Composition, form of production and packaging
The tablets covered with a film cover of white color, round, with the printed identification identification "LILLY 4112" on one side.
1 tab.
olanzapine 2.5 mg
Excipients: lactose monohydrate, giprolose (hydroxypropylcellulose), crospovidone, microcrystalline cellulose, magnesium stearate.
Sheath composition: hypromellose (methyl hydroxypropylcellulose), a mixture of white dye YS-1-18027-A, carnauba wax (for polishing), blue food ink (for labeling).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
The tablets covered with a film cover of white color, round, with the printed identification identification "LILLY 4115" on one side.
1 tab.
olanzapine 5 mg
Excipients: lactose monohydrate, giprolose (hydroxypropylcellulose), crospovidone, microcrystalline cellulose, magnesium stearate.
Sheath composition: hypromellose (methyl hydroxypropylcellulose), a mixture of white dye YS-1-18027-A, carnauba wax (for polishing), blue food ink (for labeling).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
The tablets covered with a film cover of white color, round, with the printed identification identification "LILLY 4116" on one side.
1 tab.
olanzapine 7.5 mg
Excipients: lactose monohydrate, giprolose (hydroxypropylcellulose), crospovidone, microcrystalline cellulose, magnesium stearate.
Sheath composition: hypromellose (methyl hydroxypropylcellulose), a mixture of white dye YS-1-18027-A, carnauba wax (for polishing), blue food ink (for labeling).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
The tablets covered with a film cover of white color, round, with the printed identification identification "LILLY 4117" on one side.
1 tab.
olanzapine 10 mg
Excipients: lactose monohydrate, giprolose (hydroxypropylcellulose), crospovidone, microcrystalline cellulose, magnesium stearate.
Sheath composition: hypromellose (methyl hydroxypropylcellulose), a mixture of white dye YS-1-18027-A, carnauba wax (for polishing), blue food ink (for labeling).
7 pcs. - blisters (1) - packs of cardboard.
7 pcs. - blisters (2) - packs of cardboard.
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2008.
PHARMACHOLOGIC EFFECT
Antipsychotic drug (neuroleptic) with a wide pharmacological spectrum of influence on a number of receptor systems.
In preclinical studies, the affinity of olanzapine for serotonin 5HT 2A / C -, 5HT 3 -, 5HT 6 receptors, dopamine D 1 -, D 2 -, D 3 -, D 4 -, D 5 receptors, muscarinic m1-5 -cholinoreceptors, adrenergic? 1 receptors and histamine H 1 -receptors. In experimental studies, the presence of antagonism of olanzapine with respect to serotonin 5HT receptors, dopamine and cholinergic receptors was revealed. In vivo and in vitro, olanzapine has a more pronounced affinity and activity for serotonin 5HT 2receptors compared to dopamine D 2 receptors. According to electrophysiological studies, olanzapine selectively decreases 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 causing catalepsy (a disorder reflecting a side effect on the motor function). Unlike other antipsychotics (antipsychotics), olanzapine enhances the anti-anxiety effect during the anxiolytic test.
In two placebo-controlled and two out of three comparative controlled trials involving 2,900 schizophrenic patients, olanzapine has been shown to provide statistically significant reduction in both productive (including delirium, hallucinations) and negative disorders.
PHARMACOKINETICS
Suction
After oral administration of olanzapine is well absorbed from the gastrointestinal tract, Cmax in plasma is reached after 5-8 hours. Olanzapine concentrations in plasma have a linear dependence on the dose (in the range from 1 to 20 mg). Eating does not affect the absorption of olanzapine.
Distribution
At a plasma concentration of 7 to 1000 ng / ml, binding to plasma proteins, mainly albumin and c? 1- acid glycoprotein, is about 93%.
Metabolism
Olanzapine is metabolized in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, which theoretically does not penetrate the BBB. Isozymes CYP1A2 and CYP2D6 cytochrome P 450 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Experimentalanimal studies have shown that these metabolites have significantly less pharmacological activity in vivo than olanzapine. The main pharmacological activity of the drug is due to the starting substance - olanzapine.
The activity of the cytochrome P 450 isoenzyme CYP2D6 does not affect the level of olanzapine metabolism.
Excretion
In healthy volunteers after ingestion of T 1/2 olanzapine is 33 h (21 - 54 h for 5-95%), and the average clearance in the plasma 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 special clinical cases
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 plasma (l / h)
Non-smokers 38.6 18.6
Smokers 30.4 27.7
Women 36.7 18.9
Men 32.3 27.3
Elderly (65 years and over) 51.8 17.5
Younger than 65 years old 33.8 18.2
However, the degree of changes in T 1/2 and clearance under the influence of each of these factors is significantly inferior to the degree of individual differences in these indicators.
There were no significant differences between mean T 1/2 values ​​and olanzapine clearance in patients with severe renal dysfunction compared with those with normal renal function.
In smokers with minor violations of liver function, the clearance of olanzapine is lower than that of non-smokers without such disorders.
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: treatment of exacerbations, supportive and long-term antiretroviral therapy of schizophrenia and other psychotic disorders with pronounced productive (including delirium, hallucinations, automatism) and / or negative (including 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 valproate is indicated for the treatment of acute manic or mixed episodes in bipolar affective disorder with or without psychotic manifestations and with or without rapid phase change. Olanzapine is indicated to prevent relapse 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.
DOSING MODE
In schizophrenia and similar psychotic disorders, the recommended initial dose of the drug is 10 mg 1 time / day. Zypresux can be taken regardless of food intake.Therapeutic doses range from 5-20 mg / day. The daily dose must be selected individually depending on the clinical condition of the patient. An increase in the dose above the standard dose of 10 mg / day is recommended only after an appropriate clinical examination of the patient.
In acute mania with bipolar disorder, the recommended initial dose of the drug is 15 mg 1 time / day. Therapeutic doses of olanzapine range from 5-20 mg / day. The daily dose must be selected individually depending on the clinical condition of the patient. An increase in the dose above the standard dose of 15 mg / day is recommended only after an appropriate clinical examination of the patient. Increase the dose should be gradual, with intervals of at least 24 hours.
For elderly patients, as well as for renal failure of severe or insufficient liver function of moderate severity, the drug is prescribed in an initial dose of 5 mg / day.
A decrease in the initial dose is recommended for patients with a combination of factors (female, elderly, non-smokers), which may slow the metabolism of olanzapine.
SIDE EFFECT
Very often (? 10%): drowsiness, weight gain. In 34% of patients, the prolactin concentration in the blood plasma was observed, which was weakly expressed and transient (the mean value of maximum concentrations of prolactin did not reach ULN and statistically significantly differed from placebo). Clinical manifestations of hyperprolactinemia associated with taking olanzapine (ie, gynecomastia, galactorrhea, and enlargement of the mammary glands) were rare. In most patients normalization of prolactin levels was observed without the abolition of olanzapine.
Another very frequent (? 10%) side effect associated with the use of olanzapine in clinical trials in patients with Alzheimer's dementia was gait disorders.
Often (<10% and? 1%): dizziness, asthenia, akathisia, increased appetite, peripheral edema, orthostatic hypotension, dry mouth, constipation. Occasionally, a transient, asymptomatic increase in hepatic transaminase activity (ALT, AST) was observed; in a few cases, an increase in plasma glucose levels up to ≥200 mg / dl (suspected diabetes), as well as ≥160 mg / dL, but <200 mg / dl (suspected hyperglycaemia) in patients with baseline glucose ≥140 mg / dl; in some patients asymptomatic eosinophilia was noted.
The table below summarizes the main side effects and their frequency, recorded during clinical trials and / or post-marketing periods, when treated with various olanzapine dosage forms.
System / Side Effect Frequency (%)
10 <10 and? 1 <1 and? 0.1 <0.1 and? 0.01 <0.01
Organism as a whole
2 Asthenia +
2 Increased sensitivity to light +
1 Weight gain +
The cardiovascular system
2 Bradycardia +
1 Orthostatic hypotension +
Digestive system
2 Constipation +
2 Dry mouth +
3 Hepatitis +
2 Increased appetite +
Metabolic disorders
3 Diabetic coma +
3.5 Diabetic ketoacidosis +
3 Hyperglycemia +
2 Peripheral edema +
3.6 Hypertriglyceridemia +
Nervous system
4 Violation of gait +
2 Akathisia +
2 Dizziness +
3 Seizures convulsions +
2 Drowsiness +
Skin and appendages
3 Rash +
Genitourinary system
3 Priapism +
Clinical Biochemistry
1 Increase in ALT +
1 Increase in AST +
1 Increased prolactin +
1 Single cases of elevated glucose levels of 160 mg / dL, but <200 mg / dL (suspected hyperglycemia) +
1 Single cases of increasing the level of glucose-200 mg / dl (suspected diabetes) +
Hematology
1 Eosinophilia +
3 Lakopenia +
3 Thrombocytopenia +
1 Evaluation of indicators from the database of clinical trials.
2 Side effects recorded in the clinical trials database.
3 Side effects recorded spontaneously in post-marketing studies.
4 Side effects identified in clinical studies in patients with Alzheimer's dementia.
5 In the COSTART classification, it is referred to as diabetic acidosis.
6 The COSTART classification is referred to as hyperlipidemia.
CONTRAINDICATIONS
- Hypersensitivity to the components of the drug.
PREGNANCY AND LACTATION
For planned or onset of pregnancy during therapy with olanzapine, patients should be advised to consult a doctor. Due to limited experience with olanzapine during pregnancy in humans, prescription of the drug is only possible in cases where the potential benefit of therapy for the mother significantly exceeds the potential risk to the fetus.
The study found that olanzapine is excreted in breast milk. If you need to use the drug during lactation, breastfeeding should be discontinued.
APPLICATION FOR FUNCTIONS OF THE LIVER
In severe renal failure, the drug is prescribed in an initial dose of 5 mg / day.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
If liver function is of moderate severity, the drug is prescribed in an initial dose of 5 mg / day.
SPECIAL INSTRUCTIONS
When using any antipsychotics, including olanzapine, it is possible to develop a malignant neuroleptic syndrome, a potentially fatal symptom complex. Clinical manifestations of this syndrome include a significant increase in body temperature, rigidity of the musculature, changes in mental status and autonomic disorders (unstable pulse or AD, tachycardia, cardiac arrhythmia, increased sweating). Additional signs may include increased levels of CK, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of malignant neuroleptic syndrome or a significant increase in body temperature without other symptoms of this syndrome require the withdrawal of all neuroleptics, including olanzapine.
In comparative studies lasting more than 6 weeks, treatment with olanzapine was significantly less often accompanied by the development of dyskinesia requiring drug correction than haloperidol. However, the risk of tardive dyskinesia with prolonged therapy with neuroleptics should be considered. With the development of signs of tardive dyskinesia, a dose reduction or elimination of olanzapine is recommended. Symptoms of tardive dyskinesia may increase or manifest after the drug is discontinued.
With particular caution, the drug should be used with an increase in the activity of AST and ALT in patients with insufficient liver function, limited functional reserve of the liver or in patients receiving potentially hepatotoxic drugs. In the event of increased activity of AST and / or ALT during treatment with olanzapine, careful monitoring of the patient and, if necessary, a reduction in the dose, are required.
Olanzapine should be used with caution in patients with epileptic seizures in the history or exposed to factors that reduce the threshold of convulsive readiness. In such patients, seizures were rare in the treatment with olanzapine.
Caution should be given to patients with a reduced number of leukocytes and / or neutrophils, due to various causes; with signs of oppression / toxic damage to bone marrow function under the influence of drugs in the anamnesis; with oppression of bone marrow function due to concomitant disease, radiotherapy or chemotherapy in history; with hypereosinophilia or myeloproliferative disease. In clinical studies, the use of olanzapine in patients with clozapine-dependent neutropenia or agranulocytosis in a history was not accompanied by relapses of these disorders.
In clinical trials, olanzapine therapy was rarely accompanied by side effects associated with the anticholinergic activity of the drug. However, clinical experience with olanzapine in patients with concomitant diseases is limited, and it is therefore advisable to use caution when administering olanzapine to patients with clinically significant prostatic hypertrophy, paralytic intestinal obstruction, occlusive glaucoma, and similar conditions.
In vitro, olanzapine exhibits antagonism against dopamine and, like other neuroleptics, can theoretically suppress the action of levodopa and dopamine agonists.
Given the nature of the drug on the central nervous system, caution should be used olanzapine in combination with other drugs of central action and ethanol.
Use in Pediatrics
The safety and efficacy of olanzapine in patients under the age of 18 years have not been studied.
Influence on the ability to drive vehicles and work with mechanisms
Patients taking olanzapine should exercise caution in managing mechanical means, including a car, as olanzapine may cause drowsiness.
OVERDOSE
Symptoms: very often (? 10%) - tachycardia, agitation / aggressiveness, articulation disorder, various extrapyramidal disorders and disorders of consciousness of varying severity (from sedation to coma). Other clinically significant effects of olanzapine overdose included delirium, seizures, malignant neuroleptic syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (<2% overdose), 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 1500 mg.
Treatment: there is no specific antidote for olanzapine. It is not recommended to induce vomiting artificially. Standard methods of detoxification (ie, gastric lavage, activated charcoal) are shown. Simultaneous reception of activated carbon decreases the bioavailability of olanzapine when ingested by 50-60%.
Symptomatic treatment is shown in accordance with the clinical condition and control of the functions of vital organs, including treatment of arterial hypotension, vascular collapse and support of respiratory function. Do not use epinephrine, dopamine and other sympathomimetics, which are agonists of? -adrenoceptors, becausestimulation of the latter can exacerbate arterial hypotension.
DRUG INTERACTION
The metabolism of olanzapine can be altered by inhibitors or inducers of cytochrome P 450 isoenzymes exhibiting specific activity against CYP1A2. The clearance of olanzapine increases in smokers and in patients taking carbamazepine (due to an increase in activity of CYP1A2). Known potential inhibitors of CYP1A2 can reduce the clearance of olanzapine. Olanzapine is not a potential inhibitor of CYP1A2 activity, so when taking olanzapine, the pharmacokinetics of drugs such as theophylline, which are metabolized primarily with the participation of CYP1A2, does not change.
In clinical trials, a single dose of olanzapine against the background of therapy with imipramine or its metabolite desipramine (CYP2D6, CYP3A4, CYP1A2), warfarin (CYP2C19), theophylline (CYP1A2), or diazepam (CYP3A4, CYP2C19) - was not accompanied by suppression of their metabolism. There were no signs of drug interaction with olanzapine in combination with lithium or biperiden.
Against the background of a stable concentration of olanzapine, there was no change in the pharmacokinetics of ethanol. However, the administration of ethanol with olanzapine may be accompanied by an increase in the pharmacological effects of olanzapine, for example, sedation.
A single intake of aluminum and magnesium-containing antacids or cimetidine does not affect the bioavailability of olanzapine when taken orally. Simultaneous reception of activated charcoal reduces the bioavailability of olanzapine by 50-60%.
Fluoxetine (60 mg once or 60 mg daily for 8 days) causes an increase in C max of olanzapine by an average of 16% and a decrease in the clearance of olanzapine by an average of 16%. The degree of influence of fluoxetine is significantly inferior to the severity of individual differences in these parameters, so it is usually not recommended to change the dose of olanzapine when it is administered in combination with fluoxetine.
In vitro studies using human liver microsomes showed that olanzapine slightly suppresses the process of formation of valproate glucuronide (the main pathway of valproate metabolism). Valproate also slightly affects the metabolism of olanzapine in vitro. Therefore, clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely.
According to in vitro studies using human liver microsomes, olanzapine has an extremely low potential to inhibit the activity of the following cytochrome P 450isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in a dry, protected from light at a temperature of 15 В° to 30 В° C. Shelf life for tablets is 3 years.
