OLANZAPINE 5MG

pharmachologic effect

Olanzapine is an antipsychotic (antipsychotic) drug.

Preclinical studies have established affinity for 5-HT2A / 2C-, 5-HT3-, 5-HT6serotonin receptors, D1-, D2-, D3-, D4-, D5-dofamine receptors, m-anticholinergic effects due to blockade M1-5cholinergic 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 towards 5-HT.2-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 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 during the "anxiolytic" test.

Olanzapine provides a statistically significant reaction as productive (delusions, hallucinations, etc.), and negative disorders.

A single dose of 10 mg of olanzapine by positron emission tomography (PET) on healthy volunteers showed a greater affinity of olanzapine for 5 NT2A- than to D2dopamine receptors. On tomograms of patients with schizophrenia, it is shown that in patients sensitive to olanzapine treatment there is an affinity for striatal D2-receptors are comparable to the effect in patients sensitive to receiving clozapine, and lower than in patients sensitive to treatment with other antipsychotic drugs and Risperidone.

Clinical efficacy

In an international, double-blind, comparative study of patients with schizophrenia, schizoaffective or similar disorders of varying severity of depressive symptoms (average baseline 16.6 on the Montgomery-Asberg scale for assessing depression), a prospective secondary analysis on the mood scale from baseline to endpoint control is statistically determined a significant (p = 0.001) improvement in taking olanzapine (-6.0) 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 additional intake 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.

A 12-month study on the prevention of relapses of manic episodes in patients who achieved remission while taking olanzapine and then randomly assigned to the group of the drug olanzapine showed a statistically significant advantage over placebo for the main criterion for controlling the occurrence of bipolar disorder relapse and in terms of preventing relapse of mania or relapse of depression.

In the second 12-month study on the prevention of relapses of manic episodes in patients who achieved remission when co-administering olanzapine with the lithium drug, and then randomly assigned to the olanzapine or lithium monotherapy group. The effectiveness of olanzapine intake was statistically insignificant compared with the lithium drug by the main criterion for the control of relapse of bipolar disorder (olanzapine 30.0%, lithium 38.3%, p = 0.055).

In an 18-month study of manic or mixed episodes of cat therapy in patients stabilized with olanzapine and mood stabilizing drugs (lithium or valproic acid),Long-term combined therapy with olanzapine with lithium or valproic acid was not statistically significant compared with monotherapy with lithium or valproic acid in order to delay the onset of relapse of bipolar disorder, which is determined by diagnostic signs.

Pharmacokinetics

After oral administration, olanzapine is well absorbed, Cmax in plasma it is reached in 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 blood-brain barrier. CYP1A2 and CYP2D6 isoenzymes are involved in the formation of N-desmethyl- and 2-hydroxymethylmetabolites of olanzapine. Both metabolites in animal studies had a 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 blood-brain barrier.

In healthy volunteers after oral administration, average T1/2 amounted to 33 h (21-54 h for 5-95%), and the average clearance of plasma olanzapine - 26 l / h (12-47 l / h for 5-95%).

The pharmacokinetic parameters of olanzapine vary depending on smoking, gender and age (see table 1):

Table 1

However, the degree of changes in the half-life and clearance under the influence of each of these factors is significantly inferior to the degree of differences in these indicators between individuals.

Indicators pharmacokinetics in adolescents (13-17 years) and adults are similar. 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 half-life and plasma clearance of olanzapine 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 acidic α1glycoprotein. In a study involving people 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

- for the 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;

- for the treatment of manic episode from moderate to severe;

- to prevent relapse in patients with bipolar disorder, in whom it has proven effective in the treatment of the manic phase;

- 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.

Dosing regimen

Inside Olanzapine can be taken regardless of the meal, as food does not affect the absorption of olanzapine.

Schizophrenia

The recommended starting dose of olanzapine is 10 mg once daily. Therapeutic doses of olanzapine range from 5 mg to 20 mg per day. The daily dose must be selected individually depending on the patient’s clinical condition. Increasing the dose above the standard daily dose (10 mg) is recommended only after evaluating the clinical picture. When using the drug, it is necessary to regularly assess the need to continue therapy.

Bipolar disorder

For treatment of a manic episode, the recommended initial dose of olanzapine is 15 mg once a day as monotherapy or 10 mg once a day in combination with lithium preparations or valproic acid. Therapeutic doses of olanzapine range from 5 mg to 20 mg per 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 once a 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 per 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 selection of the daily dose for special groups of patients when taken orally

Reducing the initial dose to 5 mg per 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.

Side effect

The table below (see table 2) summarizes the main side effects and their frequency, registered during clinical trials and / or in the post-registration period.

table 2