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

Excipients: lactose monohydrate (milk sugar) 50,60 / 101,20 mg, microcrystalline cellulose 51,40 / 102,80 mg, pregelatinized starch 51,40 / 102,80 mg, silicon dioxide colloid (aerosil) 0,80 / 1, 60 mg, magnesium stearate 0.80 / 1.60 mg.

Description:

Round tablets biconvex form from light yellow to yellow. Blotches of a darker color are allowed.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.H.03 Olanzapine

Pharmacodynamics:

Olanzapine is an antipsychotic agent (neuroleptic).

In preclinical studies, affinity for 5-HT_{2A / 2C}-, 5HT₃-, 5HT₆- serotonin receptors, D₁-, D₂-, D₃-, D₄-, D₅dopamine receptors, m-cholinoblocking effects are due to blockade of M_1-5-choline receptors; also has an affinity for α₁-adreno and H₁-histamine receptors. In animal experiments, antagonism was revealed with respect to serotonin, dopamine and m-cholinergic receptors. In vivo and in vitro olanzapine has a more pronounced affinity and activity with respect to 5-HT₂-serotonin receptors in comparison with D₂dopamine receptors. According to electrophysiological studies olanzapine selectively reduces the excitability of mesolimbic dopaminergic neurons, and at the same time has an insignificant effect on the striatal 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). Unlike other neuroleptics, olanzapine increases the anti-anxiety effect during the "anxiolytic" test.

Olanzapine provides a statistically reliable response as productive (delusions, hallucinations, etc.), and negative disorders.

With a single administration of 10 mg of olanzapine by positron emission tomography (PET) on healthy volunteers, a greater affinity for olanzapine to 5 NT2_2Athan to D₂dopamine receptors. On the tomograms of patients with schizophrenia, it was shown that in patients who are sensitive to olanzapine treatment, the affinity for striatal D₂receptors is comparable to the effect in patients who are sensitive to the use of clozapine, and lower than in patients that are sensitive to treatment with other antipsychotic drugs and risperidone.

Clinical efficacy

In an international, double-blind, comparative study of patients with schizophrenia, schizoaffective or similar disorders of varying severity of depressive symptoms (mean baseline value of 16.6 on the Montgomery-Asberg scale for assessing depression), a prospective secondary mood-based analysis from baseline to end point of control a statistically significant (p = 0.001) improvement was seen when taking olanzapine (-6.0) compared with haloperidol (-3.1).

Patients with a manic or mixed episode of bipolar disorder compared with placebo and valproic acid (divalproate) showed high efficacy in reducing manic symptoms within 3 weeks. Comparable results of efficacy of olanzapine and haloperidol were observed in patients with symptomatic remission of mania and depression in 6-12 weeks. In the co-therapy of patients taking a lithium or valproic acid drug for at least 2 weeks, an additional 10 mg of olanzapine (a co-therapy with a lithium or valproic acid drug) led to a significant reduction in manic symptoms compared to monotherapy with lithium or valproic acid for 6 weeks.

In a 12-month study of the prevention of recurrence of manic episodes in patients who achieved remission with olanzapine and then randomized to the group taking the drug olanzapine, a statistically significant advantage over placebo was found in the main criterion for controlling the occurrence of bipolar disorder recurrence and in terms of preventing recurrence of mania or relapse of depression.

In the second 12-month study of the prevention of recurrence of manic episodes in patients who achieved remission with co-administration of olanzapine with a lithium drug, and then randomized to a monotherapy group with olanzapine or a lithium preparation. The effectiveness of olanzapine was statistically insignificant in comparison with the lithium preparation according to the main criterion for controlling the recurrence of bipolar disorder (olanzapine 30.0%, lithium 38.3%, p = 0.055).

In a 18-month study of co-therapy of manic or mixed episodes in patients stabilized with olanzapine and mood-stabilizing drugs (lithium or valproic acid preparations), prolonged co-therapy with olanzapine with a lithium or valproic acid preparationwas statistically insignificant in comparison with monotherapy with lithium or valproic acid in order to delay the occurrence of a recurrence of bipolar disorder determined by diagnostic criteria.

Pharmacokinetics:

After oral administration olanzapine well absorbed, its maximum concentration in the plasma is achieved after 5-8 hours. Absorption of olanzapine does not depend on food intake. In studies with different doses in the range of 1-20 mg, it is shown that the concentration of olanzapine in the plasma varies linearly and in proportion to the dose.

Olanzapine is metabolized in the liver as a result of conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which theoretically does not penetrate the blood-brain barrier. Isozymes CYP1A2 and CYP2D6 participate in education 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 compound - olanzapine, which has the ability to penetrate the blood-brain barrier.In healthy volunteers after oral administration, the average half-life was 33 h (21-54 h 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

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

However, the degree of changes in the half-life and clearance due to each of these factors is significantly inferior to the degree of difference between these indicators among individuals.

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

No significant differences between the mean half-life and clearance of olanzapine in plasma in patients with severe renal impairment as compared to individuals with normal renal function is not installed.About 57% of radiolabeled olanzapine is excreted in the urine mainly in the form of metabolites.

In smokers with minor violations of liver function, the clearance of olanzapine is lower than that of non-smokers without impaired liver function.

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 to acid α₁- glycoprotein. In a study involving individuals of European, Japanese and Chinese origin, there are no differences in the pharmacokinetics of olanzapine associated with race. Isoenzyme activity CYP2D6 does not affect the metabolism of olanzapine.

Indications:

Olanzapine is indicated for the treatment of schizophrenia. Olanzapine is effective for maintaining clinical improvement in the ongoing treatment of patients with schizophrenia who responded to the initial treatment.

Olanzapine is indicated for the treatment of a manic episode from medium to severe. Olanzapine is indicated for the prevention of relapses in patients with bipolar disorder, in whom it proved effective in treating the manic phase (see the section "Pharmacodynamics").

Therapeutically resistant depression. In combination with fluoxetine olanzapine is indicated for the treatment of therapeutically-resistant depression in adult patients (major depressive episodes with a history of ineffective use of two antidepressant doses and the duration of therapy appropriate to the episode). Olanzapine in monotherapy is not indicated for the treatment of therapeutically-resistant depression.

Contraindications:

Hypersensitivity to any of the components of the drug.

Contraindicated for persons under 18 years.

Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Pregnancy and lactation:

Because of insufficient experience with olanzapine during pregnancy, the drug should be administered during pregnancy only if the potential benefit to the patient is significantly greater than the potential risk to the fetus. Patients should be warned that in the event of the onset or planning of pregnancy during treatment with olanzapine, they need to inform their physician about it.

In newborns whose mothers took antipsychotics (including olanzapine) during the third trimester of pregnancy, there is a risk of adverse reactions, including extrapyramidal disorders and / or withdrawal syndrome, whose symptoms may change in strength and duration after birth. There was reported agitation, hypertension, hypotension, tremor, drowsiness, respiratory distress syndrome, or eating disorders. Therefore, it is necessary to carefully monitor the state of newborns.

The study found that olanzapine penetrates into breast milk. The average dose received by the child (mg / kg) when the equilibrium concentration was reached in the mother was 1.8% of the mother's olanzapine dose (mg / kg). It is not recommended to breast-feed during therapy with olanzapine.

Dosing and Administration:

Inside. Olanzapine can be taken regardless of food intake, since food does not affect the absorption of olanzapine.

Schizophrenia

The recommended initial dose of olanzapine is 10 mg once daily. Therapeutic doses of olanzapine range from 5 mg to 20 mg per day. The daily dose must be selected individually depending on the clinical condition of the patient.Dose increase 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 for continued therapy.

Bipolar disorder

To treat a manic episode, the recommended initial dose of olanzapine is 15 mg once daily as monotherapy or 10 mg once daily in combination with lithium or valproic acid. Therapeutic doses of olanzapine range from 5 mg to 20 mg per day. The daily dose must be selected individually, depending on the clinical condition of the patient. Dose increase above the standard daily is recommended only after assessment of the clinical picture and with an interval of at least 24 hours.

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

For the treatment of a depressive episode olanzapine should be administered in combination with fluoxetine 1 time per 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 6-12 mg (mean daily dose 7.4 mg) and fluoxetine 25-30 mg (mean daily dose 39.3 mg). If necessary, you can change the dose of both olanzapine and fluoxetine. When using the drug, it is necessary to regularly evaluate the need for continued therapy.

Therapeutically resistant depression

Olanzapine should be prescribed in combination with fluoxetine 1 time per 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 dose 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. When using the drug, it is necessary to regularly evaluate the need for continued therapy.

General rules for choosing a daily dose for special groups of patients with oral intake

Reduction of the initial dose to 5 mg per day is recommended for elderly patients or patients with other clinical risk factors,including severe renal failure or hepatic impairment of moderate severity. A reduction in the initial dose of up to 5 mg can be recommended for patients with a combination of factors (female gender, advanced age and a lack of smoking habits) that can reduce the metabolism of olanzapine (see Table 1).

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

Side effects:

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

table 2

System / Side Effect (and a footnote to the commentary)	Frequency of adverse events (WHO classification)
	Often (≥1/10)	often (≥ 1/100 to <1/10)	infrequently (≥ 1/1000 to <1/100)	rarely (≥ 1/10000 to <1/1000)	very rarely (<1/10000) or the frequency is not installed
Violations of the blood and lymphatic system
Leukopenia^(1,3)		X
Neutropenia⁽³⁾		X
Thrombocytopenia⁽³⁾				X
Eosinophilia ⁽¹⁾		X
Immune system disorders
Allergic reactions (anaphylactic reaction, angioedema, skin itching or urticaria)⁽³⁾					X
Disorders from the metabolism and nutrition
Weight gain^(2,4)	X
Increase in glucose concentration⁽³_’⁸⁾		X
Increased cholesterol concentration^(3,9)		X
Increase in the concentration of triglycerides ⁽³_’¹⁰⁾		X
Glucosuria ⁽²⁾		X
Increased appetite		X
Development or decompensation of diabetes mellitus, in some cases accompanied by ketoacidosis or coma, including some deaths ^(3,8)			X
Hypothermia⁽³⁾				X
From the nervous system
Drowsiness ⁽¹⁾	X
Akathisia ⁽¹_’⁶⁾		X
Dizziness ⁽¹⁾		X
Parkinsonism ^(1,6)		X
Dyskinesia^(1,6)		X
Dystonia (including the oculogic crisis)^(2,6)			X
Malignant neuroleptic syndrome ^(2,3)			X
Late dyskinesia⁽³⁾			X
Dysatria
Amnesia
Convulsions ^(2,⁷⁾				X
The "cancellation" syndrome^(3,5)				X
Heart Disease
Bradycardia ⁽²⁾			X
QT interval extension ⁽³⁾			X
Ventricular tachycardia / ventricular fibrillation, sudden death /^1,3)				X
Vascular disorders
Arterial hypotension, including orthostatic hypotension ⁽¹⁾		X
Thromboembolism of the pulmonary artery and deep vein thrombosis⁽³⁾				X
Disturbances from the respiratory system, chest and mediastinal organs
Nose bleed⁽¹⁾			X
Disorders from the gastrointestinal tract
Short-term m-cholinoblocking effects, including constipation and dry mouth		X
Bloating^(2,3)			X
Pancreatitis ⁽³⁾				X
Disturbances from the liver and bile ducts
The transient increase in the activity of "liver" transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT), especially in the early period of treatment⁽³⁾		X
Hepatitis (including hepatic-cell, cholestatic or mixed liver damage)⁽³⁾				X
Disturbances from the skin and subcutaneous tissues
Rash⁽³⁾				X
Photosensitivity reactions⁽²⁾			X
Alopecia ⁽³⁾				X
Musculoskeletal disorders
Arthralgia ⁽²⁾		X
Rhabdomyolysis ⁽³⁾				X
Disorders from the kidneys and urinary tract
Urinary incontinence			X
Delayed onset of urination					X
Retention of urine ⁽³⁾				X
Violations of the genitals and mammary gland
Amenorrhea⁽³⁾			X
Gynecomastia⁽¹⁾			X
Breast augmentation in women			X
Galactorrhea			X
Priapism ⁽¹⁾					X
Reduction of libido in men and women ⁽³⁾		X
Erectile dysfunction in men⁽³⁾		X
General disorders
Asthenia, fatigue ⁽²⁾		X
Pyrexia ⁽²⁾		X
Edema ⁽²⁾		X
Laboratory data
Increase in prolactin concentration in plasma^(1,11)	X
Increase in activity of alkaline phosphatase ⁽²⁾			X
Increase in activity of creatine phosphokinase⁽³⁾			X
Increase in the concentration of total bilirubin⁽³⁾				X
Increased uric acid levels⁽²⁾		X

Comments on footnotes for Table 2:

1) Data accumulated during placebo-controlled clinical trials that were conducted for the indication of "Schizophrenia, acute phase."

2) Generalized data accumulated during all clinical trials.

3) Registered spontaneously side effects in postmarketing studies.

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

An increase in body weight of 7% or more from the mean after a short course of treatment (average duration 47 days) was very frequent (22.2%), an increase of 15% or more was frequent (4.2%) and an increase of 25% or more were infrequent (0.8%).

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

5) With a sharp abolition of olanzapine, symptoms such as increased sweating, insomnia, tremor, anxiety, nausea, or vomiting were observed.

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

In patients who took olanzapine, parkinsonism, akathisia, dystonia were observed less frequently than in patients receiving 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.

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

8) Often there was an increase in glucose concentration from normal fasting values (<5.56 mmol / l) to elevated (≥7 mmol / L). Change in glucose concentration from fasting borderline≥5.56 - <7 mmol / l) to elevated (≥7 mmol / l) was very frequent.

9) Often there was an increase in cholesterol concentration from normal fasting values (<5.17 mmol / L) to elevated (≥6.2 mmol / L).

Changing the concentration of cholesterol from borderline fasting indices (> 5.17 - <6.2 mmol / l) to elevated (≥6.2 mmol / l) was very frequent.

10) Often there was an increase in the concentration of triglycerides from normal fasting values (<1.69 mmol / l) to elevated (≥2.26 mmol / l).

The change in the concentration of triglycerides from the fasting borderline≥1.69 - <2.26 mmol / l) to elevated (≥ 2.26 mmol / l) was very frequent.

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

Undesirable effects in specific patient groups

Very frequent (≥10%), the undesirable effect of olanzapine in clinical trials in patients with psychosis associated with dementia was a violation of gait and fall.

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

Also often observed pneumonia, fever, lethargy, erythema, visual hallucinations and urinary incontinence.

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

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

Overdose:

Signs and symptoms of an overdose

Very frequent (frequency ≥10%) with symptoms of olanzapine overdose were tachycardia, agitation / aggressiveness, speech impairment, various extrapyramidal disorders and disorders of consciousness of varying severity (from sedation to coma). Other clinically relevant effects of olanzapine overdose included delirium, seizures, malignant neuroleptic syndrome, respiratory depression, aspiration, increased and decreased blood pressure, arrhythmias (<2% of overdoses) and cardiac arrest and respiratory arrest. The minimum dose for acute overdose with a lethal outcome was 450 mg, the maximum dose for an overdose with a favorable outcome (survival) is 2 g.

Medical assistance for overdose

There is no specific antidote for olanzapine.It is not recommended to provoke vomiting. Standard procedures for overdose can be shown (gastric lavage, activated charcoal reception). A joint reception of activated charcoal and olanzapine showed a decrease in the bioavailability of olanzapine upon ingestion of up to 50-60%. Symptomatic treatment is shown 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-adrenoreceptor agonists, since stimulation of these receptors can aggravate arterial hypotension.

It is necessary to monitor cardiovascular activity in order to identify possible arrhythmias. The patient should be under continuous medical supervision until complete recovery.

Interaction:

The metabolism of olanzapine can be altered by inhibitors or inducers of the cytochrome P450 isoenzyme exhibiting specific isoenzyme activity CYP1A2.The clearance of olanzapine is increased in smokers and in patients taking carbamazepine (in connection with an increase in isoenzyme activity CYP1A2). Potential inhibitors of isoenzyme CYP1A2 can reduce the clearance of olanzapine. Olanzapine is not a potential inhibitor of isoenzyme CYP1A2, so when taking olanzapine, the pharmacokinetics of medicines, such as theophylline, mainly metabolized by isoenzyme CYP1A2, does not change.

In clinical studies, it was shown that a single application of a dose of olanzapine against the background of therapy with the following drugs was not accompanied by a suppression of the metabolism of these drugs: imipramine or its metabolite desipramine (isozymes CYP2D6, CYP3A, CYP1A2), warfarin (isoenzyme CYP2C19), theophylline (isoenzyme CYP1A2) or diazepam (isoenzyme CYP3A4, CYP2C19). There were no signs of drug interaction with olanzapine in combination with lithium or biperidin.

Against the background of an equilibrium concentration of olanzapine, there was no change in the pharmacokinetics of ethanol. However, taking ethanol 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_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.

Fluvoxamine, isofrene inhibitor CYP1A2, decreases the clearance of olanzapine. The result is an average increase in C_mOh olanzapine with the administration of fluvoxamine by 54% in nonsmoking women and by 77% in male smokers, the mean increase AUC (area under the concentration-time curve) of olanzapine by 52% and 108%, respectively. Small doses of olanzapine should be given to patients who are jointly receiving fluvoxamine treatment.

In studies in vitro Using human liver microsomes, it has been shown that olanzapine slightly suppresses the formation of valproic acid glucuronide (the main pathway of valproic acid metabolism). Valproic acid also slightly affects the metabolism of olanzapine in vitro. Therefore, clinically significant pharmacokinetic interaction between olanzapine and valproic acid is unlikely.

Absorption of olanzapine is not dependent on food intake.

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

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

Special instructions:

Suicide

The risk of suicide attempts by patients with schizophrenia and bipolar disorder of the first type is due to the aforementioned diseases. In this regard, against the background of pharmacotherapy requires careful monitoring of those patients who have a risk of suicide is particularly high. When prescribing olanzapine, one should strive to minimize the number of tablets taken by the patient, so as to reduce the risk of overdose.

Malignant neuroleptic syndrome

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

Late dyskinesia

In comparative studies olanzapine treatment was significantly less often accompanied by the development of dyskinesias requiring medical correction than the use of typical and other atypical antipsychotics.However, the risk of tardive dyskinesia with prolonged therapy with neuroleptics should be considered. When developing signs of tardive dyskinesia, a dose adjustment of an antipsychotic is recommended. It should be borne in mind that when translated into olanzapine symptoms of tardive dyskinesia may develop due to the simultaneous withdrawal of previous therapy. Over time, the intensity of this symptomatology may increase, moreover, these symptoms may develop after discontinuation of therapy.

Experience in elderly patients with psychosis associated with dementia

The effectiveness of olanzapine in elderly patients with psychosis associated with dementia is not established. In this category of patients in placebo-controlled clinical trials, the incidence of lethal cases 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 a higher mortality with olanzapine include age> 80 years, sedation, concomitant use with benzodiazepines, or the presence of lung pathology (eg, pneumonia with or without aspiration).

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

Parkinson's disease

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

Dysfunction of the liver

In some cases, the use of olanzapine, usually in the early stages of therapy, was accompanied by a transient, asymptomatic increase in the activity of "hepatic" transaminases (aspartate aminotransferase (ACT) and alanine aminotransferase (ALT)) in the blood serum. There were rare cases of hepatitis. In addition, there were individual reports of cholestatic and mixed liver damage. Special caution is necessary when increasing activity ACT and (or) ALT in blood serum in patients with insufficient liver function, with limited functional reserve of the liver or in patients receiving potentially hepatotoxic drugs. In case of increase, activity ACT and (or) ALT during treatment with olanzapine, careful monitoring of the patient and, if necessary, dose reduction are required. In case of serious violations of liver function caused by taking olanzapine, its use should be discontinued.

Hyperglycemia and diabetes mellitus

There is a higher prevalence of diabetes mellitus in patients with schizophrenia. As with some other antipsychotics, cases of hyperglycemia, decompensation of diabetes mellitus, in some cases accompanied by ketoacidosis and diabetic coma, including fatal cases, were rarely noted. A thorough clinical monitoring of patients with diabetes mellitus and patients with risk factors for the development of diabetes mellitus is recommended.

Change in lipid profile

In placebo-controlled trials, patients who received olanzapine, undesirable changes in the lipid spectrum were observed.Clinical observation is recommended (see section "Side effect").

Development of risk of sudden death

Experience in the clinical use of any antipsychotic, including olanzapine, found a similar, dose-dependent, double increase in the risk of death due to acute heart failure, compared with deaths 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 (for example, 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 with cerebrovascular disorders had previous risk factors for developing cerebrovascular adverse events (for example,previously noted case of cerebrovascular undesirable phenomenon or transient ischemic attack, arterial hypertension, smoking), as well as concomitant diseases and (or) taking medications associated with cerebrovascular undesirable events.

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 exposed to factors that reduce the threshold of convulsive readiness. In such patients, seizures were rare in the treatment with olanzapine.

M-holinoblocking activity

When conducting clinical trials, olanzapine therapy was rarely accompanied by undesirable reactions caused by blockade of m-cholinergic receptors. However, clinical experience with olanzapine in patients with concomitant diseases is limited, so caution should be exercised in prescribing olanzapine to patients with clinically significant prostatic hyperplasia, paralytic intestinal obstruction, occlusive glaucoma, and similar conditions.

Blockade of dopamine receptors

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

Hematologic changes

Caution should be applied olanzapine in patients with a low content of leukocytes and (or) neutrophils in the blood; receiving drugs that can cause neutropenia; with oppression of bone marrow function due to radiation or chemotherapy disease; 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 of olanzapine in patients with neutropenia and agranulocytosis klozapinzavisimoy history was not accompanied by relapses of these faults. On neutropenia was reported mainly in combined therapy with olanzapine and valproic acid.

Interval QT

In clinical studies, clinically significant lengthening of the interval QT (interval QT with the correction of Friederation [QTcF]> 500 ms in patients with baseline, QTcF <500 ms) in patients who received olanzapine, on the background of absence, significant differences with placebo on the incidence of adverse cardiac events. However, as with other antipsychotics, caution should be exercised when using olanzapine in combination with drugs that can lengthen the interval QT, especially in elderly patients, with congenital lengthening of the interval QT, chronic heart failure, myocardial hypertrophy, hypokalemia and hypomagnesemia.

Abolition of therapy

In the case of a sharp abolition of olanzapine, extremely rarely (<0.01%) was reported on the acute development of sweating, insomnia, tremor, anxiety, nausea and vomiting.

Thromboembolism

Very rarely (<0.01%) reported on the development of venous thromboembolism in the background of olanzapine therapy. The presence of a causal relationship between the administration of olanzapine and venous thromboembolism has not been established. However, given that patients with schizophrenia often have acquired risk factors for venous thromboembolism, an overall assessment of all possible risk factors for the development of this complication is required,including immobilization of patients, and take the necessary preventive measures.

Total activity against the central nervous system

Taking into account the main effect of olanzapine on the central nervous system, caution should be exercised when using olanzapine in combination with other central drugs and alcohol.

Postural hypotension

Postural hypotension was rarely observed in clinical studies of olanzapine in the elderly. As with other antipsychotics, in the case of olanzapine, patients over 65 years of age should 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 had an increase in weight ≥ 7% of the baseline, the difference was statistically significant and was 29% in those who took olanzapine, and only 3% in the placebo group. The average weight gain in these patients who took olanzapine, in the acute phase was 2.8 kg. The body mass index (BMI) has always clinically significantly increased in the study group.With prolonged therapy with schizophrenia, olanzapine weight gain averaged 5.4 kg, in 56% of patients in the test group, body weight increased by more than 7% from the baseline. For patients who underwent long-term therapy for bipolar disorder, the average weight gain was 3.8 kg, and the number of patients with a weight increase of more than 7% was 31%.

Hyperprolactinemia

In controlled clinical trials (no more than 12 weeks), prolactin levels in the blood were increased in 30% of the patients in the test group and 10.5% in the placebo group (control group). The levels of prolactin concentration increase were moderate. The revealed clinical events included: menstruation disorder (often), violation of sexual functions (in particular, erectile dysfunction (in men), reduction or loss of libido (in men and women), abnormal orgasm) and the mammary glands (infrequently).

Dysphagia

The appearance of a violation of esophageal motility and aspiration is associated with the use of antipsychotic drugs. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's disease, which requires caution in such patients.

Regulation of body temperature

Antipsychotic drugs as a whole are attributed to a violation of the body's ability to control the internal temperature of the body. Appropriate care should be taken by patients who take olanzapine and at the same time are in conditions that increase the internal temperature of the body. For example, perform vigorous physical exercises, are exposed to high ambient temperatures, take with olanzapine any drug with anticholinergic activity or under conditions of dehydration (sweat intensively).

Children and teenagers under 18 years of age

Olanzapine is not recommended for use in children and adolescents under 18 years due to lack of sufficient data on efficacy and safety. In short-term studies that were conducted in adolescents aged 13-17 years, there was a greater increase in body weight and a change in the concentration of lipids and prolactin than in similar studies in adults.

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

Patients receiving olanzapine, the danger associated with the operation of machinery, including a vehicle, should be olanzapine may cause drowsiness and dizziness.

Form release / dosage:

Tablets, 5 mg or 10 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 1, 2, 3, 4 or 5 contour squares, together with the instructions for use, are placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 30 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002640

Date of registration:25.09.2014

Expiration Date:25.09.2019

The owner of the registration certificate:ALSI Pharma, ZAO ALSI Pharma, ZAO Russia

Manufacturer: & nbsp

ALSI Pharma, ZAO Russia

Representation: & nbspALSI Pharma CJSC ALSI Pharma CJSC Russia

Information update date: & nbsp15.08.2015

Illustrated instructions

Instructions

Olanzapine (Olanzapine)