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Active ingredients
Olanzapine
Release form
Pills
Composition
Active ingredient: olanzapine. Concentration of active ingredient (mg): 5 mg
Pharmacological effect
Antipsychotic drug (neuroleptic) with a broad pharmacological spectrum of influence on a number of receptor systems. In preclinical studies, the affinity of olanzapine for serotonin 5HT2A / C-, 5HT3-, 5HT6-receptors, dopamine D1-, D2-, D3-, D4-, D5-receptors, muscarinic M1-5 cholinergic receptors, adrenergic, etc. H1 receptors. Experimental studies have revealed the presence of olanzapine antagonism with respect to serotonin 5HT receptors, dopamine and cholinergic receptors. In vivo and in vitro, olanzapine has a more pronounced affinity and activity for serotonin 5HT2 receptors compared with dopamine D2 receptors. According to electrophysiological studies, olanzapine selectively reduces the excitability of mesolimbic dopaminergic neurons and, at the same time, has little effect on the striatal nerve pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned defensive reflex (a test that characterizes antipsychotic activity) at doses lower than the doses that cause catalepsy (a disorder reflecting a side effect on motor function). Unlike other antipsychotics (neuroleptics), olanzapine enhances against the disturbing effect when conducting anxiolytic test. In two placebo-controlled and two of three comparative controlled trials involving 2900 patients with schizophrenia, olanzapine was shown to provide a statistically significant reduction in both productive (including delusions, hallucinations) and negative disorders.
Pharmacokinetics
Absorption: After oral administration, olanzapine is well absorbed from the gastrointestinal tract, Cmax in plasma is reached in 5-8 hours. Plasma concentrations of olanzapine are linearly dose-dependent (ranging from 1 to 20 mg). Eating does not affect the absorption of olanzapine. Distribution: At a plasma concentration of 7 to 1000 ng / ml, the binding to plasma proteins, mainly albumin and the α1-acid glycoprotein, is about 93%. Metabolism: Olanzapine is metabolized in the liver by conjugation and oxidation.The major circulating metabolite is 10-N-glucuronide, which theoretically does not penetrate the BBB. CYP1A2 and CYP2D6 isoenzymes of cytochrome P450 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Experimental studies in animals have shown that these metabolites have a significantly less pronounced pharmacological activity in vivo than olanzapine. The main pharmacological activity of the drug is due to the starting material - olanzapine. CYP2D6 cytochrome P450 isoenzyme activity does not affect the level of olanzapine metabolism. Excretion: In healthy volunteers after oral administration, olanzapine T1 / 2 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 olanzapine labeled with radioisotopes is excreted in the urine, mostly as metabolites. Pharmacokinetics in special clinical situations: Pharmacokinetic indicators of olanzapine vary depending on gender, age, and smoking habits: However, the degree of T1 / 2 changes and clearance under the influence of each of these factors is significantly inferior to the degree of individual differences between these indicators. Significant differences between the mean T1 / 2 and clearance of olanzapine in patients with severe impaired renal function, compared with those with normal renal function, have not been established. In smokers with minor hepatic impairment, olanzapine clearance is lower than in non-smokers without such disorders. In a study involving people of European, Japanese and Chinese origin, differences in the pharmacokinetics of olanzapine related to race were not established.
Indications
Schizophrenia: For the treatment of exacerbations, supportive and long-term anti-relapse treatment of patients with schizophrenia and other psychotic disorders with severe productive (including delusions, hallucinations, automatisms) or negative (emotional flattening, decrease in social activity, impoverishment of speech) symptoms, as well as associated affective disorders. Bipolar affective disorder: As a monotherapy or in combination with lithium or valproatum, for the treatment of acute manic or mixed episodes in bipolar affective disorder, with psychotic manifestations and with a quick change of phases.To prevent relapse in patients with bipolar disorder, in whom olanzapine was effective in the treatment of the manic phase. Treatment Depression associated with bipolar disorder (in combination with fluoxetine).
Contraindications
Hypersensitivity to the drug.
Precautionary measures
Before you begin taking this drug, tell your doctor about medicines already used, nutritional supplements (such as vitamins, natural supplements, etc.), allergic reactions, existing diseases, and current health status (such as pregnancy, impending surgery, etc.). Side effects of the drug may be more pronounced in a certain state of your body. Take the drug as directed by your doctor or follow the instructions for use supplied with the drug. The dosage of the drug depends on your condition. Notify your doctor if your condition has not changed or worsened.
Use during pregnancy and lactation
When a planned or coming pregnancy during olanzapine therapy, patients should be advised to consult a doctor. Due to the limited experience of using olanzapine during pregnancy in a person, prescribing the drug is possible only in cases where the potential benefit of therapy for the mother greatly exceeds the potential risk to the fetus. The study found that olanzapine is excreted in breast milk. If necessary, the use of the drug during lactation breastfeeding should be discontinued.
Dosage and administration
Olanzapine dispersible pills dissolve quickly in saliva, and are easily swallowed. Remove the tablet from the mouth undissolved difficult. Due to the fragility of the tablet should be taken immediately after removal from the blister. In addition, immediately before taking the pill can be dissolved in a glass of water or other liquid (orange juice, apple juice, milk or coffee). Olanzapine can be taken regardless of the meal, because the food does not affect the absorption of the drug. The daily dose must be selected individually, depending on the clinical condition of the patient. For the treatment of schizophrenia and similar psychotic disorders. The recommended starting dose of olanzapine is 10 mg 1 time per day.Therapeutic doses of olanzapine range from 5 mg to 20 mg / day. Increasing the dose of more than the standard daily dose of 10 mg is recommended only after an appropriate clinical examination of the patient. For the treatment of acute mania in bipolar disorder: The recommended initial dose of olanzapine is 15 mg 1 day as monotherapy or 10 mg 1 day in combination with lithium or valproate. Olanzapine can be taken regardless of the meal, because the meal does not affect the absorption of the drug. Therapeutic doses of olanzapine range from 5 mg to 20 mg. It is recommended to increase the dose above the standard daily dose of 15 mg only after an appropriate clinical examination of the patient. The dose should be increased gradually, at intervals of at least 24 hours. Supportive therapy for bipolar disorderPatients who take olanzapine to treat acute mania should continue the maintenance therapy at the same dose. In patients in remission, the recommended initial dose of olanzapine is 10 mg per day. In the future, the daily dose must be selected individually, depending on the clinical condition of the patient, ranging from 5 mg to 20 mg days. Olanzapine in combination with fluoxetine should be prescribed 1 day, regardless of the meal. As a rule, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, changes in doses of both olanzapine and fluoxetine are allowed. For elderly patients or patients with other clinical risk factors, including severe renal insufficiency or moderate hepatic insufficiency, it is recommended to reduce the initial dose of olanzapine to 5 mg a day. For patients with a combination of factors that may cause a delay in the matabolism of olanzapine (female patients, old age, non-smokers) who may slow down the metabolism of olanzapine, a decrease in the initial dose of olanzapine may also be recommended. Research data from olanzapine during therapy in children and adolescents under the age of 18 years is limited. Also for convenience of dosing it is possible to use the drug: Zyprexa Zidis table. disperg. 5 mg pack. 28 Eli Lilly and Company Ltd.
Side effects
Very often ≥10% - drowsiness, weight gain. 34% - an increase in the concentration of prolactin in the blood plasma, which was mild and transient (the average value of the maximum concentration of prolactin did not reach the upper limit of normal (VGN) and was not statistically significantly different from placebo). Clinical manifestations of hyperprolactinemia associated with taking olanzapine (i.e. gynecomastia, galactorrhea, and an increase in the mammary glands) were rarely observed. In most patients, normalization of prolactin levels was observed without discontinuing olanzapine. Often: less than 10% and ≥1% - Dizziness, Asthenization, neuropsychic, akathisia, increased appetite, peripheral edema, orthostatic hypotension, dry mouth and constipation. In clinical studies (n = 107) in 1. 9% of cases were observed levels of triglycerides 2 times or more exceeding VGN, cases of exceeding VGN more than 3 times were not observed. Rarely: Transient, asymptomatic increase in hepatic transaminases (AST and ALT) in serum. In isolated cases: Increased plasma glucose to ≥ 200 mgdl (suspected diabetes mellitus), as well as from ≥160 mgdl, but to less than 200 mgdl (suspected hyperglycemia) in patients with baseline glucose ≤140 mgdl. In some cases: Asymptomatic eosinophilia. Undesirable effects in special groups of patients Patients with psychosis associated with dementia, very often (≥10%) gait disturbances and falls were observed. Elderly patients with dementia-related psychosis are often (less than 10% and ≥1%) urinary incontinence and pneumonia. Patients with psychosis induced by taking the drug (dopamine agonist) in Parkinson's disease, very often (≥ 10%) and with a higher frequency than in the placebo group, increased symptoms of Parkinsonism, hallucinations. In patients with bipolar mania receiving olanzapine in combination with lithium or valproate, very often (≥10%) an increase in body weight, dry mouth, increased appetite, and tremor was observed. often (less than 10% and ≥1%) - speech disorder
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, convulsions, neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmias (less than 2% of overdose cases) and cardiac and respiratory arrest. The minimum dose for acute overdose with a fatal outcome was 450 mg, the maximum dose for overdose with a favorable outcome (survival) - 1500 mg. Treatment: There is no specific antidote for olanzapine. Artificially induce vomiting is not recommended. Standard detoxification techniques are shown (i.e. gastric lavage, taking activated carbon). The simultaneous intake of activated carbon reduces the bioavailability of olanzapine when administered orally by 50-60%. Symptomatic treatment is shown in accordance with the clinical condition and control of the functions of vital organs, including the treatment of arterial hypotension, vascular collapse and support of the respiratory function. Epinephrine, dopamine and other sympathomimetics that are agonists of β-adrenoreceptors should not be used, since stimulation of the latter can aggravate hypotension.
Interaction with other drugs
Children and teenagers. Interaction studies were conducted only on adults. Potential interactions affecting olanzapine. Because olanzapine is metabolized by CYP1A2, substances that can specifically stimulate or inhibit this isoenzyme can affect the pharmacokinetics of olanzapine. The metabolism of olanzapine can be induced by smoking and the use of carbamazepine, which can lead to a decrease in the concentrations of olanzapine. Low to moderate increase in olanzapine clearance was observed. The clinical consequences are probably limited, but clinical monitoring is recommended, and if necessary, the question of increasing the dose of olanzapine can be considered (see section 4. 2). Inhibition of CYP1A2. It has been shown that fluvoxamine, a specific inhibitor of CYP! A2, significantly inhibits the metabolism of olanzapine. The average increase in C | gah olanzapine after exposure to fluvoxamine was 54% in non-smoking women and 77% in male smokers. The average increase in olanzapine AUC was 52% and 108%, respectively.Consideration should be given to reducing the starting dose of olanzapine in patients who use fluvoxamine or any other CYPIA2 inhibitor, for example, ciprofloxacin. The possibility of reducing the dose of olanzapine should be considered if treatment with any inhibitor of CYP1A2 is started. Reduced bioavailability. Activated charcoal reduces the bioavailability of olanzapine, administered orally, by 50-60%, so it must be administered at least two hours before or after olanzapine. Fluoxetine (a CYP2D6 inhibitor), single doses of antacid agents (aluminum, magnesium) or cimetidine, have not been found to have a significant effect on the pharmacokinetics of olanzapine. Possible effects of olanzapine on other medicinal products. Olanzapine may have an antagonistic effect on direct and indirect dopamine agonists. Olanzapine does not inhibit the major isoenzymes of CYP450 in vitro (for example, IA2, 2D6.2C9, 2C19, ZA4). Therefore, no private interaction is expected, as confirmed by in vivo studies, where no inhibition of the metabolism of the following active substances has been identified: tricyclic antidepressant (representing mainly CYP2D6 metabolic pathway), warfarin (CYP2C9), theophylline (CYPIA2) or diazepam (CYP3A4 and 2C19). Olanzapine did not reveal any interaction with the appointment together with lithium or biperidine. Therapeutic monitoring of plasma valproate levels did not indicate that a dose adjustment of valproate is required after the administration of olanzapine as a concomitant drug. Interval 07s. Caution should be exercised if olanzapine is used concurrently with medicinal products known to increase the QTc interval.
special instructions
When using any antipsychotics, including olanzapine, the development of a malignant neuroleptic syndrome, a potentially fatal symptom complex, is possible. Clinical manifestations of this syndrome include a significant increase in body temperature, muscle rigidity, changes in mental status, and autonomic disorders (unstable pulse or blood pressure, tachycardia, cardiac arrhythmia, increased sweating). Additional signs may include increased levels of CPK, myoglobinuria (rhabdomyolysis), and acute renal failure.Clinical manifestations of a malignant neuroleptic syndrome or a significant increase in body temperature without the other symptoms of this syndrome require the withdrawal of all neuroleptics, including olanzapine. In comparative studies with a duration of more than 6 weeks, treatment with olanzapine was significantly less likely to be accompanied by the development of dyskinesia requiring medical correction than the use of haloperidol. However, the risk of tardive dyskinesia during long-term neuroleptic therapy should be considered. If signs of tardive dyskinesia develop, a dose reduction or elimination of olanzapine is recommended. Symptoms of tardive dyskinesia may increase or manifest after discontinuation of the drug. With extreme caution, the drug should be used when increasing the activity of AST and ALT in patients with liver failure, limited functional reserve of the liver or in patients receiving treatment with potentially hepatotoxic drugs. In the event of an increase in AST and / or ALT activity during olanzapine treatment, careful monitoring of the patient is required and, if necessary, a dose reduction. Olanzapine should be used with caution in patients with a history of epileptic seizures or exposed to factors that reduce the threshold of seizure readiness. In these patients, olanzapine was rarely treated with olanzapine. With caution, the drug should be prescribed to patients with low white blood cell count and / or neutrophils due to various reasons; with signs of oppression / toxic impairment of bone marrow function under the influence of drugs in history; with inhibition 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 of disease was not accompanied by a relapse of these disorders. In clinical studies, olanzapine therapy was rarely accompanied by side effects associated with the anticholinergic activity of the drug.However, clinical experience with olanzapine in patients with comorbidities is limited, so caution is advised when prescribing olanzapine to patients with clinically significant prostatic hypertrophy, paralytic ileus, angle-closure glaucoma and similar conditions. In vitro, olanzapine antagonizes dopamine and, like other antipsychotics, can theoretically suppress the effects of levodopa and dopamine agonists. Given the nature of the effect of the drug on the central nervous system, olanzapine should be used with caution in combination with other drugs of central action and ethanol. Effects on the ability to drive and work with machinery: Patients taking olanzapine should be careful when operating mechanical equipment, including a car, since olanzapine can cause drowsiness. Use in violation of kidney function: In severe renal failure, the drug is prescribed in an initial dose of 5 mg / day. Use in violation of liver function: In case of insufficiency of the liver function of moderate severity, the drug is prescribed in an initial dose of 5 mg / day.