arthralgia
General disorders
	Asthenia Fatigue Peripheral edema Hyperthermia
From the respiratory system
		Nasal bleeding
Pregnancy, prenatal and postnatal period
		The syndrome of "cancellation" in newborns
Laboratory indicators
Increase in prolactin concentration in plasma⁸	Increase in activity of alkaline phosphatase Increase in activity of creatine phosphokinase Increase in the concentration of uric acid	Increase in the concentration of total bilirubin

¹In all patient groups, regardless of body mass index, a clinically significant increase in body weight was observed.

An increase in body weight of 7% or more from the mean after a short-term course of therapy (median duration 47 days) was very frequent (22.2%), an increase of 15% or more was frequent (4.2%) and an increase of 25% and more was infrequent (0.8%).With a long course of olanzapine therapy (more than 48 weeks), weight gain for ≥7%, ≥15% and ≥25% of the initial value was very frequent (64.4%), 31.7% and 12.3%, respectively).

² The mean increase in fasting lipid concentrations (total cholesterol, low-density lipoprotein (LDL) and triglycerides) was most pronounced in patients without initial signs of lipid metabolism disorders.

³Often there was an increase in cholesterol concentration from normal fasting values (<5.17 mmol / l), to high values (≥6.2 mmol / l). Changing the concentration of cholesterol from the fasting borderline (≥5,17 - <6,2 mmol / l) to elevated (≥6,2 mmol / l) was very frequent.

⁴Often there was an increase in glucose concentration from normal fasting values (<5.56 mmol / l), to increased values (≥7 mmol / L). The change in glucose concentration from the borderline values on an empty stomach (≥5.56 - <7 mmol / l) to elevated (≥7 mmol / l) was very frequent.

⁵Often there was an increase in the concentration of triglycerides from normal fasting values (<1.69 mmol / L), to elevated values (≥2.26 mmol / l). Change in the concentration of triglycerides from the boundary values (≥1.69 - <2.26 mmol / l) to elevated (≥2.26 mmol / l) was very frequent.

⁶In typical studies, there were cases of parkinsonism and dystonia in patients treated with olanzapine, but statistically significant, this figure did not differ from the placebo group. In patients who took olanzapine, fewer cases of Parkinson's disease, akathisia and dystonia were recorded than patients taking titrated doses of haloperidol. In view of the lack of detailed information about the presence of acute and late dyskinesia in patients with an anamnesis, it is currently impossible to conclude that olanzapine to a lesser degree causes the development of late dyskinesias or other late extrapyramidal syndromes.

⁷With a sharp withdrawal of olanzapine, symptoms such as sweating, insomnia, tremors, anxiety, nausea and vomiting were observed.

⁸In clinical studies of up to 12 weeks, prolactin concentrations in the blood plasma exceeded the upper limit of the norm 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 the norm.There have also been cases in which patients in the prolactin concentration spontaneously normalized without the abolition of therapy.

Undesirable effects the special patents

According to clinical studies, very frequent (≥ 10%) undesirable effect with olanzapine therapy in elderly patients with psychosis on the background of dementia, violations of gait and fall were recorded. Often (<10% and ≥1%) had pneumonia, lethargy, erythema, visual hallucinations and urinary incontinence.

In clinical studies in patients with drug (induced dopamine agonist intake) psychosis on the background of Parkinson's disease, there was an increase in the symptoms of parkinsonism very often (≥ 10%) and with a higher frequency than in the placebo group. Also, hallucinations were very common in this group of patients.

In patients with bipolar mania, combined with valproic acid, the incidence of neutropenia was 4.1%, the contributing factor was a high concentration of valproate in the blood plasma.

Patients with bipolar mania receiving olanzapine in combination therapy with lithium or valproic acid, very frequent (≥10%) undesirable effects were - weight gain, dry mouth, increased appetite, tremor. Also frequent (<10% and ≥1%) had a speech disorder.

Long-term therapy

With prolonged therapy with olanzapine (at least 48 weeks), the incidence of clinically significant adverse events (weight gain, increase in glucose concentration, total cholesterol / LDL / HDL, or triglycerides) increases with time. In adult patients who completed a 9-12 month course of treatment, an increase in the average blood glucose concentration was observed after about 6 months.

Long-term therapy with olanzapine (up to 12 months) in order to prevent relapse in patients with bipolar disorder was also accompanied by an increase in body weight.

It is not recommended to apply olanzapine in children.

It is not recommended to use olanzapine in children and adolescents under the age of 18 years.

In a short-term efficacy study for patients aged 13-17 years (the study included fewer than 200 adolescents) olanzapine used in the dose range, ranging from 2.5 and up to 20 mg / day. - the development of various adverse reactions has been documented. Long-term effects associated with these phenomena have not been studied.With a comparable effect of olanzapine in adolescents, a clinically significant increase in body weight≥7%) compared with adult patients.

The degree of change in the concentrations of total cholesterol, LDL, triglycerides and fasting prolactin was higher in adolescents than in similar studies in adult patients. Data on efficiency and safety are limited.

Overdose:

Symptoms. Very frequent (>10%) with an overdose of olanzapine are: tachycardia, agitation / aggressiveness, speech impairment, various extrapyramidal disorders and disorders of consciousness of varying severity (from sedation to coma); less than 2% of cases occur: delirium, convulsions, coma, malignant neuroleptic syndrome, respiratory depression, aspiration, increase or decrease in blood pressure, cardiac arrhythmias; in very rare cases, cardiopulmonary insufficiency. The minimum dose of olanzapine for acute overdose with a lethal outcome is 450 mg, the maximum dose was recorded in case of an overdose with a favorable outcome (survival) - 2 g.

Treatment. There is no specific antidote for olanzapine.It is not recommended to provoke vomiting. Symptomatic treatment in accordance with the clinical condition and monitoring of vital body functions, including treatment of arterial hypotension, arrhythmias, circulatory disorders and respiratory function, gastric lavage, activated charcoal (reduces the bioavailability of olanzapine up to 50-60%). Do not use epinephrine, dopamine and other sympathomimetics, which are beta-adrenergic receptor agonists, since these drugs can aggravate arterial hypotension. The patient should be under continuous medical supervision until complete recovery.

Interaction:

Potential drug interactions affecting olanzapine metabolism: olanzapine is metabolized by isoenzyme CYP1A2, therefore inhibitors or inducers of cytochrome P450 isoenzymes exhibiting specific isoenzyme activity CYP1A2, may affect the pharmacokinetic parameters of olanzapine.

Inductors of isoenzyme CYP1A2: The clearance of olanzapine may be increased in smokers or with concurrent administration of carbamazepine,which leads to a decrease in the concentration of olanzapine in the blood plasma. Clinical observation is recommended. some cases require an increase in the dose of the drug.

Inhibitor inhibitors CYP1A2: fluvoxamine, a potent specific inhibitor of the isoenzyme SUR1A2, significantly reduces the clearance of olanzapine. Average increase in maximum concentration (C_mOh) of olanzapine after the administration of fluvoxamine in non-smokers was 54%, and for men who smoke, 77%. The average increase in the area under the "concentration-time" curve (AUC) of olanzapine in these categories of patients were 52% and 108%, respectively. In patients receiving fluvoxamine or any other isoenzyme inhibitor CYP1A2 (e.g., ciprofloxacin), therapy with olanzapine is recommended to begin with smaller doses. A decrease in the dose of olanzapine may also be required if the isoenzyme inhibitors are added to therapy CYP1A2.

Drug interactions affecting / not affecting the bioavailability of olanzapine: Activated charcoal reduces absorption of olanzapine by oral intake by 50-60%, so it should be taken at least 2 hours before or after taking olanzapine.A single dose of magnesium or aluminum containing antacids or cimetidine do not affect the pharmacokinetics of olanzapine.

Fluoxetine (inhibitor of isoenzymes CYP450), with co-administration (60 mg once or 60 mg daily for 8 days) causes an increase in the maximum concentration (C_mOh) of olanzapine on average by 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, therefore, it is usually not recommended to change the dose of olanzapine when used in combination with fluoxetine.

Potential ability of olanzapine to influence other drugs

Olanzapine may reduce the effects of direct and indirect dopamine agonists.

In conditions in vitro olanzapine does not suppress the main isoenzymes CYP450 (e.g., 1A2, 2D6, 2C9, 2C19, 3A4). In vivo There was no inhibition of metabolism of the following active substances: tricyclic antidepressants (isoenzyme CYP2D6), warfarin (isoenzyme CYP2C9), theophylline (isoenzyme CYP1A2) and diazepam (isoenzymes CYP3A4 and 2C19).

No interaction was detected when used simultaneously with lithium or biperidene.Therapeutic monitoring of the content of valproic acid in plasma showed that with simultaneous administration with olanzapine, valproic acid dosage changes are not required (see "Side effect" section).

Inductors of isoenzyme CYP1A2: The clearance of olanzapine can be increased in smokers or with the simultaneous administration of carbamazepine, which leads to a decrease in the concentration of olanzapine in the blood plasma. Clinical observation is recommended. some cases require an increase in the dose of the drug.

Inhibitor inhibitors CYP1A2: fluvoxamine, a potent specific inhibitor of the isoenzyme SUR1A2, significantly reduces the clearance of olanzapine. Average increase in maximum concentration (C_mOh) of olanzapine after the administration of fluvoxamine in non-smokers was 54%, and for men who smoke, 77%.The average increase in the area under the "concentration-time" curve (AUC) of olanzapine in these categories of patients were 52% and 108%, respectively. In patients receiving fluvoxamine or any other isoenzyme inhibitor CYP1A2 (e.g., ciprofloxacin), therapy with olanzapine is recommended to begin with smaller doses. A decrease in the dose of olanzapine may also be required if the isoenzyme inhibitors are added to therapy CYP1A2. Drug interactions affecting / not affecting the bioavailability of olanzapine. Activated charcoal reduces absorption of olanzapine by oral intake by 50-60%, so it should be taken at least 2 hours before or after taking olanzapine. A single dose of magnesium or aluminum containing antacids or cimetidine do not affect the pharmacokinetics of olanzapine.

Fluoxetine (inhibitor of isoenzymes CYP450), with co-administration (60 mg once or 60 mg daily for 8 days) causes an increase in the maximum concentration (C_mOh) of olanzapine on average by 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,therefore, it is usually not recommended to change the dose of olanzapine when used in combination with fluoxetine.

Potential ability of olanzapine to influence other drugs Olanzapine may reduce the effects of direct and indirect dopamine agonists.

No interaction was detected when used simultaneously with lithium or biperidene. Therapeutic monitoring of the content of valproic acid in plasma showed that with simultaneous administration with olanzapine, valproic acid dosage changes are not required (see "Side effect" section).

Care should be taken when using other central-action drugs at the same time. Despite the fact that a single dose of alcohol (45 mg / 70 kg) has no effect pharmacokinetic, alcohol together with olanzapine may be accompanied by increased inhibitory action on the central nervous system.

Special instructions:

Hyperglycemia and diabetes mellitus

There is a higher prevalence of diabetes mellitus in a patient with schizophrenia. There are very rare reports of the development of hyperglycemia and / or decompensation of diabetes mellitus, sometimes accompanied by the development of ketoacidosis or ketoacidotic coma, including reports of several fatal cases. In some cases, there was a previous decompensation of weight gain, which could become a predisposing factor. Patients with diabetes mellitus and risk factors for the development of this disease are recommended regular clinical monitoring and monitoring of blood glucose concentrations.

Change in lipid concentration

With olanzapine therapy, it is necessary to monitor lipid concentrations in plasma in patients with dyslipidemia and in patients with risk factors for lipid metabolism. Patients taking olanzapine therapy need control of the lipid profile. When the lipid concentration changes, correction of therapy is required.

Anticholinergic activity

When conducting clinical trials, olanzapine therapy was rarely accompanied by undesirable reactions caused by blockade of M-cholinergic receptors.Since the clinical experience with olanzapine in people with concomitant diseases is limited, the drug should be used with caution in patients with clinically significant prostatic hyperplasia, paralytic intestinal obstruction, angle-closure glaucoma, and similar conditions.

The use of olanzapine in patients with Parkinson's disease

Olanzapine is not recommended for the treatment of psychoses caused by dopaminomimetic treatment in Parkinson's disease. The symptoms of parkinsonism and hallucinations increase. Wherein olanzapine on the effectiveness of psychosis treatment did not exceed the placebo.

Dopaminergic antagonism

In conditions in vitro olanzapine exhibits antagonism against dopamine receptors and, like other antipsychotics (neuroleptics), can theoretically suppress the action of levodopa and other dopamine receptor agonists.

Experience with olanzapine in elderly patients with psychosis associated with dementia. The effectiveness of olanzapine in elderly patients with psychosis associated with dementia is not established. In placebo-controlled clinical trials (6-12 weeks) in elderly patients (mean age 78 years) suffering from psychoses and behavioral disorders due to dementia,There was an increase in lethal cases in patients treated with olanzapine, compared with the placebo group (3.5% vs. 1.5%, respectively). The increase in lethality does not depend on the dose of olanzapine or the duration of therapy. Risk factors predisposing to increased mortality include: age over 75 years, dysphagia, sedation, malnutrition and dehydration, lung diseases (for example, pneumonia, including aspiration), simultaneous reception of benzodiazepines.

Cerebrovascular adverse events, including stroke in elderly patients with dementia

Cerebrovascular adverse events (stroke, transient ischemic attack), including death, were noted in studies of olanzapine in elderly patients with psychosis associated with dementia. In placebo-controlled studies, a higher incidence of cerebrovascular adverse events was noted in patients in the olanzapine group, compared with the placebo group (1.3% vs. 0.4%, respectively). All patients had previous risk factors for developing cerebrovascular adverse events (smoking, hypertension,previously noted case of cerebrovascular undesirable phenomenon or transient ischemic attacks), as well as concomitant diseases with taking medications that are associated with cerebrovascular undesirable events.

Postural hypotension

Postural hypotension was not often observed in elderly patients during clinical trials of olanzapine. As with other antipsychotic drugs, patients over 65 years of age are advised to periodically monitor blood pressure.

Interval QT

In clinical studies, the clinically significant lengthening of the interval QT (correction QT by Friderik's formula [QTcF] ≥500 milliseconds in patients with baseline QTcF<500 msec) in total (0.1% -1%) in patients treated with olanzapine in the absence of significant differences from placebo for associated cardiac events. However, as with other neuroleptic drugs, caution should be exercised in prescribing olanzapine concomitantly with drugs that are able to lengthen the interval QT, especially in elderly patients, patients with the syndrome of lengthening the interval QT, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia. During therapy with olanzapine, an electrocardiogram should be monitored.

Dysfunction of the liver

At the beginning of therapy, an asymptomatic increase in the activity of liver transaminases (ALT and ACT) in the blood serum. There were rare cases of hepatitis. In addition, there were isolated reports of cholestatic and mixed liver damage. In patients with initially increased activity ACT and / or ALT in blood serum in patients with hepatic insufficiency and conditions potentially limiting the functionality of the liver, as well as those taking hepatotoxic drugs, caution should be exercised when prescribing olanzapine. With increasing ALT and / or ACT on the background of drug therapy, it is recommended that medical supervision of the patient and, possibly, a reduction in the dose of the drug be recommended. When diagnosing hepatitis (including hepatocellular, cholestatic or mixed) olanzapine necessary cancel.

Hematologic changes

The drug should be used with caution in patients with leukopenia and / or neutropenia of any genesis, myelosuppression of drug origin, as well as against radiation or chemotherapy, due to concomitant diseases, in patients with hypereosinophilic conditions or myeloproliferative diseases. Neutropenia has often been noted with the simultaneous use of olanzapine and valproic acid (see the "Side effect" section).

Malignant neuroleptic syndrome (CNS)

ZNS is a potentially life-threatening condition associated with antipsychotic medication (neuroleptics), incl. olanzapine. Clinical manifestations of ZNS: fever, rigidity of muscles, impaired consciousness, vegetative disorders (unstable pulse or labile blood pressure, tachycardia, increased sweating, arrhythmias).

Additional symptoms of ZNS: increased CK, myoglobinuria (against rhabdomyolysis) and acute renal failure. With the development of symptoms of the ZNS, as well as an increase in body temperature for no apparent reason, it is necessary to cancel all neuroleptics, including. olanzapine.

Convulsive Syndrome

Olanzapine should be cautiously prescribed to patients with a history of seizures or the presence of risk factors that reduce the threshold of convulsive readiness. On the background of taking olanzapine, seizures were rarely recorded.

Late dyskinesia

In comparative studies, olanzapine therapy was significantly less likely to be associated with the development of tardive dyskinesia requiring medication correction than the use of typical and other atypical antipsychotics. The risk of developing tardive dyskinesia increases with increasing duration of therapy. When developing signs of tardive dyskinesia in a patient taking olanzapine, a dose adjustment is recommended. Symptoms of dyskinesia may temporarily increase after the drug is discontinued.

Total activity against the central nervous system

Caution should be exercised when using olanzapine and other central medicines at the same time and avoiding the use of alcohol.

Thromboembolism

When taking olanzapine very rarely (less than 0.01%) recorded cases of venous thromboembolism. The causal relationship between olanzapine therapy and vein thrombosis has not been established.Since patients with schizophrenia often have acquired risk factors for venous thrombosis, all possible other factors (eg, immobilization) should be identified and preventive measures taken.

Sudden death

Experience in the clinical use of any antipsychotic, including olanzapine, revealed a similar, dose-dependent increase in the risk of sudden death due to acute heart failure. In a retrospective observational cohort study, the risk of presumed sudden cardiac death in patients treated with olanzapine was approximately doubled compared to patients who did not apply antipsychotics. In the study, the risk for olanzapine was comparable to the risk for atypical antipsychotics included in the cumulative analysis.

Prolonged therapy with the drug

With prolonged therapy with olanzapine (up to 12 months), in order to prevent relapses in patients with bipolar disorders, there was an increase in body weight> 7% of the baseline (in 39.9% of patients). With longer therapy (more than 48 weeks), clinically significant changes were observed - weight gain, glucose concentration, total cholesterol / LDL / HDL or triglyceride levels.In adult patients who completed a 9-12 month course of treatment, an increase in the average blood glucose concentration was observed after about 6 months. Patients with risk factors for concomitant diseases who are on long-term therapy with olanzapine need to see a specialist at the doctor's side throughout the course of therapy.

The withdrawal syndrome

With a sharp discontinuation of olanzapine, it is very rare (less than 0.01%) to develop the following symptoms: sweating, insomnia, tremor, anxiety, nausea, or vomiting. With the withdrawal of the drug, a gradual dose reduction is recommended.

Use in children

Olanzapine is not recommended for use in children and adolescents under 18 years, due to the lack of sufficient data on efficacy and safety. In short-term studies in patients aged 13-17 years, a greater increase in body weight and a change in the concentration of lipids and prolactin was recorded than in similar studies in adults (see "Side effect").

Effect on the ability to drive transp. cf. and fur:

Patients receiving olanzapine, during the treatment period, care must be taken when driving vehicles and occupying others,potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions, since olanzapine may cause drowsiness and dizziness.

Form release / dosage:

Tablets, 5 mg, 7.5 mg, 10 mg.

Packaging:For 7 or 14 tablets in a blister from Al / Al or from OBA / Al / PVC: Al.

One blister with 7 tablets or 14 tablets or two blisters with 7 tablets or four blisters with 7 tablets together with instructions for use in a cardboard box.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002687

Date of registration:29.10.2014

Expiration Date:29.10.2019

The owner of the registration certificate:Firm EUROSERVICE, CJSC Firm EUROSERVICE, CJSC Russia

Manufacturer: & nbsp

SYNTHON HISPANIA, S.L. Spain

Representation: & nbspFirm EUROSERVICE, CJSCFirm EUROSERVICE, CJSCRussia

Information update date: & nbsp03.06.2017

Illustrated instructions

Instructions

Olanzapine (Olanzapine)