Olanzapine

General characteristics. Structure:

Active ingredient: 5 mg or 10 mg of olanzapine.

Excipients: lactoses monohydrate (sugar milk), cellulose of microcrystallic 51,40/102,80 mg, starch of prezhelatinizirovanny 51,40/102,80 mg, silicon dioxide colloid (aerosil) of 0,80/1,60 mg, magnesium stearate.

The drug appointed by the specialist doctor (the psychiatrist, the neurologist) at schizophrenia, maniacal episodes, some other states (schizoaffective or bipolar disorder, a depression in a combination with fluoxetine). Treatment by this drug usually long (for a maintenance therapy). Drug eliminates both productive, and negative symptoms of these diseases. Therapy by olanzapine when comparing with treatment by a haloperidol gives the bigger period of remission (lack of aggravations of a basic disease) and improves indicators on Montgomery-Asberg's scale for depression assessment.

Pharmacological properties:

Pharmacodynamics. Olanzapine is antipsychotic means (neuroleptic). In preclinical trials affinity to 5-HT2A/2C-, 5-HT3-, 5-HT6-serotoninovym is established to receptors, D1-, D2-, D3-, D4-, D5 - dopamine receptors, m-holinoblokiruyushchiye effects are caused by blockade M1-5-holinoretseptorov; also has affinity to a1-adreno-and to H1-histamine receptors. In experiments on animals antagonism in relation to serotoninovy, dopamine and m-holinoretseptoram was revealed. In vivo and in vitro olanzapine has more expressed affinity and activity in relation to 5-HT2-serotoninovym to receptors in comparison with D2 - dopamine receptors. According to electrophysiologic researches olanzapine selectively reduces excitability of mesolimbic dofaminergichesky neurons, and at the same time has insignificant effect on the striatal nerve pathways participating in regulation of motor functions. Olanzapine reduces a conditioned protective reflex (the test characterizing antipsychotic activity) in doses lower, than the doses causing a katalepsy (the frustration reflecting collateral influence on motor function). Unlike other neuroleptics, olanzapine strengthens antialarming effect when carrying out the "anxiolytic" test.

Olanzapine provides statistically reliable reaction as productive (nonsense, hallucinations, etc.), and negative frustration.

At a single dose of 10 mg of olanzapine by means of the positron emission tomography (PET) on healthy volunteers bigger affinity of olanzapine to 5 NT2A-what to D2 - dopamine receptors is established. On tomograms of patients with schizophrenia it is shown that at the patients sensitive to treatment by olanzapine affinity to striatal D2 receptors is comparable to effect at the patients sensitive to clozapine reception, and below than at the patients sensitive to treatment by other antipsychotic drugs and risperidony.

Clinical performance. In the international, double blind person, a comparative research of patients with schizophrenia, schizoaffective or similar disorders of varying severity of depressive symptoms (an average reference value 16,6 on Montgomery-Asberg's scale for depression assessment), the prospective secondary analysis on a mood scale from initial to a final point of control improvement at reception of olanzapine (-6,0) in comparison with a haloperidol is established statistically significant (р =0,001) (-3,1).

At patients with the maniacal or mixed episode of bipolar disorder in comparison with placebo and drug of valproic acid (divalproatum) high performance in reduction of maniacal symptoms within 3 weeks is shown. Comparable results of efficiency of olanzapine and a haloperidol observed at patients with symptomatic remission of a mania and depression in 6-12 weeks. In a koterapiya of the patients accepting drug of lithium or valproic acid at least within 2 weeks, additional reception of 10 mg of olanzapine (a koterapiya with drug of lithium or valproic acid) led to considerable decrease in symptoms of a mania in comparison with monotherapy by drugs of lithium or valproic acid within 6 weeks.

In the 12th monthly research of prevention of a recurrence of maniacal episodes at the patients who reached remission at reception of olanzapine and then randomized in group accepting drug olanzapine, statistically significant advantage over placebo by the main criterion of control of emergence of a recurrence of bipolar disorder and from the point of view of prevention of a recurrence of a mania or a recurrence of a depression is established.

In the second 12th monthly research of prevention of a recurrence of maniacal episodes at the patients who reached remission at joint reception of olanzapine with lithium drug and then randomized in group of monotherapy by olanzapine or drug of lithium. Efficiency from reception of olanzapine was statistically not significant in comparison with lithium drug by the main criterion of control of a recurrence of bipolar disorder (olanzapine of 30,0%, lities of 38,3%, р = 0,055).

In the 18th monthly research of a koterapiya of the maniacal or mixed episodes at the patients stabilized by the olanzapine and drugs stabilizing mood (drugs of lithium or valproic acid) long joint therapy by olanzapine with drug of lithium or valproic acid it was statistically not significant in comparison with monotherapy by drug of lithium or valproic acid for the purpose of retardation of emergence of a recurrence of the bipolar disorder determined by diagnostic characters.

Pharmacokinetics. After intake olanzapine is well soaked up, its maximum concentration in plasma is reached in 5–8 h. Absorption of olanzapine does not depend on meal. In researches with different doses in the range of 1-20 mg it is shown that concentration of olanzapine in plasma changes linearly and in proportion to a dose.

Olanzapine is metabolized in a liver as a result of processes of conjugation and oxidation. The main circulating metabolite is the 10-N-glucuronide which theoretically does not get through a blood-brain barrier. Isoenzymes of CYP1A2 and CYP2D6 participate in formation of N-dezmetil-and 2 hydroxymethylmetabolites of olanzapine. Both metabolites in researches on animals had considerably less expressed pharmacological activity of in vivo, than olanzapine. The main pharmacological activity of drug is caused by initial connection – the olanzapine having ability to get through a blood-brain barrier.

At healthy volunteers after intake the average elimination half-life made 33 h (21–54 h for 5–95%), and average clearance of olanzapine of plasma — 26 l/h (12–47 l/h for 5–95%).

Pharmacokinetic indicators of olanzapine vary depending on smoking, gender and age (see table 1):

Table 1

Characteristics of patients	Elimination half-life, (h)	Clearance in plasma (l/h)
Attitude towards smoking
Non-smoking	38,6	18,6
Smokers	30,4	27,7
Floor
Women	36,7	18,9
Men	32,3	27,3
Age
Elderly (65 years are also more senior)	51,8	17,5
Younger 65 years	33,8	18,2

However extent of changes of an elimination half-life and clearance under the influence of each of the specified factors considerably concedes to degree of distinctions of these indicators between individuals.

Pharmacokinetics indicators at teenagers (13–17 years) and at adults are similar. According to clinical trials, exposure size at teenagers is 27% higher, than at adults. The difference of demographic parameters between population of adults and teenagers was that among teenagers there were less smokers, and also lower average values of body weight were noted.

Reliable distinctions between average values of an elimination half-life and clearance of olanzapine in plasma at persons with heavy renal failures, in comparison with persons with normal function of kidneys, it is not established. About 57% are radioactive marked olanzapine is removed with urine generally in the form of metabolites.

At the smoking persons with insignificant abnormal liver functions the clearance of olanzapine is lower, than at non-smoking without abnormal liver function.

At plasma concentration of olanzapine of 7-1000 ng/ml its communication with proteins of plasma makes about 93%. Olanzapine generally contacts albumine and an acid a1-glycoprotein. In a research with participation of persons of the European, Japanese and Chinese origin, the distinctions in pharmacokinetics of olanzapine connected with race it is not established. Activity of an isoenzyme of CYP2D6 does not influence olanzapine metabolism.

Indications to use:

Olanzapine is shown for treatment of schizophrenia. Olanzapine is effective for maintenance of clinical improvement within the continuing therapy of the patients with schizophrenia who answered initial treatment.

Olanzapine is shown for treatment of a maniacal episode for average to heavy degree.

Olanzapine is shown for prevention of a recurrence at patients with bipolar disorder at which it was effective at treatment of a maniacal phase (see the section "Pharmacodynamics").

Therapeutic resistant depression. In a combination with fluoxetine olanzapine is shown for treatment therapeutic to a resistant depression at adult patients (big depressive episodes in the presence in the anamnesis of inefficient use of two antidepressants on a dose and duration of a course of therapy, adequate to this episode). Olanzapine in monotherapy is not shown for treatment therapeutic to a resistant depression.

Route of administration and doses:

Inside. Olanzapine can be accepted irrespective of meal as food does not influence olanzapine absorption.

Schizophrenia. The recommended initial dose of olanzapine makes 10 mg once a day. Therapeutic doses of olanzapine fluctuate in the range from 5 mg to 20 mg a day. The daily dose needs to be selected individually depending on a clinical condition of the patient. Increase in a dose above a standard daily dose (10 mg) is recommended to be carried out only after assessment of a clinical picture. At use of drug it is necessary to estimate need of continuation of therapy regularly.

Bipolar disorder. For treatment of a maniacal episode the recommended initial dose of olanzapine makes 15 mg as monotherapy or 10 mg in a combination with drugs of lithium or valproic acid once a day once a day. Therapeutic doses of olanzapine fluctuate in the range from 5 mg to 20 mg a day. The daily dose needs to be selected individually, depending on a clinical condition of the patient. Increase in a dose is higher standard daily it is recommended to spend only after assessment of a clinical picture and with an interval not less than 24 hours.

Maintenance therapy at bipolar disorder: the patients accepting olanzapine for treatment of a maniacal episode need to continue a maintenance therapy in the same dose. At patients in remission the recommended initial dose of olanzapine makes 10 mg once a day. Further the daily dose needs to be selected individually; depending on a clinical condition of the patient, ranging from 5 mg to 20 mg a day.

For treatment of a depressive episode it is necessary to appoint olanzapine in a combination with fluoxetine once a day, in the evening, irrespective of meal. As a rule, the initial dose makes 5 mg of olanzapine and 20 mg of fluoxetine. Antidepressive activity is confirmed at use of olanzapine in a dose of 6-12 mg (an average daily dose — 7,4 mg) and fluoxetine in a dose of 25-30 mg (an average daily dose — 39,3 mg). If necessary change of a dose both olanzapine, and fluoxetine is allowed. At use of drug it is necessary to estimate need of continuation of therapy regularly.

Therapeutic resistant depression. It is necessary to appoint olanzapine in a combination with fluoxetine once a day, in the evening, irrespective of meal. As a rule, the initial dose makes 5 mg of olanzapine and 20 mg of fluoxetine. If necessary change of a dose both olanzapine, and fluoxetine is allowed. Antidepressive activity is confirmed at use of olanzapine in a dose of 6-12 mg and fluoxetine in a dose of 25-30 mg. At use of drug it is necessary to estimate need of continuation of therapy regularly.

General rules of the choice of a daily dose for special groups of patients at oral administration. Decrease in an initial dose to 5 mg a day is recommended to elderly patients or patients with other clinical risk factors, including a heavy renal failure or a liver failure of moderate severity. Decrease in an initial dose to 5 mg can be recommended for patients with a combination of factors (a female, advanced age and lack of a habit to smoking) which can reduce olanzapine metabolism (see table 1).

Use of olanzapine was not studied at persons more young than 13 years.

Features of use:

Because of insufficient experience of use of olanzapine during pregnancy, it is necessary to appoint drug during pregnancy only if the potential advantage for the patient considerably exceeds potential risk for a fruit. Patients have to be warned that in case of approach or planning of pregnancy during treatment by olanzapine they need to report about it to the attending physician.

Newborns whose mothers accepted anti-psychotics (including olanzapine) during the third trimester of pregnancy, have a risk of emergence of side reactions, including extrapyramidal disturbances and / or a withdrawal which symptoms can change after the birth on force and duration. It was reported about agitation, arterial hyper - and hypotension, a tremor, drowsiness, respiratory a distress syndrome or frustration of food. Therefore it is necessary to control a condition of newborns carefully.

In a research it was revealed that olanzapine gets into breast milk. The average dose received by the child (mg/kg) at achievement of equilibrium concentration at mother made 1,8% of a dose of olanzapine of mother (mg/kg). Feeding is not recommended by a breast during therapy by olanzapine.
Suicide

The risk of commission of suicide attempt by patients with schizophrenia and bipolar disorder of the first type is caused by the specified diseases. In this regard against the background of carrying out pharmacotherapy careful observation of those patients at whom the risk of a suicide is especially high is required. At purpose of olanzapine it is necessary to aim at a minimilization of quantity of the pill taken by the patient to reduce risk of overdose.

Malignant antipsychotic syndrome. The Malignant Antipsychotic Syndrome (MAS) (potentially lethal symptom complex) can develop at treatment by any neuroleptics, including olanzapine. Clinical manifestations of a malignant antipsychotic syndrome include substantial increase of body temperature, rigidity of muscles, change of the mental status and vegetative disturbances (unstable pulse or arterial pressure, tachycardia, cardiac arrhythmias, the increased sweating). Accessory signs, can include increase in activity of a kreatinfosfokinaza, a myoglobinuria (рабдомиолиз) and an acute renal failure. Clinical manifestations of a malignant antipsychotic syndrome or substantial increase of body temperature without other symptoms of a malignant antipsychotic syndrome demand cancellation of all neuroleptics, including olanzapine.

Late dyskinesia. In comparative researches treatment by olanzapine was followed by development of diskineziya, the demanding medicamentous correction authentically less often, than use of typical and other atypical neuroleptics. However it is necessary to consider risk late diskineziya at long therapy by neuroleptics. At development of symptoms of late dyskinesia dose adjustment of a neuroleptic is recommended. It is necessary to consider that at transfer into olanzapine symptoms late diskineziya can develop owing to single-step cancellation of the previous therapy. Over time intensity of the specified symptomatology can increase, moreover, the specified symptoms can develop also after the therapy termination.

Experience of use for elderly patients with the psychosis connected with dementia. Efficiency of olanzapine at elderly patients with the psychosis connected with dementia is not established. At this category of patients in placebo - controlled clinical trials the frequency of lethal cases in group of olanzapine was higher, than in group of placebo (3,5% against 1,5% respectively). Risk factors which can contribute this group of patients to higher mortality at treatment with olanzapine include age> 80 years, sedation, the combined use with benzodiazepines or existence of pathology of lungs (for example, pneumonia with aspiration or without it).

There are no enough data to establish distinctions in the frequency of emergence of cerebrovascular disturbances and (or) mortality (in comparison with placebo) and in risk factors at this group of patients at olanzapine reception inside and at intramuscular injections.

Parkinson's disease. Use of olanzapine at treatment of the psychoses induced by reception of agonists of dopamine receptors at Parkinson's disease is not recommended. In clinical trials at patients with the psychosis induced by administration of drug (an agonist of dopamine receptors) at Parkinson's disease, strengthening of symptoms of parkinsonism was noted very often (³10%) and with higher frequency, than in group of placebo. Hallucinations were also noted very often (³10%) and with higher frequency, than in group of placebo.

Abnormal liver functions. In some cases olanzapine reception, as a rule at early stages of therapy, was followed by tranzitorny, asymptomatic increase in activity of "hepatic" transaminases (aspartate aminotransferase (ACT) and alaninaminotranspherase (ALT)) in blood serum. Exceptional cases of hepatitis were celebrated. Besides, arrived, single messages on the cholestatic and mixed damage of a liver. Extra care is necessary at increase in activity of ACT and (or) ALT in blood serum at patients with insufficiency of function of a liver, with a limited functional reserve of a liver or at the patients receiving treatment by potentially gepatotoksichny drugs. In case of increase, activity of ACT and (or) ALT during treatment by olanzapine, needs careful observation of the patient and, if necessary, a dose decline. At the heavy abnormal liver functions caused by olanzapine reception, its use should be stopped.

Hyperglycemia and diabetes mellitus. Higher prevalence of a diabetes mellitus at patients with schizophrenia is noted. As well as at reception of some other antipsychotic drugs cases of a hyperglycemia, the diabetes mellitus decompensation which in certain cases is followed by ketoacidosis and a diabetic coma including with a lethal outcome were seldom noted. Careful clinical monitoring of patients with a diabetes mellitus and patients with risk factors of development of a diabetes mellitus is recommended.

Change of a lipidic profile. During placebo - controlled researches, at the patients receiving olanzapine undesirable changes of a lipidic range were observed. Clinical observation is recommended (see the section "Side effect").

Development of risk of sudden death. Experience of a clinical use of any neuroleptics, including olanzapine, revealed the similar, depending on a dose, double increase in risk of emergence of death owing to an acute heart failure, in comparison with death cases owing to an acute heart failure at the patients who were not applying neuroleptics.

The cerebrovascular undesirable phenomena, including a stroke, at elderly patients with dementia. The cerebrovascular undesirable phenomena (for example, a stroke, the tranzitorny ischemic attack), including lethal outcomes, were noted in olanzapine researches at elderly patients with the psychosis connected with dementia. In placebo - controlled researches higher frequency of the cerebrovascular undesirable phenomena at patients in group of olanzapine, in comparison with group of placebo was noted (1,3% against 0,4% respectively).

All patients with cerebrovascular disturbances had the previous risk factors of development of the cerebrovascular undesirable phenomena (for example, the case of the cerebrovascular undesirable phenomenon or the tranzitorny ischemic attack noted earlier, arterial hypertension, smoking), and also the associated diseases and (or) administration of drugs on time connected with the cerebrovascular undesirable phenomena.

Olanzapine is not shown for treatment of patients with the psychosis connected with dementia.

Spasms. Olanzapine should be applied with care at patients with spasms in the anamnesis or the factors subject to influence reducing a threshold of convulsive readiness. At such patients at treatment by olanzapine convulsive attacks were observed seldom.

M-holinoblokiruyushchaya activity. At conduct of clinical trials therapy by olanzapine seldom was followed by the undesirable reactions caused by blockade of m-holinoretseptorov. However clinical experience of use of olanzapine for patients with associated diseases is limited therefore patients are recommended to show care at purpose of olanzapine with clinically significant hyperplasia of a prostate, paralytic intestinal impassability, closed-angle glaucoma and similar states.

Blockade of dopamine receptors. In the conditions of in vitro olanzapine finds antagonism concerning dopamine receptors and, as well as other antipsychotic means (neuroleptics), action of a levodopa and other agonists of dopamine receptors can theoretically suppress.

Hematologic changes. With care it is necessary to apply olanzapine at patients with the low maintenance of leukocytes and (or) neutrophils in blood; receiving drugs which can cause a neutropenia; with the oppression of function of marrow caused by a disease beam or chemotherapy; and also at patients with an eosinophilia and (or) myeloproliferative diseases. About development of a neutropenia it was reported, mainly, at an olanzapine combination to Valproatum.

In clinical trials use of olanzapine for patients with a klozapinzavisimy neutropenia or an agranulocytosis in the anamnesis was not followed by a recurrence of the specified disturbances. About development of a neutropenia it was reported, mainly, at the combined therapy by olanzapine and valproic acid.

QT interval. In clinical trials clinically significant lengthening of an interval of QT was infrequently noted (QT interval with Friderition's [QTcF] correction> 500 ms at patients with an initial indicator, QTcF <500 ms) at the patients receiving olanzapine against the background of absence, significant distinctions from placebo on the frequency of emergence of the undesirable phenomena from heart. However, as well as at use of other antipsychotic means, it is recommended to be careful at use of olanzapine in combination with the drugs capable to extend QT interval, especially at patients of advanced age, with inborn lengthening of an interval of QT, chronic heart failure, a myocardium hypertrophy, a hypopotassemia and a hypomagnesiemia.

Therapy cancellation. In case of sharp cancellation of olanzapine extremely seldom (<0,01%) it was reported about acute development of perspiration, sleeplessness, a tremor, alarm, nausea and vomiting.

Thromboembolism. Extremely seldom (<0,01%) it was reported about development of a venous thromboembolism against the background of therapy by olanzapine. Existence of relationship of cause and effect between reception of olanzapine and a venous thromboembolism is not established. However considering that patients with schizophrenia often have acquired risk factors of a venous thromboembolism, it is required to carry out cumulative assessment of all possible risk factors of development of this complication, including an immobilization of patients and to take necessary measures for prevention.

The general activity concerning TsNS. Taking into account the main effect of olanzapine on TsNS, it is necessary to be careful at use of olanzapine in combination with other medicines of the central action and alcohol.

Postural hypotension. Postural hypotension was infrequently observed in clinical trials of olanzapine at elderly. Also as well as at use of other antipsychotic means, in a case olanzapine use to patients 65 years are more senior it is recommended to exercise control of arterial pressure periodically.

Body weight. During treatment (up to 6 weeks) an acute phase of schizophrenia when during placebo - controlled tests of use of olanzapine, a percentage indicator for patients at whom the increase in weight ≥ 7% of the basic line was observed the difference was statistically significant and made 29% at accepting olanzapine, and only 3% in group of placebo. The average increase in the weight of these patients accepting olanzapine in an acute phase made 2,8 kg. The Body Weight Index (BWI) always clinically significantly raised in the studied group. At long therapy of schizophrenia olanzapine the increase in weight averaged 5,4 kg, at 56% of patients in test group body weight increased more than by 7% of the basic line. For patients who underwent long therapy of bipolar disorder the average increase in weight made 3,8 kg, and the number of patients with increase in weight more than for 7% made 31%.

Giperprolaktinemiya. During controlled clinical tests (no more than 12 weeks) increase in level of prolactin in blood was established at 30% of patients of test group and 10,5% in group of placebo (control). Levels of increase in concentration of prolactin were moderate. The revealed clinical emergence included: disturbance of periods (frequent), disturbance of sexual functions (in particular, erectile dysfunction (at men), decrease or loss of a libido (at men and women), an abnormal orgasm) and from chest glands (infrequently).

Dysphagy. Emergence of disturbance of motility of a gullet and aspiration are connected using antipsychotic medicines. Aspiration pneumonia is the frequent reason of incidence and mortality at patients with the expressed Alzheimer's disease that demands care concerning such patients.

Regulation of body temperature. In general disturbance of ability of an organism to control internal body temperature is attributed to antipsychotic drugs. The corresponding care should be observed to patients who accept olanzapine and at the same time are in the conditions promoting increase in internal body temperature. For example, carry out vigorous physical exercises, are subject to influence of high temperature of the environment, accept together with olanzapine any medicine with anticholinergic activity or are in dehydration conditions (intensively sweat).

Children and teenagers up to 18 years. Olanzapine is not recommended to use for children and teenagers up to 18 years due to the lack of sufficient data by efficiency and safety. In short-term researches which were conducted at teenagers of 13-17 years, more significant increase in body weight and change of concentration of lipids and prolactin, than in similar researches at adults was noted.

Influence on ability to manage vehicles and other mechanisms. The patients accepting olanzapine should be warned about the danger connected with operation of mechanisms including the car as olanzapine can cause drowsiness and dizziness.

Side effects:

In the table provided below (see table 2) the main side effects and their frequency registered during clinical tests and/or in the post-registration period are briefly stated.

Table 2.

Comments to footnotes for table 2:

1)   The data which are saved up during placebo - controlled clinical tests which were carried out for the indication "Schizophrenia, an acute phase".

2)   The generalized data which are saved up during all clinical tests.

3)   The registered spontaneously side effects at post-market researches.

4)   At all groups of patients, irrespective of body weight, clinically significant increase in body weight was observed.

Increase in body weight for 7% and more from average value after carrying out a short course of treatment (average duration – 47 days) was observed very often (22,2%), increase by 15% also more was frequent (4,2%) and increase by 25% and more was infrequent (0,8%).

The patients receiving prolonged treatment (not less than 48 weeks), for ≥7, ≥15 and ≥25% had very frequent increase (64,4; 31,7 and 12,3% respectively).

5)   At sharp cancellation of olanzapine such symptoms as the increased sweating, sleeplessness, a tremor, alarm, nausea or vomiting were observed.

6)   During clinical trials, the patients accepting olanzapine had frequent cases of parkinsonism and dystonia, but distinction with group of placebo is statistically not significant.

At the patients accepting olanzapine, parkinsonism, the akathisia, dystonia were observed less than at the patients receiving the titrated haloperidol doses. In view of lack of detailed information on existence at patients in the anamnesis of acute and late diskineziya, it is impossible to draw a conclusion now that olanzapine to a lesser extent causes development of late diskineziya or other late extrapyramidal syndromes.

7)   Spasms generally at patients with spasms in the anamnesis or with risk factors of development of spasms.

8)   Increase in concentration of glucose from normal values on an empty stomach (<5,56 mmol/l) to raised was often observed (³7 mmol/l).

Change of concentration of glucose from boundary indicators on an empty stomach (³5,56– <7 mmol/l) to raised (³7 mmol/l) was very frequent.

9)   Increase in concentration of cholesterol from normal values on an empty stomach (<5,17 mmol/l) to raised was often observed (³6,2 mmol/l).

Change of concentration of cholesterol from boundary indicators on an empty stomach (³5,17– <6,2 mmol/l) to raised (³6,2 mmol/l) was very frequent.

10) Increase in concentration of triglycerides from normal values on an empty stomach (<1,69 mmol/l) to raised was often observed (³2,26 mmol/l).

Change of concentration of triglycerides from boundary indicators on an empty stomach (³1,69– <2,26 mmol/l) to raised (³2,26 mmol/l) was very frequent.

11) In clinical trials lasting up to 12 weeks concentration of prolactin in plasma exceeded the upper bound of norm approximately at 30% of patients with normal initial indicators of prolactin. Most of such patients had a moderate increase in concentration of prolactin, and less than exceeded the upper bound of norm twice.

Undesirable effects at special groups of patients. (³10%) undesirable effect at use of olanzapine in clinical trials at patients with the psychosis connected with dementia disturbance of gait and falling was very frequent.

(<10 and ³1%) undesirable effects at use of olanzapine for elderly patients with the psychosis connected with dementia the incontience of urine and pneumonia were frequent.

Pneumonia, fervescence, lethargy, erythema, visual hallucinations and incontience of urine were also often observed.

In clinical trials at patients with the psychosis induced by administration of drug (an agonist of dopamine receptors) at Parkinson's disease, strengthening of symptoms of parkinsonism was noted very often (³10%) and with higher frequency, than in group of placebo. Hallucinations were also noted very often (³10%) and with higher frequency, than in group of placebo.

The patients with a bipolar mania receiving olanzapine in a combination with drugs of lithium or valproic acid, very frequent (³10%) undesirable effects had an increase in body weight, dryness in a mouth, increase in appetite, a tremor and frequent (<10 and ³1%) an alalia.

Interaction with other medicines:

Metabolism of olanzapine can change under the influence of inhibitors or the inductors of an isoenzyme of P450 cytochrome showing specific activity concerning CYP1A2 isoenzyme. The clearance of olanzapine increases at the smoking patients and at the patients accepting carbamazepine (in connection with increase in activity of an isoenzyme of CYP1A2). Potential inhibitors of an isoenzyme CYP1A2 can reduce clearance of olanzapine. Olanzapine is not potential inhibitor of an isoenzyme CYP1A2 therefore at olanzapine reception the pharmacokinetics of medicines, such as theophylline, generally metaboliziruyemy CYP1A2 isoenzyme, does not change.

In clinical trials it is shown that single use of a dose of olanzapine against the background of therapy by the following drugs was not followed by suppression of metabolism of the specified medicines: Imipraminum or its metabolite desipramine (isoenzymes of CYP2D6, CYP3A, CYP1A2), warfarin (CYP2C19 isoenzyme), theophylline (CYP1A2 isoenzyme) or diazepam (isoenzyme of CYP3A4, CYP2C19). Also signs of medicinal interaction at use of olanzapine in combination with drugs of lithium or Biperidinum are not revealed.

Against the background of equilibrium concentration of olanzapine of change of pharmacokinetics of ethanol it was not noted. However reception of ethanol together with olanzapine can be followed by strengthening of pharmacological effects of olanzapine, for example, of sedative action.

Fluoxetine (60 mg once or 60 mg daily within 8 days) causes increase in the maximum concentration (Cmax) in olanzapine on average by 16% and decrease in clearance of olanzapine on average by 16%. Extent of influence of this factor considerably concedes to expressiveness of individual distinctions of the specified indicators therefore usually it is not recommended to change an olanzapine dose at its use in a combination with fluoxetine.

Fluvoksamin, CYP1A2 izofrement inhibitor, reduces clearance of olanzapine. It average increase in Cmax of olanzapine at introduction of a fluvoksamin for 54% at non-smoking women and for 77% at the smoking men, average increase in AUC (the area under a curve "concentration time") is result of olanzapine for 52% and 108% respectively. Patients who jointly receive treatment fluvoksaminy need to appoint small doses of olanzapine.

In the researches in vitro with use of microsomes of a liver of the person it is shown that olanzapine slightly suppresses process of formation of a glucuronide of valproic acid (the main way of metabolism of valproic acid). Valproic acid also slightly influences metabolism of in vitro olanzapine. Therefore clinically significant pharmacokinetic interaction between olanzapine and valproic acid is improbable.

Absorption of olanzapine does not depend on meal.

Single dose aluminum - or magniysoderzhashchy antacids or Cimetidinum did not break bioavailability of olanzapine at intake. Simultaneous use of absorbent carbon and olanzapine reduced bioavailability of the last at intake to 50–60%.

According to the researches in vitro with use of microsomes of a liver of the person, olanzapine also showed extremely small potential of inhibition of activity of the following isoenzymes of P450 cytochrome: CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A.

Contraindications:

Hypersensitivity to any of drug components.

It is contraindicated to persons up to 18 years.

Deficit of lactase, lactose intolerance, glyukozo-galaktozny malabsorption.

Overdose:

Signs and symptoms of overdose. Tachycardia, agitation/aggression, disturbance of the speech, various extrapyramidal disorders and disturbances of awareness of various degrees of severity (from sedation to a coma) were very frequent (frequency of ³10%) symptoms at overdose of olanzapine. Other clinically significant effects of overdose of olanzapine included a delirium, spasms, a malignant antipsychotic syndrome, respiratory depression, aspiration, increase and a lowering of arterial pressure, arrhythmias (<2% of cases of overdose) both a cardiac standstill and breath. The minimum dose at acute overdose with a lethal outcome made 450 mg, the maximum dose at overdose with a favorable outcome (survival) – 2 g.

Medical care at overdose. The specific antidote for olanzapine does not exist. Provoking of vomiting is not recommended. Standard procedures at overdose (a gastric lavage, reception of absorbent carbon) can be shown. Joint reception of absorbent carbon and olanzapine showed decrease in bioavailability of olanzapine at intake to 50–60%. The symptomatic treatment according to a clinical state and control of the vital functions of an organism, including correction of reduced arterial pressure, disturbance of blood circulation and maintenance of respiratory function is shown. It is not necessary to apply Epinephrinum, a dopamine and other adrenomimetik which are agonists of b-adrenoceptors as stimulation of these receptors can aggravate arterial hypotension.

Monitoring of cardiovascular activity for the purpose of detection of possible arrhythmias is necessary. The patient has to be under continuous medical observation to an absolute recovery.

Storage conditions:

In the place protected from light at a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets on 5 mg or 10 mg.

On 10 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished.

On 1, 2, 3, 4 or 5 blister strip packagings together with the application instruction place in a pack from a cardboard.