Composition, form of production and packaging
The tablets covered with a film membrane of yellow color, oblong, biconcave, with risk on one side and engraving "E 402" - on another, without or almost without a smell.
1 tab.
olanzapine dihydrochloride trihydrate 7.03 mg,
which corresponds to the content of olanzapine 5 mg
Excipients: microcrystalline cellulose - 40.99 mg, lactose monohydrate - 40.98 mg, giprolose (hydroxypropylcellulose) - 5 mg, crospovidone - 5 mg, magnesium stearate - 1 mg.
The composition of the membrane: hypromellose 1.4 mg, dye quinoline yellow 0.014 mg, opadrai Y-1-700 white 2.79 mg (hypromellose 62.5%, titanium dioxide 31.25%, macrogol 400 6.25%).
7 pcs. - blisters (4) - packs of cardboard.
7 pcs. - blisters (8) - packs of cardboard.
The tablets covered with a film cover of yellow color, round, biconcave, with engraving "E 404" on one side, without or almost without a smell.
1 tab.
olanzapine dihydrochloride trihydrate 14.06 mg,
which corresponds to the content of olanzapine 10 mg
Excipients: microcrystalline cellulose - 81.97 mg, lactose monohydrate - 81.97 mg, giprolose (hydroxypropyl cellulose) - 10 mg, crospovidone - 10 mg, magnesium stearate - 2 mg.
Sheath composition: hypromellose - 2.4 mg, dye quinoline yellow - 0.023 mg, opadrai Y-1-700 white - 4.68 mg (hypromellose - 62.5%, titanium dioxide - 31.25%, macrogol 400 - 6.25%).
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 2016.
PHARMACHOLOGIC EFFECT
Olanzapine is an antipsychotic agent (neuroleptic) with a broad pharmacological spectrum of influence on a number of receptor systems.
It has an affinity for serotonin (5-HT 2A / C , 5HT 3 , 5HT 6 ), dopaminovym (D 1 , D 2 , D 3 , D 4 , D 5 ), muscarinic (M 1-5 ) receptors, adrenoreceptors ) and histamine (H 1 ) receptors.
Antagonism to serotonin (5HT), dopamine and cholinergic receptors was revealed. It has more pronounced affinity and activity with respect to serotonin 5HT 2 receptors, in comparison with dopamine D 2 -receptors.
Selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, has an insignificant effect on the striatum (A9) nerve pathways involved in the regulation of motor functions. Reduces the conditioned protective reflex in lower doses than the doses causing catalepsy. Strengthens the anti-anxiety effect during the anxiolytic test. Reliably reduces the productive (including delirium, hallucinations) and negative symptoms.
PHARMACOKINETICS
Suction and distribution
Olanzapine is well absorbed after ingestion. With MAX after oral administration is achieved after 5-8 hours. Food does not affect the absorption of the drug.
When taken in the dose range of 1-20 mg, the concentration in the plasma changes linearly, in proportion to the dose.
At a plasma concentration of 7-1000 ng / ml, binding to proteins is 93%; mainly with albumin and alpha 1- acid glycoprotein.
Metabolism and excretion
Metabolised in the liver by conjugation and oxidation. The main circulating metabolite is 10-N-glucuronide, it does not penetrate the GEB. Isozymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine.
The main pharmacological activity of the drug is due to olanzapine, the activity of its metabolites is less pronounced.
It is excreted by the kidneys - 57% (mainly in the form of metabolites).
In healthy volunteers after ingestion of T 1/2 olanzapine is 33 h (21-54 h), and the average plasma clearance is 26 l / h (12-47 l / h). T 1/2 olanzapine may vary depending on age and sex, as well as smoking status: non-smokers (clearance 18.6 l / h, T 1/2 - 38.6 h), smoking (27.7 l / h, T 1 / 2 - 30.4 hours), women (ground clearance - 18.9 l / h, T 1/2 - 36.7 h), men (clearance 27.3 l / h, T 1/2 - 32.3 h), patients 65 years and older (ground clearance - 17.5 l / h, T 1/2 - 51.8 h), patients under 65 years of age (ground clearance - 18.2 l / h, T 1/2 - 33.8 h).
The degree of changes of T 1/2 and plasma clearance under the influence of each of these factors is significantly inferior to the degree of individual differences in these parameters. There were no significant differences between mean T 1/2 values ​​and plasma clearance of olanzapine in patients with severe renal dysfunction and in patients with normal renal function.
INDICATIONS
- treatment of schizophrenia;
- Supportive and prolonged anti-relapse therapy in patients with schizophrenia who responded to the initial treatment;
- Treatment of a manic episode of moderate and severe severity;
- prevention of relapses in patients with bipolar disorder, in whom the drug was effective in the treatment of a manic episode;
- in combination with fluoxetine 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 for this episode). Egolans В® as monotherapy is not indicated for the treatment of therapeutically-resistant depression;
- in combination with fluoxetine for the treatment of a depressive episode in the structure of bipolar disorder. Egolans В® as monotherapy is not indicated for the treatment of a depressive episode in the structure of bipolar disorder.
DOSING MODE
Inside, regardless of food intake, once - 5-20 mg / day.
In schizophrenia in adults, the recommended initial dose is 10 mg / day.
In acute mania associated with bipolar disorders, adults - 15 mg / day (1 time) as monotherapy or 10 mg / day (1 time) in combination with lithium or valproic acid (maintenance therapy at the same dose).
Prevention of recurrence of bipolar disorder : the recommended initial dose is 10 mg / day. Patients who previously received olanzapine to treat a manic episode should continue treatment at the same dose to prevent relapse. In the presence of a new manic, mixed or depressive episode, taking olanzapine should be continued (if necessary, specifying the dose); In the presence of clinical indications should additionally prescribe drugs to eliminate mood disorders.
In the treatment of schizophrenia, a manic episode, as well as to prevent the recurrence of bipolar disorder, the daily dose can be subsequently adjusted in the range of 5 to 20 mg, taking into account the clinical state of the individual patient. Dose correction beyond the recommended dose as the initial dose is recommended only after careful clinical analysis, and should normally occur at intervals of at least 24 hours.
Before stopping taking olanzapine, you should gradually reduce the dose. The maximum daily dose of olanzapine is 20 mg.
A lower initial dose (5 mg / day) is not required for all patients, but is possible for patients aged 65 years and older with clinical indications.
For patients with impaired hepatic function / or kidney function , a reduction in the initial dose (up to 5 mg / day) may be required. For moderate hepatic insufficiency (cirrhosis, class A or B by Child-Pugh) , an initial dose of 5 mg should be given and increased with caution.
Women should be prescribed the drug in the same doses as men.
Smoking patients should be prescribed the drug at the same doses as non-smokers. In the presence of more than one factor that can cause a slowdown in metabolism (female, elderly, non-smokers), the need to reduce the initial dose to 5 mg / day should be considered. If necessary, further increase in dose with caution.
SIDE EFFECT
The frequency of side effects noted when taking the drug is given in accordance with the WHO classification: very often (> 1/10), often (> 1/100 and <1/10), infrequently (> 1/1000 and <1/100) , rarely (> 1/10 000 and <1/1000), very rarely (<1/10 000, including individual reports).
From the nervous system: very often - drowsiness; often - dizziness, akathisia, parkinsonism, asthenia, dyskinesia; rarely - convulsive syndrome (more often in the background of convulsive syndrome in anamnesis); very rarely - dystonia (including the oculogic crisis) and tardive dyskinesia. It is very rare to develop ZNS. Clinical manifestations of CNS are fever, rigidity of muscles, changes in mental state, instability of autonomic functions (unstable levels of heart rate and blood pressure, tachycardia, sweating, cardiac arrhythmia). Additional signs may be an increase in the level of CK, myoglobinuria (rhabdomyolysis) and acute renal failure. When the patient develops symptoms and signs of the CNS or the occurrence of unexplained fever without additional clinical manifestations of the NSA, all antipsychotics, including olanzapine.
With a sharp withdrawal of the drug, it is very rare to notice such symptoms as increased sweating, insomnia, tremor, anxiety, nausea, or vomiting.
From the side of the cardiovascular system: often - arterial hypotension (including orthostatic); infrequently - a bradycardia with a collapse or without; very rarely - an increase in the interval of QT c on the ECG, ventricular tachycardia / fibrillation and sudden death; very rarely - thromboembolism (including pulmonary artery embolism and deep vein thrombosis).
From the side of the digestive system: often - transitory anticholinergic effects, incl. constipation and dryness of the oral mucosa, transient, asymptomatic increase in hepatic transaminase activity (ALT, ACT), especially at the beginning of therapy; rarely - hepatitis (including hepatocellular, cholestatic or mixed liver damage); very rarely - pancreatitis, increased activity of AP and total bilirubin.
From the side of metabolism: very often - an increase in body weight; often - increased appetite, hypertriglyceridemia; very rarely - hyperglycemia and / or decompensation of diabetes mellitus, sometimes manifested by ketoacidosis or coma, including death; hypercholesterolemia, hypothermia.
On the part of the organs of hematopoiesis: often - eosinophilia; rarely - leukopenia; very rarely - thrombocytopenia, neutropenia; in isolated cases - asymptomatic eosinophilia.
From the musculoskeletal system: very rarely - rhabdomyolysis.
From the genitourinary system: very rarely - urinary retention, priapism.
On the part of the skin: infrequently - the reaction of photosensitization; very rarely - alopecia.
Allergic reactions: rarely - skin rash; very rarely - anaphylactoid reactions, angioedema, skin itching or urticaria.
Laboratory indicators: hyperprolactinemia is very common, but clinical manifestations (eg, gynecomastia, galactorrhea and breast enlargement) are rare; in most patients, the level of prolactin spontaneously normalizes without the abolition of therapy. Infrequent - increased activity of CK; in isolated cases there was an increase in the concentration of glucose in the blood plasma, triglycerides, cholesterol.
Other: often - asthenia, peripheral edema; very rarely - withdrawal syndrome.
In elderly patients with dementia, a large incidence of deaths and cerebrovascular disorders (stroke, transient ischemic attacks) is documented in studies. Very frequent in this category of patients were violations of gait and fall. Also often observed pneumonia, fever, lethargy, erythema, visual hallucinations and urinary incontinence.
Among patients with medicinal (against the background of dopamine agonists) psychoses on the background of Parkinson's disease often recorded worsening of parkinsonian symptoms and the development of hallucinations.
There are data on the development of neutropenia (4.1%) against a combination therapy with valproic acid in patients with bipolar mania. Simultaneous therapy with valproic acid or lithium helps to increase the frequency (more than 10%) of tremors, dryness of the oral mucosa, increase appetite or weight gain. Violations of speech (from 1 to 10%) were also recorded.
CONTRAINDICATIONS
- risk of development of an angle-closure glaucoma;
- Children and adolescence under 18 years (due to inadequate clinical data);
- lactose intolerance, lactase deficiency or glucose-galactose malabsorption (the preparation contains lactose);
- Hypersensitivity to the components of the drug.
With caution
Hepatic insufficiency, renal failure, prostatic hyperplasia, epilepsy, a history of convulsive syndrome, myelosuppression (including leukopenia, neutropenia), myeloproliferative diseases, hypereosinophilic syndrome, paralytic intestinal obstruction, pregnancy, cardiovascular and cerebrovascular diseases or other conditions predisposing to arterial hypotension, congenital increase in the QT interval on the ECG (increasing the interval of QT c on the ECG), or in the presence of conditions potentially capable cause an increase in the QT interval (for example, simultaneous administration of drugs prolonging the QT interval, congestive heart failure, hypokalemia, hypomagnesemia), advanced age, and simultaneous intake of other central-action drugs; immobilization.
PREGNANCY AND LACTATION
Due to the lack of experience in pregnant women, the drug should be prescribed during pregnancy only if the intended benefit to the mother significantly exceeds the potential risk to the fetus. Patients should be cautioned that if they are onset or planning a pregnancy during treatment with olanzapine, they need to inform their doctor about it.
Very spontaneous reports were received that newborns whose mothers took olanzapine in the third trimester of pregnancy had tremors, muscle hypertonia, lethargy, and drowsiness.
Studies have shown that olanzapine is excreted in breast milk. The average dose received by the child (mg / kg) when the C ss 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.
Influence on fertility is unknown.
APPLICATION FOR FUNCTIONS OF THE LIVER
For patients with impaired renal function, a reduction in the initial dose (up to 5 mg / day) may be required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
For patients with impaired hepatic function , a reduction in the initial dose (up to 5 mg / day) may be required. For moderate hepatic insufficiency (cirrhosis, class A or B by Child-Pugh) , an initial dose of 5 mg should be given and increased with caution.
APPLICATION FOR CHILDREN
Contraindicated use of the drug in children and adolescents under 18 years due to inadequate clinical data.
APPLICATION IN ELDERLY PATIENTS
A lower initial dose (5 mg / day) is not required for all patients, but is possible for patients aged 65 years and older with clinical indications.
SPECIAL INSTRUCTIONS
During the administration of antipsychotics, the improvement of the clinical state of patients can occur within a few days or weeks. During this period, patients need careful monitoring.
Psychosis and / or behavioral disorders associated with dementia
Olanzapine is not approved for the treatment of psychosis and / or behavior disorders associated with dementia, and this drug is not recommended for use in such patients because of increased mortality and risk of impaired cerebral circulation. With olanzapine in elderly patients with psychosis against a background of dementia, cerebrovascular disorders (stroke, transient ischemic attack), including lethal outcomes, were noted. These patients had previous risk factors (cerebrovascular disorders (history), transient ischemic attacks, hypertension, smoking), as well as concomitant diseases and / or drug use associated with cerebrovascular disorders.
The use of olanzapine is not recommended for the treatment of psychoses associated with the administration of dopamine agonists in patients with Parkinson's disease.
Malignant neuroleptic syndrome (CNS)
In the treatment with neuroleptics (including olanzapine), the ZNS can develop. Clinical manifestations of CNS are fever, rigidity of muscles, changes in mental state, instability of autonomic functions (unstable levels of heart rate and blood pressure, tachycardia, sweating, cardiac arrhythmia). Additional signs may be an increase in the level of CK, myoglobinuria (rhabdomyolysis) and acute renal failure. When the patient develops symptoms and signs of the CNS or the occurrence of unexplained fever without additional clinical manifestations of the NSA, all antipsychotics, including olanzapine.
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.
Changes in lipid levels
When lipid levels change with olanzapine taking, appropriate treatment should be prescribed, especially in patients with dyslipidemia or risk factors for fat metabolism disorders.
Anticholinergic activity
Despite the fact that olanzapine in vitro has anticholinergic activity, due to the limited clinical experience of olanzapine in patients with concomitant diseases, caution is recommended when prescribing this drug to patients with prostatic hypertrophy, paralytic intestinal obstruction and other similar conditions.
Liver function
Particular care is required with an increase in liver transaminase, ALT and / or ACT in patients with hepatic failure or treated with potentially hepatotoxic drugs. It requires observation of the patient and, if necessary, dose reduction. In identifying hepatitis (including hepatocellular, cholestatic liver injury or mixed) olanzapine should cease.
neutropenia
Olanzapine should be used with caution in patients with a reduction in the number of white blood cells, including neutrophils; with symptoms of depression or toxic disturbances of the bone marrow under the influence of drugs (history); with inhibition of bone marrow function due to concurrent disease, radio- or chemotherapy (history); with hypereosinophilic or myeloproliferative disease. Neutropenia is often seen during concomitant use of olanzapine and valproate. Use of olanzapine in patients with neutropenia and agranulocytosis klozapinzavisimoy (history) is not accompanied by relapses of these faults.
Discontinuation of the drug
In a dramatic olanzapine in very rare cases (<0.01%) acute symptoms have been reported, for example, insomnia, tremor, anxiety, nausea, or vomiting.
Interval QT
As in the case of other antipsychotic drugs during treatment with olanzapine should be careful, if this drug is given together with drugs that prolong the interval of the QT c , particularly in elderly patients, patients with a syndrome of congenital lengthening of the QT, congestive heart failure, hypertrophy heart, hypokalemia, hypomagnesemia, or prolongation of the QT family history.
It should avoid the simultaneous use of other antipsychotics or drugs also lengthen QT interval or causing hypokalemia.
thromboembolism
Coincidence of olanzapine and venous thromboembolism registered in rare cases (less than 0.01%). The causal relationship of symptoms of venous thromboembolism and olanzapine has not been established. However, since patients with schizophrenia often have acquired venous thromboembolism risk factors, should identify all possible risk factors for venous thromboembolism, such as immobility of patients and to take preventive measures.
Seizures
Olanzapine should be used with caution in patients with a history of seizures or are exposed to factors that reduce the seizure threshold. Seizures in patients treated with olanzapine, are rare. In most of these cases are registered in the history of seizures or risk factors for seizures.
Tardive dyskinesia
With the development of symptoms of tardive dyskinesia recommended dose reduction or elimination of olanzapine. The symptoms of tardive dyskinesia can grow or manifest after drug withdrawal.
Orthostatic hypotension
In clinical trials, olanzapine orthostatic hypotension was observed infrequently in older patients. As in the case of receiving other antipsychotics, it is recommended periodically to measure blood pressure in patients older than 65 years.
Using Pediatric
Olanzapine is not recommended for use in the treatment of children and adolescents. Studies in patients aged 13-17 yearsRevealed various undesirable reactions, including weight gain, changes in metabolic parameters and increase in prolactin levels. Long-term outcomes of these events have not been studied and remain unknown.
Lactose
This formulation contains lactose, so it should not be given to patients with the rare genetic disorders tolerance galactose, hereditary deficiency Sami lactase or glucose-galactose malabsorption.
Additional Information
Caution must be exercised when the use of olanzapine in combination with other centrally acting drugs and ethanol.
Impact on the ability to drive vehicles and manage mechanisms
During the period of treatment must be careful when driving and classes of potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE
Symptoms: tachycardia, agitation / aggression, articulation disorder, extrapyramidal disorders, depression of varying severity consciousness (from sedation to coma), delirium, seizures, neuroleptic malignant syndrome, respiratory depression, aspiration, increase or decrease in blood pressure, arrhythmia, heart failure and breathing.
The minimum dose for acute lethal overdose was 450 mg, the maximum dose with a favorable outcome (survival) - 1500 mg.
Treatment:gastric lavage, appointment of activated carbon, symptomatic therapy, maintenance of respiratory function. Should not be used sympathomimetics (including noradrenaline, dopamine) that are agonists of the? -adrenoceptor (stimulation of these receptors may aggravate blood pressure reduction). Careful medical supervision and monitoring should continue until the patient recovers.
DRUG INTERACTION
Isoenzyme inducers or inhibitors of CYP1A2 can alter the metabolism of olanzapine.
Inducers of CYP1A2 isoenzyme: olanzapine clearance is increased in smokers and patients with concomitant use of carbamazepine, leading to a decrease in olanzapine plasma concentrations. You may need to increase the dose.
Inhibitors of CYP1A2 isoenzyme: fluvoxamine significantly inhibit the metabolism of olanzapine. Reducing clearance olanzapine increases C max olanzapine in nonsmoking women 54% and 77% - in male smokers, AUC - 52% and 108%, respectively, however patients receiving fluvoxamine or any other inhibitor of isozyme CYP1A2 (e.g., ciprofloxacin) follows consider the possibility of using a lower initial dose of olanzapine.
Activated charcoal reduces the bioavailability of olanzapine by 50-60% and should be taken at least 2 hours before or 2 hours after olanzapine.
Fluoxetine (an inhibitor of CYP2D6), and a single intake of antacids (aluminum or magnesium) or cimetidine, had no significant effect on the pharmacokinetics of olanzapine.
Ethanol did not affect the pharmacokinetics of olanzapine in the equilibrium state, however, the reception of ethanol together with olanzapine may be associated with increased pharmacological effects of olanzapine (sedation).
Olanzapine significantly suppresses the formation of glucuronide valproic acid (main metabolic pathway). Valproic acid does not significantly affect the metabolism of olanzapine. Clinically significant pharmacokinetic interaction between valproic acid and olanzapine unlikely.
Need for caution in the use of olanzapine with drugs prolong the interval QT c (amitriptyline, chlorpromazine, droperidol, thioridazine, pimozide, quinidine, procainamide, sotalol, ephedrine, adrenaline, terbutatinom, erythromycin, trimethoprim / sulfamethoxazole, ketoconazole, fluconazole and others) disruptor electrolyte balance or inhibiting the metabolism of olanzapine in the liver.
Concomitant use of olanzapine and anti-Parkinsonian drugs in patients with Parkinson's disease and dementia is not recommended.
Olanzapine exhibits antagonism against dopamine and, theoretically, can inhibit the action of levodopa and dopamine agonists.
Olanzapine does not inhibit the basic isozymes CYP in vitro (e.g., 1A2, 2D6, 2C9, 2C19, 3A4), clinically significant interaction unlikely.
Not detected following the suppression of metabolic active substances: the tricyclic antidepressants (representing mainly path CYP2D6), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and 2C19).
There were no interaction while the use of lithium or biperidenom.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored out of reach of children at a temperature of no higher than 25 В° C. Shelf life - 5 years.
