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

Tablets 5 mg. Round biconvex tablets of light yellow color with impregnations of a darker (yellow) color, marked "O5", applied by stamping on one side of the tablet.

Tablets 10 mg. Round biconvex tablets from light yellow color with impregnations of a darker (yellow) color, marked "O7", stamping on one side of the tablet.

Pharmacotherapeutic group:antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.H.03 Olanzapine

Pharmacodynamics:

Antipsychotic drug (neuroleptic) with a wide pharmacological spectrum of influence on a number of receptor systems.

In preclinical studies, the affinity of olanzapine was established for 5HT_{2A / C}, 5HTs, 5HT₆-serotoninovid receptors, D₁-, D₂-, D₃-, D₄-, D₅dopamine receptors, M_1-5-muscarinic cholinergic receptors, α₁-adrenergic receptors and H₁-histamine receptors. In vivo and in vitro olanzapine has a more pronounced affinity and activity with respect to 5HT₂-serotonin receptors in comparison with D₂dopamine receptors.

Olanzapine reduces the conditioned protective reflex (a test characterizing antipsychotic activity) at doses lower than the doses causing catalepsy (a disorder reflecting a side effect on the motor function).

Olanzapine increases the anti-anxiety effect during the anxiolytic test.

Olanzapine significantly reduces and productive (delirium, hallucinations and others) and negative disorders.

Pharmacokinetics:

After oral administration olanzapine is well absorbed from the gastrointestinal tract (GIT), the maximum concentration in the blood plasma (C_max) is achieved in 5-8 hours.

The concentrations of olanzapine in blood plasma have a linear dependence on the dose of olanzapine in the range from 1 to 20 mg. Eating does not affect the absorption of olanzapine.

At a plasma concentration of 7 to 1000 ng / ml, binding to plasma proteins, mainly with albumin and with an α1-acid glycoprotein, 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 penetrate the blood-brain barrier (BBB). Isozymes CYP1A2 and CYP2D6 cytochrome P450 are involved in the formation of n-desmethyl metabolites and 2-hydroxymetabolites olanzapine. Metabolites have significantly less pharmacological activity than olanzapine.

The activity of the isoenzyme CYP2D6-cytochrome P450 does not affect the level of metabolism of olanzapine.

After oral administration, the mean half-life (T_1/2) olanzapine is 33 h (21-54 h for 5-95%), and the average plasma clearance is 26 l / h (12-47 l / h for 5-95%).

About 57% of radio-labeled olanzapine is excreted in the urine, mainly in the form of metabolites.

Pharmacokinetics in different groups of patients

Race does not affect the pharmacokinetics of olanzapine. The pharmacokinetic parameters of olanzapine vary depending on sex, age, the presence of a predilection for smoking:

Characteristics of patients	T_1/2 (h)	Clearance in blood 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
Elderly (65 years and over)	51,8	17,5
Younger than 65 years	33,8	18,2

Reliable differences between the mean values of T_1/2and clearance of olanzapine in patients with severe renal dysfunction, compared with those with normal renal function, is not established. In smokers with minor violations of liver function, the clearance of olanzapine is lower than that of non-smokers without such disorders.

Indications:

- Schizophrenia: treatment of exacerbations, sustained and prolonged anti-relapse therapy for schizophrenia;

- 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 shown to prevent relapse in patients with bipolar disorder who have olanzapine was effective in treating the manic phase.

Contraindications:

- Hypersensitivity to olanzapine or other components of the drug;

- lactation period;

- age up to 18 years;

- lactose intolerance, lactase deficiency, glucose-galactose malabsorption;

- Closed-angle glaucoma.

Carefully:

Hepatic insufficiency, prostatic hyperplasia, epilepsy, myelosuppression (including leukopenia, neutropenia), myeloproliferative diseases, hypereosinophilic syndrome, paralytic intestinal obstruction.

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.

The study found that olanzapine excreted in breast milk. The average dose received by the child (mg / kg) 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 during therapy with olanzapine.

Dosing and Administration:

With schizophrenia the recommended initial dose of the drug is 10 mg per day.

The drug can be taken regardless of food intake.Therapeutic doses fluctuate in the range of 5-20 mg per day and are selected individually depending on the clinical condition of the patient.

In acute mania with bipolar disorder the recommended initial dose of the drug is 15 mg per day once or <10 mg per day once in combination with lithium preparations. With depression associated with bipolar disorders, 5 mg per day once in combination with 20 mg of fluoxetine (if necessary, changes in the doses of drugs).

Elderly patients, patients with risk factors (including those with severe hepatic insufficiency or hepatic insufficiency of moderate severity) and patients with a combination of at least two factors, which can slow the metabolism of olanzapine (female sex, senility, non-smokers), it is recommended that the initial dose be reduced to 5 mg per day and, if necessary, a slower increase in the dose.

Side effects:

Frequency of side effects: very often (1/10 or more); often (1/100 or more, less than 1/10); infrequently (1/1000 and more, less than 1/100); the frequency is unknown (that is, it can not be determined from the available data).

From the side of the circulatory and lymphatic systems: often - eosinophilia, infrequently - leukopenia, neutropenia; frequency unknown - thrombocytopenia.

From the immune system: the frequency is unknown - allergic reactions (angioedema, itching, urticaria).

From the side of metabolism: very often - an increase in body weight (regardless of the index of the mass of the case); often - hypercholesterolemia^1,2, hyperglycemia³, hypertriglyceridemia^1,4Glucosuria, increased appetite, edema; frequency unknown - development or decompensation of diabetes mellitus, ketoacidosis, diabetic coma, including fatal outcome, hypothermia.

¹The average increase in fasting lipids (cholesterol, low density lipoprotein (LDL), triglycerides) is more pronounced in patients without initial signs of lipid metabolism.

²An increase in the concentration of cholesterol from normal fasting values (<5.17 mmol / l) to elevated (≥ 6.2 mmol / l) is observed frequently.

Cholesterol concentration change from fasting fasting (≥ 5.17 mmol / L - <6.2 mmol / l) to elevated (≥ 6.2 mmol / l) is observed very often.

³Increase in glucose concentration from normal fasting values (<5.56 mmol / l) to elevated (≥ 7 mmol / l) is observed frequently.

Change in glucose concentration from fasting borderline≥ 5.56 mmol / L - <7 mmol / l) to elevated (≥ 7 mmol / l) is observed very often.

⁴An increase in the concentration of triglycerides from normal fasting values (<1.69 mmol / l) to elevated (≥ 2.26 mmol / l) is observed frequently.

A change in the concentration of triglycerides from fasting marginal indices (≥ 1.69 mmol / L - <2.26 mmol / l) to elevated (≥ 2.26 mmol / l) is very frequent.

From the nervous system: very often - drowsiness; often dizziness, - akathisia, parkinsonism, dyskinesia, fatigue, asthenia; frequency is unknown - seizures in patients with a history of seizures or with the presence of risk factors for seizures, malignant neuroleptic syndrome (NSA), dystonia (including oculogyric crisis), tardive dyskinesia, withdrawal syndrome (sweating, insomnia, tremors, anxiety, nausea, vomiting).

From the skin: often - a rash; infrequently - photosensitivity, alopecia.

From the side of the musculoskeletal system: the frequency is unknown - rhabdomyolysis.

From the urinary system: infrequent urinary incontinence; frequency unknown - delay in the onset of urination.

From the digestive system: often - short-term anticholinergic effects (including constipation and dryness of the oral mucosa),transient increase in the activity of "hepatic" transferases (alanine aminotransferase, aspartate aminotransferase); frequency unknown - pancreatitis, hepatitis (including hepatic cell, hepatocellular and mixed), hepatic cholestasis.

From the side of the cardiovascular system: often - orthostatic hypotension; infrequent bradycardia, prolongation of the QT interval on an electrocardiogram (ECG); frequency unknown - ventricular tachycardia, ventricular fibrillation, sudden death, pulmonary embolism, deep vein thrombosis.

From the side of the reproductive system: often - decreased libido, erectile dysfunction; infrequently - an increase in mammary glands, amenorrhea, galactorrhea in women, gynecomastia in men; frequency is unknown - priapism.

Laboratory indicators: very often hyperprolactinemia; infrequently - an increase in the activity of creatine phosphokinase (CK), hyperbilirubinemia; frequency unknown - increased activity of alkaline phosphatase.

Side effects in special therapeutic groups

In patients with psychosis in the background of dementia - very often - violations of gait and fall.

In elderly patients with psychosis in the background of dementia - often - incontinence of urine and pneumonia.

In patients with psychosis induced by the drug (dopamine receptor agonist) in Parkinson's disease - very often - increased symptoms of parkinsonism, as well as hallucinations.

In patients with bipolar mania (olanzapine in combination with preparations of lithium and valproic acid) - very often - weight gain, dryness of the oral mucosa, increased appetite, tremor; often - speech disorder.

Overdose:

Very frequent symptoms: tachycardia, agitation / aggressiveness, frustration, articulation, various extrapyramidal disorders and disorders of consciousness of varying severity (from sedative to coma), as well as delirium, seizures, CNS, respiratory depression, aspiration, increased blood pressure, lowering of arterial pressure, arrhythmias , cardiac arrest and respiration.

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 1500 mg.

Treatment: there is no specific antidote. It is not recommended to induce vomiting artificially. Standard methods of detoxification, that is, gastric lavage, reception of activated charcoal (the bioavailability of olanzapine can be reduced by 50-60% are shown.Symptomatic treatment is shown in accordance with the clinical condition and control of the functions of vital organs, including treatment of arterial hypotension, circulatory disorders and support of respiratory function. Do not use epinephrine, dopamine and other sympathomimetics, which are β-adrenergic receptor agonists, since stimulation of the latter can exacerbate arterial hypotension.

Interaction:

Inductors or inhibitors of the CYP1A2 isoenzyme may alter the metabolism of olanzapine.

The clearance of olanzapine increases in smoking patients and with simultaneous use with carbamazepine, as this increases the activity of the isoenzyme CYP1A2.

Ethanol did not affect the pharmacokinetics of olanzapine in the equilibrium state, but the administration of ethanol together with olanzapine may be accompanied by an increase in the pharmacological effects of olanzapine (sedation).

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

Fluoxetine (60 mg once or 60 mg daily for 8 days) increases C_max olanzapine by 16% and reduces clearance by 16%, which has no clinical significance (no correction of olanzapine dose is required).

Fluvoxamine (an inhibitor of the isoenzyme CYP1A2), decreasing the clearance of olanzapine, increases C_max olanzapine in non-smokers for 54% and 77% for men who smoke, the area under the concentration-time curve (AUC) is 52% and 108%, respectively (a dose reduction of olanzapine is necessary).

Olanzapine slightly suppresses the formation of valproic acid glucuronide (the main pathway of metabolism). Valproic acid slightly affects the metabolism of olanzapine. Clinically significant pharmacokinetic interaction between olanzapine and valproic acid is unlikely.

Known potential inhibitors of the CYP1A2 isoenzyme may reduce the clearance of olanzapine. Olanzapine is not a potential inhibitor of the activity of the isoenzyme CYP1A2, so when taking olanzapine, the pharmacokinetics of drugs such as theophylline, mainly metabolized with the participation of the isoenzyme CYP1A2, does not change.

Single administration of olanzapine against the background of therapy with the following drugs was not accompanied by suppression of the metabolism of these drugs: imipramine or its metabolite desipramine (isozymes CYP2D6, CYP3A, CYP1A2), warfarin (isoenzyme CYP2C19), theophylline (isoenzyme CYP1A2) or diazepam (isoenzymes CYP3A4, CYP2C19).

There were no signs of interaction when using olanzapine in combination with lithium or biperidin.

A single dose of aluminum-or magnesium-containing antacid or cimetidine did not interfere with the bioavailability of olanzapine when ingested.

In vitro olanzapine also very little suppressed the activity of cytochrome P450 isoenzymes (isozymes CYP2D6, CYP3A, CYP1A2, CYP2C9, CYP2C19).

Caution should be exercised when taking olanzapine with drugs that increase the QT interval on the ECG.

Caution should be exercised when using olanzapine in combination with other central-action drugs or containing ethanol.

Special instructions:

Malignant neuroleptic syndrome (CNS)

In the treatment with neuroleptics (including olanzapine), NSA can develop (hyperthermia, rigidity of muscles, changes in mental status, autonomic disorders, including unstable pulse or increased blood pressure, tachycardia, cardiac arrhythmias, increased sweating, increased activity of CK, myoglobinuria as a result rhabdomyolysis, acute renal failure).

When identifying clinical manifestations of the NSA or significant hyperthermia without other clinical manifestations of the NSA, the removal of olanzapine is required.

Late dyskinesia

In the development of signs of late dyskinesia, a dose reduction or abolition of olanzapine is recommended. Symptoms of tardive dyskinesia may increase or manifest after the drug is discontinued.

Experience in elderly patients with psychosis on the background of dementia

When taking olanzapine (in studies), in elderly patients with psychosis against a background of dementia, cerebrovascular disorders (stroke, transient ischemic attack), including fatal outcomes, were noted. These patients had previous risk factors (cerebrovascular disorders (history), transient ischemic attack, hypertension, smoking), as well as concomitant diseases and / or medications, associated with cerebrovascular disorders. The increased risk of death does not depend on the dose of olanzapine or the duration of therapy. Risk factors predisposing to death include: age over 65 years, dysphagia, sedation, malnutrition and dehydration, lung diseases (for example, pneumonia, including aspiration), simultaneous reception of benzodiazepines.

Olanzapine is not recommended for the treatment of elderly patients with psychosis on the background of dementia, since efficacy is not established.

The duration of the QT interval on the ECG

In clinical studies, a clinically significant prolongation of the QT interval on the ECG (QT interval with Fderia [QTcF]> 500 msec correction in patients with a baseline QTcF <500 msec) in patients who received olanzapine, in the absence of significant differences with placebo in the frequency of occurrence of adverse events from the heart. However, as with other antipsychotics, caution should be exercised in prescribing olanzapine in combination with drugs that can prolong the QT interval on the ECG, especially in elderly patients, with congenital QT interval prolongation, congestive heart failure, myocardial hypertrophy, hypokalemia and hypomagnesemia.

Abolition of therapy

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

Dysfunction of the liver

A special precaution is needed when increasingactivity of alanine aminotransferase and / or aspartate aminotransferase in patients with hepatic impairment or receiving potentially hepatotoxic drugs. It is necessary to monitor the patient and, if necessary, reduce the dose.

Hyperglycemia and diabetes mellitus

There is a higher prevalence of diabetes mellitus in patients with schizophrenia. Very rarely there were cases of hyperglycemia, development of diabetes mellitus or exacerbation of pre-existing diabetes mellitus, ketoacidosis and diabetic coma. There is no causal relationship between antipsychotic drugs and these conditions. Clinical monitoring of patients with diabetes mellitus or with risk factors for its development is recommended.

Epileptic seizures

Olanzapine should be used with caution in patients with epileptic seizures in the history or in the presence of factors that reduce the threshold of convulsive readiness.

Hematologic changes

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

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

M-holinoblocking activity

It is recommended to be cautious when prescribing olanzapine to patients with prostatic hyperplasia with clinical manifestations, paralytic intestinal obstruction, in connection with the established affinity for cholinergic receptors.

Dopaminergic antagonism

Olanzapine exhibits antagonism against dopamine receptors and, theoretically, can suppress the action of levodopa and dopamine receptor agonists.

General activity in relation to the central nervous system

Caution should be exercised when using olanzapine in combination with other central-action drugs or containing ethanol.

Parkinson's disease

It is not recommended to use olanzapine in psychoses induced by dopamine receptor agonists in the treatment of Parkinson's disease because of the high risk of enhancing symptoms of parkinsonism and / or hallucinations.

Development of risk of sudden death

Experience in the clinical use of any antipsychotic, including olanzapine, revealed 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.

Thromboembolism

On the background of olanzapine therapy, the development of venous thromboembolism is extremely rare, but a cause-and-effect relationship is not established. Given that patients with schizophrenia often have acquired risk factors for venous thromboembolism, it is required to conduct a comprehensive assessment of all possible risk factors for the development of this complication, including immobilization of patients, and to take the necessary preventive measures.

Neutropenia

The development of neutropenia was reported, mainly, with the simultaneous administration of olanzapine and valproic acid.However, caution should be exercised olanzapine in patients with low leukocyte and / or neutrophil count in the blood; receiving drugs that can cause neutropenia; with oppression of bone marrow function, disease caused by radiation sickness or chemotherapy; as well as in patients with eosinophilia and / or myeloproliferative diseases.

Change in lipid profile

Clinical observation of patients receiving olanzapine, for the purpose of controlling undesirable changes in the lipid profile.

Postural hypotension

Postural hypotension was rarely observed in clinical studies of olanzapine in the elderly. Just as with the use of other antipsychotics, in the case of olanzapine, patients older than 65 years are advised to periodically monitor blood pressure.

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 some 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.

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 reduce the number of tablets taken by the patient in order to reduce the risk of overdose.

Effect on the ability to drive transp. cf. and fur:During treatment with olanzapine, care should be taken when driving vehicles and engaging in potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions, since olanzapine can cause drowsiness.

Form release / dosage:

Tablets, 5 mg and 10 mg.

Packaging:

For 7 tablets in a blister of aluminum foil, PVC film and polyamide.

For 2, 4 or 8 blisters together with instructions for use in a cardboard bundle.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001465

Date of registration:26.01.2012

Date of cancellation:2017-04-21

The owner of the registration certificate:Ranbaxy Laboratories LimitedRanbaxy Laboratories Limited India

Manufacturer: & nbsp

RANBAXY LABORATORIES, Ltd. India

Representation: & nbspRABBAYS LABORATORY LIMITEDRABBAYS LABORATORY LIMITED

Information update date: & nbsp21.04.2017

Illustrated instructions

Instructions

Olanex (Olanex)