Zolafren Fast tablets 20 mg No. 28
Composition
active ingredient: olanzapine;
1 tablet contains 10 mg or 20 mg of olanzapine;
excipients: mannitol (E 421), crospovidone, aspartame (E 951), orange flavoring, colloidal anhydrous silicon dioxide, sodium stearyl fumarate.
Dosage form
Orodispersible tablets.
Main physicochemical properties:
10 mg tablets: yellow, flat, round tablets, engraved with “10” on one side, 8 mm in diameter, without visible inclusions or inclusions;
20 mg tablets: yellow, flat, round tablets, engraved with “20” on one side, 10 mm in diameter, without visible inclusions or inclusions.
Pharmacotherapeutic group
Antipsychotics. ATX code N05A H03.
Pharmacological properties
Pharmacodynamics
Olanzapine is an antipsychotic, antimanic drug, it also stabilizes mood, has a spectrum of pharmacological action due to its effect on various receptors.
In preclinical studies, olanzapine has been shown to bind to serotonin 5HT2A/2C, 5HT3, 5HT6 receptors, dopamine D1, D2, D3, D4, D5 receptors, muscarinic M1-M5 receptors, α1 adrenergic receptor, and histamine H1 receptor. In behavioral studies in animals treated with olanzapine, olanzapine has been shown to antagonize both serotonin 5HT receptors and dopamine and cholinergic receptors. Olanzapine has a higher level of binding to serotonin 5HT2 receptors than to dopamine D2 receptors in both in vitro and in vivo models. Electrophysiological studies have shown that olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, while showing little effect on striatal (A9) pathways involved in motor function. Olanzapine inhibits the conditioned avoidance reflex, which indicates its antipsychotic activity at doses lower than those that cause catalepsy, which is a sign of motor side effects. Unlike other antipsychotic drugs, olanzapine increases responses to stimuli in an anxiolytic test.
A single oral dose of 10 mg olanzapine was found to have higher binding to 5HT2A receptors than to dopamine D2 receptors in healthy volunteers using positron emission tomography (PET). In addition, analysis of single-photon emission computed tomography (SPECT) images of patients with schizophrenia showed that olanzapine-sensitive patients had lower binding to striatal D2 receptors than other antipsychotic- and risperidone-sensitive patients, compared with clozapine-sensitive patients.
Clinical efficacy
In two of two placebo-controlled and two of three comparator-controlled studies involving over 2,900 patients with schizophrenia with positive and negative symptoms, olanzapine showed statistically significant improvements in both negative and positive symptoms.
In an international double-blind comparative study of 1,484 patients with schizophrenia, schizoaffective disorder, and related disorders with varying degrees of impairment associated with depressive symptoms (16.6 points on the Montgomery-Asberg Depression Scale), a prospective secondary study from baseline to end of the assessment of mood changes showed a statistically significant improvement (p = 0.001) after treatment with olanzapine (-6.0) compared with haloperidol (-3.1).
In patients with manic or mixed episodes in bipolar disorder, olanzapine demonstrated superior efficacy in reducing manic symptoms over 3 weeks compared with placebo and sodium valproate. Olanzapine also demonstrated comparable efficacy to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks of treatment. In a study, when lithium or valproate were added to olanzapine 10 mg for 2 weeks, significant reductions in manic symptoms were observed compared with lithium or valproate monotherapy after 6 weeks of treatment.
In a 12-month study of the prevention of recurrence of manic episodes in patients who achieved remission with olanzapine and were subsequently randomized to olanzapine or placebo, olanzapine demonstrated a statistically significant advantage over placebo on the endpoint of recurrence of bipolar disorder. Olanzapine also demonstrated a statistically significant advantage over placebo in preventing recurrence of mania or recurrence of depression.
In an 18-month study of patients stabilized on olanzapine as adjunctive treatment for manic or mixed episodes, lithium or valproate were used as mood stabilizers; long-term concomitant treatment with olanzapine and lithium or valproate did not demonstrate a statistically significant advantage over lithium or valproate monotherapy in delaying relapse of bipolar disorder defined by syndromic (diagnostic) criteria.
Children
Experience in adolescents (aged 13 to 17 years) is limited based on short-term efficacy data in schizophrenia (6 weeks) and mania associated with bipolar disorder (3 weeks) in less than 200 adolescents. The starting dose of olanzapine was 2.5 mg and was increased up to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight compared to adults. Adolescents had increases in total cholesterol, low-density lipoprotein cholesterol, triglycerides and prolactin compared to adults (see sections 4.4 and 4.8). Data on maintenance of treatment effect and long-term studies from open-label, uncontrolled clinical trials are limited (see sections 4.4 and 4.8).
Pharmacokinetics
Olanzapine orodispersible tablets are bioequivalent to olanzapine film-coated tablets, which demonstrate a similar rate and extent of absorption. Olanzapine orodispersible tablets may be used as an alternative to olanzapine film-coated tablets.
Absorption
The drug is well absorbed after oral administration, its maximum concentration (Cmax) in the blood plasma is reached after 5-8 hours. Food intake does not affect the absorption of olanzapine. The absolute bioavailability of the oral form of olanzapine compared with the intravenous form has not been established.
Distribution
The level of binding of olanzapine to plasma proteins was approximately 93% for concentrations ranging from 7 to 1000 ng/mL. Olanzapine binds primarily to albumin and α1-acid glycoprotein.
Biotransformation
Olanzapine is metabolized in the liver by conjugation and oxidation. The major circulating metabolite is the 10-N-glucuronide, which does not cross the blood-brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, which exhibit significantly less pharmacological activity in vivo than olanzapine in animal studies. The predominant pharmacological activity is due to the parent olanzapine.
Breeding
After oral administration, the mean elimination half-life of olanzapine in volunteers varied depending on age and gender.
In healthy elderly volunteers (aged 65 years and over), the mean elimination half-life was longer (51.8 vs. 33.8 hours) and plasma clearance was reduced (17.5 vs. 18.2 l/h, respectively) compared to younger volunteers. The pharmacokinetic variations observed in elderly volunteers are within the range observed in younger volunteers. In 44 schizophrenic patients aged 65 years and over, doses of 5 to 20 mg/day were not associated with any distinctive adverse reaction profile.
In women compared to men, the mean half-life was longer (36.7 vs. 32.3 hours) and plasma clearance was reduced (18.9 vs. 27.3 L/h). However, olanzapine (5-20 mg) showed a comparable safety profile in both women (n = 467) and men (n = 869).
Patients with renal failure
In patients with renal insufficiency (creatinine clearance 100–150%, radiolabeled olanzapine is present in the urine, mainly as metabolites.
Patients who smoke
In patients with mild hepatic impairment who smoke, the mean elimination half-life was longer (39.3 hours) and plasma clearance was reduced (18.0 l/h) compared to those in patients without hepatic impairment who do not smoke (48.8 hours and 14.1 l/h, respectively).
In non-smokers compared to smokers (men and women), the mean half-life was longer (38.6 vs. 30.4 hours) and plasma clearance was reduced (18.6 vs. 27.7 L/h).
Olanzapine plasma clearance is lower in elderly patients compared to younger patients, in women compared to men, and in non-smokers compared to smokers. However, the magnitude of the effect of factors such as age, gender, and smoking may have little effect on olanzapine plasma clearance and half-life compared to the overall interindividual variability.
In studies involving European, Japanese, and Chinese patients, no differences in the pharmacokinetics of olanzapine were identified.
Teenagers and adults
The pharmacokinetics of olanzapine are similar in adolescents and adults. In clinical trials, the mean exposure to olanzapine was approximately 27% higher in adolescents than in adult patients. Demographic differences between adolescents and adults include lower mean body weight and lower rates of smoking among adolescent patients. These factors are likely to contribute to the higher mean exposure to olanzapine observed in adolescents.
