Olanzapine 10mg №30

Active substance:

olanzapine * (Olanzapine *)

Antipsychotic agent (neuroleptic) [Neuroleptics] Composition pills 1 tab.

active substance:

olanzapine 5 mg 10 mg auxiliary substances: lactose monohydrate (milk sugar) - 50.6 / 101.2 mg; MCC - 51.4 / 102.8 mg; pregelatinized starch - 51.4 / 102.8 mg; colloidal silicon dioxide (Aerosil) - 0.8 / 1.6 mg; Magnesium stearate - 0.8 / 1.6 mg Description of the dosage form Tablets: round biconvex form from light yellow to yellow. Inserts of a darker color are allowed.

Mechanism of action

- antipsychotic.

Olanzapine is an antipsychotic (antipsychotic) drug. In preclinical studies, an affinity was established for 5-HT2A / 2C-, 5-HT3-, 5-HT6-serotonin receptors, D1-, D2-, D3-, D4-, D5-dopamine receptors, m-anticholinergic blocking effects due to blockade m1- 5-cholinergic receptors; also has affinity for α1-adreno and H1-histamine receptors. In animal experiments, antagonism was revealed in relation to serotonin, dopamine and m-cholinergic receptors. In vivo and in vitro, olanzapine has a more pronounced affinity and activity for 5-HT2-serotonin receptors compared with D2-dopamine receptors. According to electrophysiological studies,Olanzapine selectively reduces the excitability of mesolimbic dopaminergic neurons and at the same time has a slight 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 neuroleptics, olanzapine enhances the anti-anxiety effect when conducting anxiolytic test. Olanzapine provides a statistically significant reduction of both productive (including delusions, hallucinations) and negative disorders. A single dose of 10 mg of olanzapine by positron emission tomography in healthy volunteers was found to have a greater affinity of olanzapine for 5 HT2A- than for D2-dopamine receptors. On tomograms of patients with schizophrenia, it was shown that in patients sensitive to treatment with olanzapine, affinity for striatal D2 receptors is comparable to the effect in patients sensitive to receiving clozapine and lower than in patients sensitive to treatment with other antipsychotic drugs and Risperidone.

In an international double-blind comparative study of patients with schizophrenia, schizoaffective disorders, or similar disorders of varying severity of depressive symptoms (mean initial value of 16.6 on the Montgomery-Asberg scale for assessing depression),A prospective secondary analysis on the mood scale from the initial to the final control point was found to have a statistically significant (p = 0.001) improvement in the administration of olanzapine (-6) 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 for 3 weeks. Comparable results of the effectiveness of olanzapine and haloperidol were observed in patients with symptomatic remission of mania and depression after 6-12 weeks. In the therapy of patients who took lithium or valproic acid for at least 2 weeks, the addition of 10 mg of olanzapine (lithium or valproic acid) resulted in a significant reduction in the symptoms of mania compared to monotherapy with lithium or valproic acid for 6 weeks. In a 12-month study on the prevention of relapses of manic episodes in patients who achieved remission while taking olanzapine and then randomized into the group taking this drug, a statistically significant advantage was found when compared with the placebo group for the main criterion for controlling the occurrence of bipolar disorder relapse or relapse depression. In the second 12-month study on the prevention of relapses of manic episodes in patientswhen they took olanzapine together with a lithium drug and then randomly assigned to the olanzapine or lithium monotherapy group, the effectiveness of olanzapine was statistically insignificant compared to lithium by the main criterion for controlling relapse of bipolar disorder (olanzapine 30%, lithium 38.3% = 0.055). In an 18-month study of manic or mixed episodes of cat therapy in patients stabilized by olanzapine and mood stabilizing drugs (lithium or valproic acid), long-term combined therapy of olanzapine with lithium or valproic acid was statistically insignificant compared to monotherapy with lithium or valproic acid in order to delay the onset of relapse of bipolar disorder, determined by diagnostic features.

After oral administration, olanzapine is well absorbed, its Tmax in plasma is 5-8 hours. The absorption of olanzapine does not depend on food intake. In studies with different doses in the range of 1-20 mg, it was shown that plasma olanzapine concentration varies linearly and proportionally to the dose. Olanzapine is metabolized in the liver as a result of conjugation and oxidation. The major circulating metabolite is 10-N-glucuronide, which theoretically does not penetrate the BBB. CYP1A2 and CYP2D6 isoenzymes are involved in the formation of N-desmethyl- and 2-hydroxymethylmetabolites of olanzapine.Both metabolites in animal studies had significantly less pronounced pharmacological activity in vivo than olanzapine. The main pharmacological activity of the drug is due to the parent compound, olanzapine, which has the ability to penetrate the BBB. In healthy volunteers, after oral administration, the average T1 / 2 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 Patient characteristics T1 / 2, h Plasma clearance, l / h Smoker: Non-smokers 38.6 18.6 Smokers 30.4 27.7 Sex Women 36.7 18.9 Men 32.3 27.3 Age Elderly (65 years and older) 51.8 17.5 Younger than 65 years 33.8 18.2 However, the degree of changes in T1 / 2 and clearance under the influence of each of these factors is significantly lower than the degree of differences in these indicators between individuals.

According to clinical studies, the amount of exposure in adolescents is 27% higher than in adults. The difference in demographic parameters between the population of adults and adolescents was that there were fewer smokers among adolescents, as well as lower average body weight. Significant differences between the mean values ​​of T1 / 2 and plasma olanzapine clearance in individuals with severe impaired renal function compared with those with normal renal function have not been established. About 57% of the radioactively labeled olanzapine is excreted in the urine mainly as metabolites.In smokers with minor hepatic impairment, olanzapine clearance is lower than in non-smokers without impaired liver function. When the plasma concentration of olanzapine is 7-1000 ng / ml, its connection with plasma proteins is about 93%. Olanzapine is mainly associated with albumin and an acid α1-glycoprotein. In a study involving persons of European, Japanese, and Chinese origin, differences in the pharmacokinetics of olanzapine related to race were not established. The activity of the isoenzyme CYP2D6 does not affect the metabolism of olanzapine. Indications of the drug Olanzapine treatment of schizophrenia. Olanzapine is effective in maintaining clinical improvement as part of the ongoing treatment of patients with schizophrenia who responded to initial treatment; treatment of manic episode from moderate to severe; prevention of relapse in patients with bipolar disorder, in whom olanzapine was effective in the treatment of the manic phase (see “Pharmacodynamics”); therapeutically resistant depression. In combination with Fluoxetine , olanzapine is indicated for the treatment of therapeutically resistant depression in adult patients (major depressive episodes if there is a history of ineffective use of two antidepressants with respect to the dose and duration of therapy appropriate to this episode). Olanzapine in monotherapy is not indicated for the treatment of therapeutically resistant depression. Contraindications hypersensitivity to any of the components of the drug; lactase deficiency, lactose intolerance , glucose-galactose malabsorption; persons under 18 years old.Use during pregnancy and breastfeeding Because of insufficient experience with olanzapine during pregnancy, the drug should be prescribed during pregnancy only if the potential benefit to the patient greatly exceeds the potential risk to the fetus. Patients should be warned that during pregnancy or its planning during the period of treatment with olanzapine, they should be informed about this by their attending physician. Newborns whose mothers took antipsychotics (including olanzapine) during the third trimester of pregnancy have a risk of adverse reactions, including extrapyramidal disorders and / or withdrawal syndrome, the symptoms of which may change in strength and duration after birth. Agitation, hypertension and hypotension, tremor, drowsiness, respiratory distress syndrome or an eating disorder have been reported. Therefore, it is necessary to carefully monitor the condition of newborns. The study found that olanzapine passes into breast milk. The average dose received by the child (mg / kg) upon reaching Css in the mother was 1.8% of the dose of mother olanzapine (mg / kg). Breast feeding during olanzapine therapy is not recommended. Side Effects The following are a summary of the main side effects and their frequency, registered during clinical trials and / or in the post-registration period. The frequency of side effects is given in accordance with the WHO classification: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000) or frequency not set.From the side of blood and lymphatic system: often - leukopenia1,3, neutropenia3, eosinophilia1; rarely thrombocytopenia3. On the part of the immune system: very rarely - allergic reactions (anaphylactic reaction, angioedema, pruritus or urticaria) 3. On the part of metabolism and nutrition: very often - an increase in body mass2,4; often - an increase in the concentration of glucose 3,8, an increase in the concentration of cholesterin 3,9, an increase in the concentration of triglycerides 3,10, glycosuria 2, an increase in appetite; infrequently - development or decompensation of diabetes mellitus, in some cases accompanied by ketoacidosis or coma, including some deaths3,8; rarely - hypothermia3. On the part of the nervous system: very often - drowsiness1; often - akathisia1,6, dizziness1, parkinsonism1,6, dyskinesia1,6; infrequently - dystonia (including oculogy crisis) 2,6, neuroleptic malignant syndrome 2,3 (NNS), tardive dyskinesia3; rarely - convulsions2,7, withdrawal syndrome3,5; dysarthria, amnesia. Cardiac: infrequently - bradycardia2, prolongation of the QT3 interval; rarely, ventricular tachycardia / ventricular fibrillation, sudden death1,3. From the side of vessels: often - arterial hypotension, incl. orthostatic1; rarely, pulmonary embolism and deep vein thrombosis3. On the part of the respiratory system, organs of the chest and mediastinum: rarely - nosebleeds1. On the part of the gastrointestinal tract: often - short-term m-anticholinergic effects, including constipation and dry mouth; infrequently - abdominal distention; rarely, pancreatitis3.Liver and biliary tract: often a transient increase in liver transaminase activity (ALT, AST), especially in the early period of treatment3; rarely, hepatitis (including hepatocellular, cholestatic, or mixed liver damage) 3. On the part of the skin and subcutaneous tissues: infrequently - photosensitivity reactions2; rarely - rash, alopecia. On the part of the musculoskeletal tissue: often - arthralgia2; rarely, rhabdomyolysis3. On the part of the kidneys and urinary tract: infrequently - urinary incontinence; rarely, urinary retention3; very rarely - delayed onset of urination. Genital and mammary gland organs: often - decreased libido in men and women3, erectile dysfunction in men3; infrequently - amenorrhea3, gynecomastia1, an increase in the mammary glands in women, galactorrhea; very rarely - priapism1. General disorders: often - asthenia, fatigue2, pyrexia2, edema2.
Laboratory data: very often - an increase in the concentration of prolactin in the plasma1,11; often - increased concentration of uric acid2; infrequently - an increase in the activity of alkaline phosphatus, an increase in the activity of KFK3; rarely, an increase in total bilirubin concentration3.
1. Data accumulated during placebo-controlled clinical trials, which were conducted for the indication of schizophrenia, the acute phase.
2. Summarized data accumulated during all clinical trials.
3. Spontaneously reported side effects from post-marketing research.
4. In all groups of patients, regardless of body weight, a clinically significant increase in body weight was observed.The increase in body weight by 7% or more from the average value after a short course of treatment (the average duration is 47 days) was observed very often (22.2%), an increase by 15% or more was frequent (4.2%) and an increase by 25% or more was infrequent (0.8%). In patients receiving long-term treatment (at least 48 weeks), an increase of ≥7, ≥15 and ≥25% was very frequent (64.4; 31.7 and 12.3%, respectively).
5. With abrupt withdrawal 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. Patients who took olanzapine, parkinsonism, akathisia, dystonia were observed less frequently than patients who received titrated doses of haloperidol. Due to the lack of detailed information on the presence of acute and late dyskinesias in a history of patients, it is currently not possible to conclude that olanzapine is less likely to cause the development of late dyskinesias or other extrapyramidal syndromes.
7. Seizures, mainly in patients with a history of seizures or with risk factors for seizures.
8. Often there was an increase in glucose concentration from normal fasting (<5.56 mmol / l) to elevated (≥7 mmol / l). The change in glucose concentration from borderline fasting parameters (≥5.56- <7 mmol / l) to elevated (≥7 mmol / l) was very frequent.
9. An increase in cholesterol concentration from normal fasting (<5.17 mmol / l) to elevated (≥6.2 mmol / l) was often observed. The change in cholesterol concentration from borderline fasting indicators (≥5.17- <6.2 mmol / l) to elevated (≥6.2 mmol / l) was very frequent.
10. An increase in the concentration of triglycerides from normal fasting values ​​(<1.69 mmol / l) to elevated (≥2.26 mmol / l) was often observed. The change in the concentration of triglycerides from borderline fasting (≥ 1.69 to <2.26 mmol / l) to elevated (≥2.26 mmol / l) was very frequent.
11. In clinical studies with a duration of up to 12 weeks, plasma prolactin concentration exceeded VGN in approximately 30% of patients with normal baseline prolactin levels. In most of these patients, an increase in the concentration of prolactin was moderate and less than 2 times higher than VGN.

Special patient groups
A very frequent (≥10%) undesirable effect when using olanzapine in clinical studies in patients with dementia-related psychosis was impaired gait and falling. Frequent (<10 and ≥1%) undesirable effects when using olanzapine in elderly patients with dementia-related psychosis were urinary incontinence and pneumonia. Pneumonia, fever, lethargy, erythema, visual hallucinations and urinary incontinence have also been frequently observed. In clinical studies in patients with psychosis induced by taking the drug (dopamine receptor agonist) in Parkinson's disease, an increase in parkinsonian symptoms was noted very often (≥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%) undesirable effects were weight gain, dry mouth, increased appetite, tremor, and frequent (<10 and ≥1%) breakdown speech.

The metabolism of olanzapine can be altered by the action of inhibitors or inducers of cytochrome P450 isoenzyme, showing specific activity against the CYP1A2 isoenzyme. The clearance of olanzapine is increased in smoking patients and those taking Carbamazepine (due to an increase in the activity of the CYP1A2 isoenzyme). Potential inhibitors of the isoenzyme CYP1A2 can reduce the clearance of olanzapine. Olanzapine is not a potential inhibitor of CYP1A2 isoenzyme; therefore, when taking olanzapine, the pharmacokinetics of drugs, such as theophylline, which are mainly metabolized by the isoenzyme CYP1A2, do not change. In clinical studies have shown that a single application dose olanzapine therapy following medications are not accompanied by the suppression of metabolism of these drugs: imipramine or its metabolite desipramine (isoenzymes CYP2D6, CYP3A, CYP1A2), Warfarin (isoenzyme CYP2C19), theophylline (isoenzyme CYP1A2) or diazepam ( isoenzyme CYP3A4 , CYP2C19). There are also no signs of drug interactions when using olanzapine in combination with lithium preparations or biperidine. There was no change in the pharmacokinetics of ethanol against the background of Css olanzapine. However, taking ethanol together with olanzapine may be accompanied by an increase in the pharmacological effects of olanzapine, for example, a sedative effect. Fluoxetine (60 mg once or 60 mg daily for 8 days) causes an increase in Cmax of olanzapine by an average of 16% and a decrease in clearance of olanzapine by an average of 16%. The degree of influence of this factor is significantly inferior to the severity of individual differences of these indicators, so it is usually not recommended to change the dose of olanzapine when it is used in combination with fluoxetine. Fluvoxamine, an inhibitor of the isoenzyme CYP1A2, reduces the clearance of olanzapine. The result of this is the average increase in Cmax of olanzapine with the introduction of fluvoxamine by 54% in non-smoking women and 77% in male smokers, the average increase in AUC of olanzapine by 52 and 108%, respectively. Small doses of olanzapine should be administered to patients who are receiving fluvoxamine together. In vitro studies using human liver microsomes have shown that olanzapine slightly suppresses the formation of valproic acid glucuronide (the main metabolic pathway of valproic acid). Valproic acid also slightly affects the metabolism of olanzapine in vitro. Therefore, a clinically significant pharmacokinetic interaction between olanzapine and valproic acid is unlikely.

A single dose of aluminum- or magnesium-containing antacids or cimetidine did not violate the bioavailability of olanzapine when taken orally. The simultaneous use of Activated carbon and olanzapine reduced the bioavailability of the latter when taken orally up to 50-60%. According to in vitro studies using human liver microsomes, olanzapine also demonstrated an extremely small potential for inhibiting the activity of the following cytochrome P450 isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A. Dosage and administration Inside, regardless of the meal, because food does not affect the absorption of olanzapine. Schizophrenia. The recommended starting dose of olanzapine is 10 mg 1 time per day. Therapeutic doses of olanzapine range from 5 to 20 mg / day. The daily dose must be selected individually, depending on the clinical condition of the patient. Increasing the dose above the standard daily (10 mg) is recommended only after evaluating the clinical picture. When using the drug should regularly assess the need for continued therapy. Bipolar disorder. For treatment of a manic episode, the recommended initial dose of olanzapine is 15 mg 1 time per day as monotherapy or 10 mg 1 time per day in combination with lithium preparations or valproic acid. Therapeutic doses of olanzapine range from 5 to 20 mg / day. The daily dose must be selected individually, depending on the clinical condition of the patient. Increasing the dose above the standard daily is recommended only after evaluating the clinical picture and with an interval of at least 24 hours.Supportive Therapy for Bipolar Disorder: Patients who take olanzapine to treat a manic episode should continue supportive therapy at the same dose. In patients in remission, the recommended initial dose of olanzapine is 10 mg 1 time per day. In the future, the daily dose must be selected individually, depending on the clinical condition of the patient, in the range of 5 to 20 mg / day. For the treatment of a depressive episode, olanzapine should be administered in combination with fluoxetine once a day, in the evening, regardless of the meal. As a rule, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. Antidepressant activity was confirmed when using olanzapine in a dose of 6–12 mg (average daily dose — 7.4 mg) and fluoxetine at a dose of 25–30 mg (average daily dose — 39.3 mg). If necessary, change the dose of both olanzapine and fluoxetine. When using the drug, it is necessary to regularly assess the need to continue therapy. Therapeutically resistant depression. Olanzapine should be administered in combination with fluoxetine 1 time per day, in the evening, regardless of the meal. As a rule, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, change the dose of both olanzapine and fluoxetine. Antidepressant activity was confirmed when using 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 assess the need to continue therapy.General rules for the choice of the daily dose for special groups of patients with oral administration. Reducing the initial dose to 5 mg / day is recommended for elderly patients or patients with other clinical risk factors, including severe renal insufficiency or moderately severe liver failure. Reducing the initial dose to 5 mg can be recommended for patients with a combination of factors (female gender, old age and no smoking habits), which can reduce the metabolism of olanzapine (see table 1).

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

Symptoms: Very frequent (≥10%) symptoms in an overdose of olanzapine were tachycardia, agitation / aggressiveness, speech disorder, various extrapyramidal disorders and disorders of consciousness of varying severity (from sedation to coma). Other clinically significant consequences of an overdose of olanzapine included delirium, seizures, CSN, respiratory depression, aspiration, increased or decreased blood pressure, arrhythmias (<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 an overdose with a favorable outcome (survival) - 2 g.
Treatment: the specific antidote of olanzapine does not exist. Induction of vomiting is not recommended. Standard overdose procedures (gastric lavage, intake of activated carbon) may be indicated. The combined intake of activated carbon and olanzapine showed a decrease in the bioavailability of olanzapine when ingested up to 50-60%. Symptomatic therapy in accordance with the clinical condition and control of vital body functions, including the correction of reduced blood pressure, impaired blood circulation and the maintenance of the respiratory function, are shown. Epinephrine, dopamine and other adrenomimetics that are β-adrenoreceptor agonists should not be used. stimulation of these receptors may exacerbate hypotension. Monitoring of cardiovascular activity is necessary in order to identify possible arrhythmias. The patient must be under continuous medical supervision until full recovery.

The risk of a suicidal attempt by patients with schizophrenia and bipolar disorder of the first type is due to these diseases themselves. In this regard, against the background of pharmacotherapy requires careful monitoring of those patients whose risk of suicide is particularly high. When prescribing olanzapine, you should strive to minimize the number of pills taken by the patient to reduce the risk of overdose. ZNS ZNS (potentially lethal symptom complex) can develop with any antipsychotic medication, including olanzapine. Clinical manifestations of NNS include a significant increase in body temperature, muscle rigidity, changes in mental status, and autonomic disorders (unstable pulse or blood pressure, tachycardia, cardiac arrhythmias, sweating).Additional signs may include an increase in CPK activity, myoglobinuria (rhabdomyolysis) and acute renal failure. Clinical manifestations of NNS or a significant increase in body temperature without other symptoms of NNS require the elimination of all neuroleptics, including olanzapine. Late dyskinesia In comparative studies, treatment with olanzapine was significantly less frequently accompanied by the development of dyskinesia requiring medical correction than the use of typical and other atypical antipsychotics. However, the risk of tardive dyskinesia during long-term neuroleptic therapy should be considered. If signs of tardive dyskinesia develop, a dose adjustment of the neuroleptic is recommended. It should be borne in mind that when transferred to olanzapine, symptoms of tardive dyskinesia may develop as a result of the simultaneous cancellation of previous therapy. Over time, the intensity of these symptoms may increase, moreover, these symptoms may develop after cessation of therapy.

The effectiveness of olanzapine in elderly patients with psychosis associated with dementia has not been established. In this category of patients in placebo-controlled clinical trials, the incidence of fatal cases in the olanzapine group was higher than in the placebo group (3.5 vs. 1.5%, respectively). The risk factors that may predispose this group of patients to higher mortality with olanzapine, include age> 80 years, sedation, concomitant use with benzodiazepines, or the presence of lung disease (for example, pneumonia with or without aspiration). There is not enough data to establish differences in the incidence of cerebrovascular disorders and / or mortality (compared with placebo) and risk factors in this group of patients when taking olanzapine by mouth and intramuscular injections.

The use of olanzapine in the treatment of psychosis induced by taking dopamine receptor agonists in Parkinson’s disease is not recommended. In clinical studies in patients with psychosis induced by taking the drug (dopamine receptor agonist) in Parkinson's disease, an increase in the symptoms of parkinsonism was noted very often (≥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. Abnormal liver function In some cases, olanzapine, usually in the early stages of therapy, was accompanied by a transient, asymptomatic increase in the activity of hepatic transaminases (ACT and ALT) in blood serum. Rare cases of hepatitis have been reported. In addition, there were single