ZYPREXA ZIDIS
Active material: Olanzapine
When ATH: N05AH03
CCF: Antipsychotic drug (anxiolytic)
ICD-10 codes (testimony): F20, F21, F22, F23, F25, F29, F31
When CSF: 02.01.02.02
Manufacturer: ELI LILLY NEDERLS B.V. (Netherlands)
Pharmaceutical form, composition and packaging
Dispersible tablets yellow color, round.
| 1 tab. | |
| olanzapine | 5 mg |
| -“- | 10 mg |
Excipients: gelatin, mannitol, Aspartame, methylparaben sodium, sodium propyl parahydroxybenzoate.
7 PC. – blisters (4) – packs cardboard.
Dispersible tablets yellow color, round.
| 1 tab. | |
| olanzapine | 15 mg |
| -“- | 20 mg |
Excipients: gelatin, mannitol, Aspartame, Sodium methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate.
7 PC. – blisters (4) – packs cardboard.
Pharmacological action
Antipsychotic drug (anxiolytic) with a wide pharmacological spectrum of influence on a number of receptor systems.
Preclinical studies have established the affinity of olanzapine for serotonin 5-HT2A/2C, 5-NT3, 5-NT6; dopaminovыm D1, D2, D3, D4, D5; muscarinic M1-5; a1-to adrenoreceptors and histamine N1-Receptor. Experimental studies on animals revealed the presence of olanzapine antagonism towards serotonin 5-HT-, dopamine and cholinergic receptors. Under in vitro and in vivo conditions, olanzapine has greater affinity and activity for serotonin 5-HT.2-receptors, compared to dopamine D2-receptors. According to electrophysiological studies, olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, and at the same time has an insignificant effect on striatal (A9) nerve pathways, involved in the regulation of motor functions. Olanzapine reduces the conditioned defense reflex (test, characterizing antipsychotic activity) at lower doses, than doses, causing catalepsy (disorder, reflecting side effects on motor function). Olanzapine enhances the anti-anxiety effect when “anxiolytic” test.
Olanzapine provides a statistically significant reduction in both productive (incl. delirium, hallucinations), and negative disorders.
Pharmacokinetics
Olanzapine dispersible tablets and olanzapine tablets, coated, bioequivalent and have similar rates and extent of absorption. Olanzapine dispersible tablets are administered in the same quantity and frequency, same as olanzapine tablets, coated. Olanzapine dispersible tablets can be used instead of olanzapine tablets, coated.
Absorption
After oral administration, olanzapine is well absorbed from the gastrointestinal tract.. Cmax plasma achieved through 5-8 no. The absorption of olanzapine is not affected by food intake.. In studies with different doses ranging from 1 mg 20 mg shown, that olanzapine plasma concentrations vary linearly and proportionally to dose.
Distribution
At plasma concentrations from 7 to 1000 ng/ml plasma protein binding is about 93%. Olanzapine binds mainly to albumin and acid α1-glycoprotein.
Metabolism
Olanzapine is metabolized in the liver as a result of conjugation and oxidation processes. The main circulating metabolite is 10-N-glucuronide, which theoretically does not penetrate the BBB. Isoenzymes CYP1A2 and CYP2D6 are involved in the formation of N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Both metabolites in experimental animal studies had significantly less pronounced pharmacological activity in vivo, than olanzapine. The main pharmacological activity of the drug is due to the unchanged substance – olanzapine, having the ability to penetrate the BBB.
The activity of the CYP2D6 isoenzyme does not affect the level of metabolism of olanzapine.
Deduction
In healthy volunteers after oral administration, the average T1/2 is 33 no (21-54 h for 5-95%), and the average plasma clearance of olanzapine – 26 l / (12-47 l/h for 5-95%). About 57% radiolabeled olanzapine is excreted in the urine and 30% with feces, mainly in the form of inactive metabolites.
Pharmacokinetics in special clinical situations
Variability of olanzapine pharmacokinetic parameters depending on smoking, gender and age are presented in the table.
| Characteristics patients |
T1/2 (no) | Plasma clearance (l /) |
| Non-smokers | 38.6 | 18.6 |
| Smoking | 30.4 | 27.7 |
| Women | 36.7 | 18.9 |
| Men | 32.3 | 27.3 |
| Elderly (65 and older) | 51.8 | 17.5 |
| Younger 65 years | 33.8 | 18.2 |
However, the degree of change T1/2 and clearance under the influence of each of these factors is significantly inferior to the degree of differences in these indicators between individuals.
Significant differences between mean T values1/2 and plasma clearance of olanzapine in persons with severe renal impairment, compared to individuals with normal kidney function, not installed.
Olanzapine clearance is lower in smokers with mild hepatic impairment., than in non-smokers without liver dysfunction.
In a study involving people of European, Japanese and Chinese descent, differences in the pharmacokinetics of olanzapine, racially related, not installed.
Testimony
Schizophrenia:
- for the treatment of exacerbations, maintenance and long-term anti-relapse therapy for patients with schizophrenia and other psychotic disorders with pronounced productive (incl. delirium, hallucinations, automatisms) and/or negative (emotional flatness, decrease in social activity, unification of words) symptoms, as well as concomitant affective disorders.
Bipolar affective disorder:
- as monotherapy or in combination with lithium or valproate – for the treatment of acute manic or mixed episodes in bipolar affective disorder with/without psychotic manifestations and with/without rapid phase changes;
- to prevent relapses in patients with bipolar disorder, in whom olanzapine was effective in treating manic phase.
Treatment of depression, associated with bipolar disorder (in combination with fluoxetine).
Dosage regimen
Olanzapine dispersible tablets dissolve quickly in saliva, and are easy to swallow. It is difficult to remove the undissolved tablet from your mouth. Due to its fragility, the tablet should be taken immediately after removal from the blister.. Besides, immediately before taking the tablet, you can dissolve it in a glass of water or other liquid (Orange juice, Apple juice, milk or coffee).
Olanzapine can be taken with or without food, tk. food does not affect drug absorption.
The daily dose must be selected individually, depending on the clinical condition of the patient.
To treatment of schizophrenia and similar psychotic disorders The recommended starting dose of olanzapine is 10 mg 1 time / day. Therapeutic doses of olanzapine range from 5 mg 20 mg / day. Increasing the dose beyond the standard daily dose 10 mg is recommended only after appropriate clinical examination of the patient.
For the treatment of acute mania in bipolar disorder The recommended starting dose of olanzapine is 15 mg 1 once a day as monotherapy or 10 mg 1 once a day in combination with lithium or valproate. Olanzapine can be taken with or without food, since food intake does not affect the absorption of the drug. Therapeutic doses of olanzapine range from 5 mg 20 mg per day. Increasing the dose above the standard daily dose 15 mg is recommended only after appropriate clinical examination of the patient. The dose should be increased gradually, at minimum intervals 24 no.
Maintenance therapy for bipolar disorder: patients, taking olanzapine to treat acute mania, it is necessary to continue maintenance therapy at the same dose. In patients in remission, the recommended starting dose of olanzapine is 10 mg 1 time / day. In the future, the daily dose must be selected individually depending on the clinical condition of the patient., between 5 mg 20 mg / day.
Olanzapine in combination with fluoxetine should be appointed 1 time / day, regardless of the meal. Usually, starting dose is 5 mg olanzapine and 20 mg fluoxetine. If necessary, dose changes such as olanzapine are allowed, so is fluoxetine.
Patient Seniors or patients with other clinical risk factors, including severe renal failure or moderate liver failure It is recommended to reduce the initial dose of olanzapine to 5 mg / day.
For patients with a combination of factors, if available it is possible slowing down the metabolism of olanzapine (female patients, senile, non-smokers), which may slow down the metabolism of olanzapine, a reduction in the starting dose of olanzapine may also be recommended.
Data from studies of olanzapine in therapy with children and adolescents under the age of 18 years limited.
Side effect
Often: ≥10% – drowsiness, weight gain; 34% – increase in plasma prolactin concentration, which was mild and transient (the mean maximum prolactin concentration did not reach the ULN and was not statistically significantly different from placebo). Clinical manifestations of hyperprolactinemia, associated with olanzapine (ie. gynecomastia, galactorrhea and breast enlargement), rarely noted. In most patients, normalization of prolactin levels was observed without discontinuation of olanzapine.
Often: < 10% and ≥1% – dizziness, asthenia, akathisia, increase in appetite, peripheral edema, orthostatic hypotension, dry mouth and constipation. In clinical studies, (n=107) in 1.9% cases, triglyceride levels were noted in 2 times or more exceeding ULN on an empty stomach, cases of exceeding ULN > 3 never observed.
Rarely: transient, asymptomatic increase in liver transaminases (IS ALT) serum.
In rare cases,: increase in plasma glucose levels to ≥ 200 mg / dL (suspected diabetes mellitus), and from ≥160 mg/dl, but before < 200 mg / dL (suspected hyperglycemia) in patients with baseline glucose levels ≤140 mg/dL.
In some cases,: asymptomatic eosinophilia.
Adverse effects in special groups of patients
In patients with psychosis, dementia related, Often (≥10%) gait disturbance and falls were observed.
In elderly patients with psychosis, dementia related, often (< 10% and ≥1%) – urinary incontinence and pneumonia.
In patients with psychosis, drug-induced (dopamine agonist) Parkinson's disease, Often (≥ 10%) and at a higher frequency, than placebo, increased symptoms of parkinsonism were observed, hallucinations.
In patients with bipolar mania, receiving olanzapine in combination with lithium or valproate, Often (≥10%) there was an increase in body weight, dry mouth, increased appetite, tremor; often (< 10% and ≥1%) – speech disorder.
The table below summarizes the main side effects and their frequency, registered during clinical trials and/or in the post-registration period
The main side effects during treatment with various dosage forms of olanzapine are presented in the table.
| System/Side Effect | Frequency | ||||
| ≥ 10% | < 10% and ≥ 1% | < 1% and ≥0.1% | <0.1% and ≥ 0.01% | <0.01% | |
| From the body as a whole | |||||
| 3,6 Allergic reaction | X | ||||
| 2 Asthenia | X | ||||
| 3,7 Reaction to cancellation | X | ||||
| 2 Increased sensitivity to light | X | ||||
| 1 Weight gain | X | ||||
| Cardio-vascular system | |||||
| 2 Bradycardia | X | ||||
| 1 Orthostatic hypotension | X | ||||
| 3 Venous thromboembolism | X | ||||
| From the digestive system | |||||
| 2 Constipation | X | ||||
| 2 Dry mouth | X | ||||
| 3 Hepatitis | X | ||||
| 2 Increased appetite | X | ||||
| 3 Pancreatitis | X | ||||
| Metabolism | |||||
| 3 Diabeticheskaya coma | X | ||||
| 3,4 Diabetic ketoacidosis | X | ||||
| 3 Giperglikemiâ | X | ||||
| 3,5 Hypertriglyceridemia | X | ||||
| 1 Peripheral edema | X | ||||
| On the part of the musculoskeletal system | |||||
| 3 Raʙdomioliz | X | ||||
| CNS | |||||
| 2 Akathisia | X | ||||
| 2 Dizziness | X | ||||
| 3 Seizures | X | ||||
| 2 Drowsiness | X | ||||
| Dermatological reactions | |||||
| 3 Rash | X | ||||
| On the part of the reproductive system | |||||
| 3 Priapism | X | ||||
| From the laboratory parameters | |||||
| 1 Increased ALT | X | ||||
| 1 Increased AST | X | ||||
| 1 Increased prolactin | X | ||||
| 1 Isolated cases of increased blood glucose levels from ≥160 mg/dL to <200 mg / dL (suspected hyperglycemia) |
X | ||||
| 1 Isolated cases of increased blood glucose levels to ≥200 mg/dL (suspected diabetes mellitus) | X | ||||
| 1 Isolated cases of increased triglyceride levels ≥2 times ULN | X | ||||
| From the hematopoietic system | |||||
| 1 Eozinofiliya | X | ||||
| 3 Leukopenia | X | ||||
| 3Thrombocytopenia | X | ||||
1evaluation of indicators from the clinical trials database.
2 side effects, registered in the clinical trials database.
3 side effects, reported spontaneously during post-marketing studies.
4 in the COSTART classification it is designated as diabetic acidosis.
5 in the COSTART classification it is designated as hyperlipidemia.
6 eg, anaphylactic reaction, angioedema, itching or hives.
7 ie. Sweating, nausea or vomiting.
Contraindications
- Hypersensitivity to the drug.
Pregnancy and lactation
There is insufficient clinical experience with olanzapine during pregnancy, therefore, prescribing the drug is possible only in cases, when the expected benefit of therapy for the mother significantly exceeds the potential risk to the fetus.
Patients should be warned, that if pregnancy occurs or is planned during treatment with olanzapine, they should inform their doctor.
The study revealed, that olanzapine is excreted in breast milk. The average dose (mg / kg), received by the child upon reaching Css mother, was 1.8% dose (mg / kg) mother. If it is necessary to use the drug during lactation, it is recommended to stop breastfeeding.
Cautions
Neuroleptic malignant syndrome (potentially fatal symptom complex) may develop during treatment with any antipsychotics, including olanzapine, However, no data available at this time, confirming a reliable connection between taking olanzapine and the development of this condition. Clinical manifestations of NMS include a significant increase in body temperature, Muscle rigidity, mental status changes and autonomic disturbances (unstable pulse or blood pressure, tachycardia, cardiac arrhythmias, increased perspiration). Additional signs may include increased CPK levels, mioglobinuriju (raʙdomioliz) and acute kidney failure. Clinical manifestations of neuroleptic malignant syndrome or a significant increase in body temperature without other symptoms of NMS require discontinuation of all antipsychotics, including olanzapine.
In comparative studies, treatment with olanzapine was significantly less likely to be accompanied by the development of dyskinesia, requiring medication correction, than the use of typical and other atypical antipsychotics. However, the risk of tardive dyskinesia should be taken into account during long-term therapy with antipsychotics.. If signs of tardive dyskinesia develop, dose adjustment of the antipsychotic is recommended.. It should be taken into account, that when switching to olanzapine, symptoms of tardive dyskinesia may develop as a result of immediate withdrawal of previous therapy.
Efficacy of olanzapine in elderly patients with psychosis, dementia related, not installed. In this category of patients in placebo-controlled clinical trials, the incidence of deaths was higher in the olanzapine group, than placebo (3.5% against 1.5 % respectively). Risk factors, which may predispose this group of patients to higher mortality when treated with olanzapine, include age ≥80 years, sedation, combined use with benzodiazepines or the presence of lung pathology (eg, pneumonia with or without aspiration).
There is not enough data, to determine differences in the incidence of cerebrovascular events and/or mortality (compared to placebo), and in risk factors in this group of patients when taking olanzapine orally and with intramuscular injections.
In some cases, taking olanzapine, usually in the early stages of therapy, accompanied by transient, asymptomatic increase in liver transaminase levels (IS ALT) serum. Rare cases of hepatitis have been reported. Particular caution is required when serum AST and/or ALT levels increase in patients with hepatic impairment., with limited liver functional reserve or in patients, receiving treatment with potentially hepatotoxic drugs. If AST and/or ALT levels increase during treatment with olanzapine, requires careful monitoring of the patient and, if necessary, dose reduction.
There is a higher prevalence of diabetes mellitus in patients with schizophrenia. As with some other antipsychotic drugs, cases of hyperglycemia have been reported very rarely., Diabetes, exacerbation of pre-existing diabetes, ketoacidosis and diabetic coma. A causal relationship between antipsychotic drugs and these conditions has not been established. Close clinical monitoring of patients with diabetes mellitus and patients with risk factors for developing diabetes mellitus is recommended..
Olanzapine should be used with caution in patients with a history of epileptic seizures or exposure to, lowering the seizure threshold. Seizures were rare in these patients when treated with olanzapine..
Cerebrovascular adverse reactions (for example stroke, tranzitornaya ishemicheskaya attack), including deaths, observed in studies of olanzapine in elderly patients with psychosis, dementia related. In placebo-controlled studies, there was a higher incidence of cerebrovascular adverse events in patients in the olanzapine group, compared with the placebo group (1.3% against 0.4% respectively).
All patients with cerebrovascular disorders had previous risk factors for the development of cerebrovascular adverse reactions (eg, a previous case of cerebrovascular adverse reaction or transient ischemic attack, arterial hypertension, smoking), as well as concomitant diseases and/or medications, temporally associated with cerebrovascular adverse reactions. Olanzapine is not indicated for the treatment of patients with psychosis, dementia related.
As with the use of other antipsychotics, Caution should be exercised when treating olanzapine in the following groups of patients::
– patients with a reduced number of leukocytes and/or neutrophils in peripheral blood, due to various reasons;
– patients with a history of drug-induced bone marrow suppression/toxicity;
– patients with bone marrow suppression, caused by concomitant disease, history of radiotherapy or chemotherapy;
– patients with hypereosinophilia or myeloproliferative disease.
In clinical studies, the use of olanzapine in patients with a history of clozapine-dependent neutropenia or agranulocytosis was not accompanied by relapses of these disorders.
Olanzapine therapy was rarely associated with anticholinergic side effects in clinical trials.. However, clinical experience with olanzapine in patients with concomitant diseases is limited., Therefore, caution is recommended when prescribing olanzapine to patients with clinically significant prostatic hypertrophy., paralytic ileus, angle-closure glaucoma and similar conditions.
Taking into account the main action of olanzapine on the central nervous system, Caution should be exercised when using olanzapine in combination with other centrally acting drugs., and also with alcohol.
Effects on ability to drive vehicles and management mechanisms
Patients, taking olanzapine, Caution should be exercised when operating mechanical equipment, including vehicles, because olanzapine may cause drowsiness.
Overdose
Symptoms: Often (≥10%) – tachycardia, agitation/aggression, articulation disorder, various extrapyramidal disorders and disturbances of consciousness of varying severity (from sedation to coma). Other clinically significant symptoms – convulsions, neuroleptic malignant syndrome, respiratory depression, Aspiration, hypertension or hypotension, cardiac arrhythmias (< 2% cases of overdose), cardiac arrest and respiratory. Minimum dose for acute fatal overdose was 450 mg, the maximum dose of an overdose of a favorable outcome (survival) – 1.5 g.
Treatment: There is no specific antidote for olanzapine. Inducing vomiting is not recommended. Standard procedures for overdose may be indicated. (gastric lavage, appointment of activated carbon). Co-administration of activated charcoal showed a decrease in the bioavailability of olanzapine when taken orally before 50-60%.
Symptomatic therapy is indicated in accordance with the clinical condition and monitoring the functions of vital organs, including treatment of arterial hypotension, circulatory disorders and maintenance of respiratory function. Do not use epinephrine, dopamine and other sympathomimetics, which are β-adrenergic receptor agonists, tk. stimulation of these receptors may aggravate hypotension.
Drug Interactions
The metabolism of olanzapine may be altered by inhibitors or inducers of cytochrome P450 isoenzymes, exhibiting specific activity against CYP1A2. The clearance of olanzapine is increased in patients who smoke and in patients, taking carbamazepine (due to increased CYP1A2 activity). Known potential inhibitors of CYP1A2 may reduce the clearance of olanzapine. Olanzapine is not a potential inhibitor of CYP1A2 activity, Therefore, when taking olanzapine, the pharmacokinetics of drugs, such as theophylline, mainly metabolized by CYP1A2 does not change.
In clinical studies have shown, that a single dose of olanzapine during therapy with the following drugs was not accompanied by suppression of the metabolism of these drugs: imipramine or its metabolite desipramine (CYP2D6, CYP3A, CYP1A2), varfarinom (CYP2C19), theophylline (CYP1A2) or diazepam (CYP3A4, CYP2C19). There were also no signs of drug interactions when using olanzapine in combination with lithium or biperidine.
Against the background of steady-state concentrations of olanzapine, no changes in the pharmacokinetics of ethanol were observed.. However, taking ethanol together with olanzapine may be accompanied by an increase in the pharmacological effects of olanzapine, eg, sedative action.
Single dose aluminum- or a magnesium-containing antacid or cimetidine did not interfere with the oral bioavailability of olanzapine. Co-administration of activated charcoal reduced the oral bioavailability of olanzapine to 50-60%. Fluoxetine (60 mg once or 60 mg daily for 8 days) causes an increase in Cmax olanzapine in the average of 16% and a decrease in the clearance of olanzapine in the mean of 16%. The degree of influence of this factor is significantly inferior to the severity of individual differences in these indicators, Therefore, it is generally not recommended to change the dose of olanzapine when given in combination with fluoxetine.
Fluvoxamine, CYP1A2 inhibitor, reduces clearance of olanzapine. The result of this is an average increase in Cmeat olanzapine when administering fluvoxamine to 54% in non-smoking women and 77% in smoking men. Mean increase in olanzapine AUC 52% and 108% respectively. Low doses of olanzapine should be prescribed to patients, who are receiving fluvoxamine treatment together.
In vitro studies using human liver microsomes have shown, that olanzapine slightly inhibits the formation of valproate glucuronide (major metabolic pathway for valproate). Valproate also has little effect on the metabolism of olanzapine in vitro. Therefore, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely..
In vitro, olanzapine antagonizes dopamine and, like other antipsychotics (neuroleptics), theoretically may inhibit the effects of levodopa and dopamine agonists.
Absorption of olanzapine is independent of food intake.
Based on in vitro studies using human liver microsomes, olanzapine also showed very little potential to inhibit the activity of the following cytochrome P450 isoenzymes: CYP1А2, CYP2C9, CYP2C19, CYP2D6 и CYP3A.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
List B. The drug should be stored out of reach of children, in its original packaging, dry, protected from light at a temperature of 15° to 30°C. Shelf life – 2 year.
