Zyprexa Zydis, pills 5mg, 28pcs

Composition

1 tablet contains:

Active ingredient:

olanzapine 5 mg,

excipients:

gelatin,

mannitol,

aspartame,

sodium methylparahydroxybenzoate,

sodium propylparahydroxybenzoate.

Pharmacological action

Ziprex Zadis has an antipsychotic effect.

Pharmacodynamics

In preclinical studies, the affinity of olanzapine for serotonin 5-HT_2A/2C,5-HT₃,5-HT₆; dopamine_D1, _D2, D3, D4, D5; muscarinic M_1-5;_α1-adrenergic receptors and histamine_H1-receptors was established. In experimental animal studies, the presence of olanzapine antagonism against serotonin 5-HT, dopamine and holinoreceptors was revealed. In vitro and in vivo, olanzapine has a more pronounced affinity and activity for serotonin 5-HT2receptors compared to dopamine_D2receptors.

According to electrophysiological studies, olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons and at the same time has a minor effect on striatal (A9) nerve pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned protective reflex (a test that characterizes antipsychotic activity) at doses lower than those that cause catalepsy (a disorder that reflects an adverse effect on motor function). Olanzapine enhances the anti-anxiety effect during the anxiolytic test.

Olanzapine provides statistically significant reduction of both productive (including delusions, hallucinations) and negative disorders.

Pharmacokinetics

Dispersible olanzapine tablets and coated olanzapine tablets are bioequivalent and have a similar rate and degree of absorption. Dispersible olanzapine tablets are used in the same quantity and frequency as coated olanzapine tablets. Dispersible olanzapine tablets can be used instead of coated olanzapine tablets.

Suction. After oral use, olanzapine is well absorbed from the gastrointestinal tract. _cmax in plasma is reached in 5-8 hours. The absorption of olanzapine does not depend on food intake. In studies with different doses ranging from 1 to 20 mg, plasma concentrations of olanzapine have been shown to vary linearly and proportionally to the dose.

Distribution. At plasma concentrations from 7 to 1000 ng/ml, the binding to plasma proteins is about 93%. Olanzapine mainly binds to albumin and acidic_α1-glycoprotein.

Metabolism. Olanzapine is metabolized in the liver by conjugation and oxidation processes. The main circulating metabolite is 10-N-glucuronide, which theoretically does not cross the BBB. CYP1A2 and CYP2D6 are involved in the formation of N – desmethyl and 2-hydroxymethyl metabolites of olanzapine. Both metabolites in experimental animal studies have significantly less pronounced pharmacological activity in vivo than olanzapine. The main pharmacological activity of the drug is due to an unchanged substance-olanzapine, which has the ability to penetrate the BBB.

The activity of the CYP2D6 isoenzyme does not affect the level of olanzapine metabolism.

Output. In healthy volunteers, after oral use, the average T_1/2 was 33 h (21-54 h for 5-95%), and the average plasma clearance of olanzapine was 26 l/h (12-47 l/h for 5-95%). About 57% of radioisotope-labeled olanzapine is excreted in the urine and 30% in the faeces, mainly as inactive metabolites.

Pharmacokinetics in special clinical cases

The table shows the variability of olanzapine pharmacokinetic parameters depending on smoking, gender, and age.

However, the degree of changes in T_1/2 and clearance under the influence of each of the factors listed in the table is significantly lower than the degree of differences in these indicators between individuals.

There were no significant differences between the mean T_1/2 and plasma clearance of olanzapine in patients with severe renal impairment compared to those with normal renal function.

Olanzapine clearance is lower in smokers with minor hepatic impairment than in non-smokers without hepatic impairment.

In a study involving individuals of European, Japanese, and Chinese descent, no differences in the pharmacokinetics of olanzapine related to race were found.

Indications

• treatment of exacerbations of schizophrenia;
• support and long-lasting anti-relapse treatment of patients with schizophrenia and other psychotic disorders with a strong productive (including delusions, hallucinations, automatism) and/or negative (emotional flatness, reduced social activity, the depletion of speech) symptoms and related affective disorders);
• treatment of acute manic or mixed episodes in bipolar affective disorder with or without psychotic symptoms and with/without quick change of phases (as monotherapy or in combination with lithium or valproate);
• prevention of relapse in patients with bipolar disorder, which olanzapine was effective in the treatment of manic phase;
• treatment of depression associated with bipolar disorder (in combination with fluoxetine).

Use during pregnancy and lactation

There is insufficient clinical experience with the use of olanzapine during pregnancy, so the drug can only be prescribed in cases where the expected benefit of therapy for the mother significantly exceeds the potential risk to the fetus.

Patients should be advised that if pregnancy occurs or is planned during olanzapine treatment, they should inform their healthcare provider.

The study found that olanzapine is excreted in breast milk. The average dose (mg/kg) received by the child when reaching C_SS in the mother was 1.8% of the maternal dose (mg/kg). If it is necessary to use the drug during lactation, it is recommended to stop breastfeeding.

Use in patients with impaired liver and kidney function. For patients with moderate hepatic insufficiency and severe renal insufficiency, it is recommended to reduce the initial dose of olanzapine to 5 mg / day.

Contraindications

Hypersensitivity.

Side effects

Very common (≥10%) – drowsiness, weight gain; 34% – increase in plasma prolactin concentration, which was mild and transient (the average value of maximum prolactin concentrations did not reach the upper limit of normal (ULN) and did not statistically significantly differ from placebo). Clinical manifestations of olanzapine-related hyperprolactinemia (i. e., gynecomastia, galactorrhea, and breast enlargement) were rare. In most patients, normalization of prolactin levels was observed without discontinuation of olanzapine.

Frequently (≥1%, but less than 10%) — dizziness, asthenia, akathisia, increased appetite, peripheral edema, orthostatic hypotension, dry mouth and constipation. In clinical studies (n=107), in 1.9% of cases, triglyceride levels were found to be 2 times or more higher than the ULN (no cases exceeding the ULN by more than 3 times were observed).

Rare: transient, asymptomatic increase in hepatic transaminases (AST and ALT) in the blood serum.

In isolated cases: an increase in blood glucose levels up to ≥200 mg / dl (suspected diabetes mellitus), as well as from ≥160 mg / dl, but up to less than 200 mg/dl (suspected hyperglycemia) in patients with a baseline glucose level of ≤140 mg/dl.

In some cases: asymptomatic eosinophilia.

Undesirable effects in special groups of patients

In patients with dementia-related psychosis, gait and fall disorders were very common (≥10%).

In elderly patients with dementia-related psychosis, often (≥1%, but less than 10%) – urinary incontinence and pneumonia.

In patients with drug-induced psychosis (dopamine agonist) in Parkinson’s disease, very often (≥10%) and with a higher frequency than in the placebo group, increased symptoms of Parkinsonism, hallucinations were noted.

In patients with bipolar mania receiving olanzapine in combination with lithium or valproate, weight gain, dry mouth, increased appetite, tremor were very common (≥10%); often (≥1%, but less than 10%) — speech disorder.

The main side effects and their frequency reported during clinical trials and/or in the post-marketing period are described below.

From the body as a whole: ≥10% — weight gain 1; ≥1%, but <10% — asthenia 2; ≥0.1%, but <1% — hypersensitivity to light 2; less than 0.01% — allergic reaction 3,4; reaction to withdrawal 3,5.

From the cardiovascular system: ≥0.1%, but less than 1% – bradycardia 2; ≥1%, but less than 10% – orthostatic hypotension 1; less than 0.01% – venous thromboembolism 3.

From the digestive system: ≥1%, but less than 10% – constipation 2; dry mouth 2; increased appetite 2; less than 0.01% – hepatitis 3; pancreatitis 3.

Metabolic disorders: less than 0.01% – diabetic coma 3; diabetic ketoacidosis 3,4; hyperglycemia 3; hypertriglyceridemia 3,7; ≥1%, but less than 10% – peripheral edema 1.

Musculoskeletal disorders: less than 0.01% — rhabdomyolysis 3.

From the central nervous system: ≥1%, but less than 10% – akathisia 2; dizziness 2; ≥0.01%, but less than 0.1% – convulsive seizures 3; ≥10% – drowsiness 2.

Dermatological reactions: ≥0.01%, but less than 0.1% – rash 3.

From the side of the reproductive system: less than 0.01% – priapism 3.

On the part of laboratory parameters: ≥1%, but less than 10% – an increase in ALT 1 and AST 1 levels; isolated cases of increased blood glucose levels from ≥160 mg / dl to less than 200 mg / dl (suspected hyperglycemia)1; isolated cases of elevated blood glucose levels to ≥200 mg / dl (suspected diabetes mellitus)1; isolated cases of an increase in the level of triglycerides by ≥2 times ULN 1; ≥10% – an increase in the level of prolactin 1.

From the hematopoietic system: in ≥1% but less than 10% of cases, eosinophilia 1; in ≥0,01% but less than 0.1% of cases — leukopenia 3; less than 0.01% 3 thrombocytopenia.

1 performance evaluation of a database of clinical trials

2 side effects that are registered in the database of clinical trials

3 side effects was spontaneously during post-marketing studies

4 example: anaphylactic reaction, angioedema, pruritus or urticaria

5 i. e. sweating, nausea or vomiting

6 in the classification COSTART referred to as diabetic acidosis,

7 classification COSTART referred to as hyperlipidemia.

Interaction

Olanzapine metabolism can be altered by inhibitors or inducers of cytochrome P450 isoenzymes that exhibit specific activity against CYP1A2. Olanzapine clearance is increased in smokers and in patients taking carbamazepine (due to increased CYP1A2 activity). Known potential CYP1A2 inhibitors may reduce the clearance of olanzapine. Olanzapine is not a potential inhibitor of CYP1A2 activity, so the pharmacokinetics of drugs that are mainly metabolized with the participation of CYP1A2 (such as theophylline) do not change when taking olanzapine.

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), warfarin (CYP2C19), theophylline (CYP1A2) or diazepam (CYP3A4, CYP2C19). There were also no signs of drug interaction when olanzapine was used in combination with lithium or biperiden.

No changes in the pharmacokinetics of ethanol were observed at steady-state concentrations of olanzapine. However, taking ethanol together with olanzapine may be accompanied by an increase in the pharmacological effects of olanzapine, for example, sedation.

Single doses of antacids containing aluminum or magnesium or cimetidine did not interfere with the oral bioavailability of olanzapine. Co-use of activated charcoal reduced the oral bioavailability of olanzapine by up to 50-60%. Fluoxetine (60 mg once or 60 mg daily for 8 days) causes an increase in olanzapine cmax by an average of 16% and a decrease in olanzapine clearance by an average of 16%. The degree of influence of this factor is significantly lower than the severity of individual differences in these indicators, so it is usually not recommended to change the dose of olanzapine when it is prescribed in combination with fluoxetine.

Fluvoxamine, a CYP1A2 inhibitor, reduces the clearance of olanzapine. The result is an average increase in olanzapine cmax with fluvoxamine use of 54% in non-smoking women and 77% in smoking men, and an average increase in olanzapine AUC of 52 and 108%, respectively. Small doses of olanzapine should be given to patients receiving co-treatment with fluvoxamine.

In vitro studies using human liver microsomes have shown that olanzapine slightly inhibits the formation of valproate glucuronide (the main route of valproate metabolism). Valproate also has little effect on olanzapine metabolism in vitro. Therefore, a clinically significant pharmacokinetic interaction between olanzapine and valproate is unlikely.

In vitro, olanzapine exhibits dopamine antagonism and, like other antipsychotics (neuroleptics), can theoretically inhibit the action of levodopa and dopamine agonists.

The absorption of olanzapine is independent of food intake.

According to in vitro studies using human liver microsomes, olanzapine also showed extremely low potential in suppressing the activity of the following cytochrome P 450 isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

How to take, course of use and dosage

Inside, regardless of food intake. Due to its fragility, the tablet should be taken immediately after removal from the blister. Dispersible olanzapine tablets dissolve quickly in saliva and are easily swallowed. In addition, just before taking the tablet, you can dissolve it in a glass of water or other liquid (orange juice, apple juice, milk or coffee).

The daily dose should be selected individually, depending on the patient’s clinical condition.

For the treatment of schizophrenia and similar psychotic disorders, the recommended starting dose of olanzapine is 10 mg once a day. Therapeutic doses of olanzapine range from 5 to 20 mg / day. An increase in the dose above the standard daily dose of 10 mg is recommended only after an 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 time/day as monotherapy or 10 mg 1 time/day in combination with lithium or valproate. Therapeutic doses of olanzapine range from 5 to 20 mg per day. An increase in the dose above the standard daily dose of 15 mg is recommended only after an appropriate clinical examination of the patient. The dose should be increased gradually, at intervals of at least 24 hours.

Maintenance therapy for bipolar disorder: patients who have taken olanzapine for the treatment of acute mania should continue maintenance therapy at the same dose. In patients in remission, the recommended starting dose of olanzapine is 10 mg once daily. In the future, the daily dose should be selected individually, depending on the patient’s clinical condition, in the range from 5 to 20 mg/day.

Olanzapine in combination with fluoxetine should be administered 1 time / day, regardless of food intake. As a rule, the initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, it is allowed to change the doses of both olanzapine and fluoxetine.

For elderly patients or patients with other clinical risk factors, including severe renal insufficiency or moderate hepatic insufficiency, it is recommended to reduce the initial dose of olanzapine to 5 mg / day.

For patients with a combination of factors that may slow down olanzapine metabolism (female patients, senile people, non-smokers), a reduction in the initial dose of olanzapine may also be recommended.

Data from olanzapine therapy studies in children and adolescents under 18 years of age are limited.

Overdose

Symptoms: very common (≥10%) – tachycardia, agitation / aggressiveness, articulation disorders, various extrapyramidal disorders and consciousness disorders of varying severity (from sedation to coma). Other clinically significant symptoms include seizures, neuroleptic malignant syndrome, respiratory depression, aspiration, hypertension or hypotension, and cardiac arrhythmias ( The minimum dose for acute overdose with a fatal outcome was 450 mg, the maximum dose for overdose with a favorable outcome (survival) — 1.5 g.

Treatment: standard procedures for overdose are indicated (gastric lavage, use of activated charcoal). There is no specific antidote for olanzapine. Induction of vomiting is not recommended. Co-use of activated charcoal showed a 50-60% reduction in oral bioavailability of olanzapine.

It is indicated to conduct symptomatic therapy in accordance with the clinical condition and monitor the functions of vital organs, including the treatment of arterial hypotension, circulatory disorders and maintenance of respiratory function. Do not use epinephrine, dopamine, or other sympathomimetics that are beta-adrenergic agonists, as stimulation of these receptors may worsen hypotension.

Special instructions

Neuroleptic malignant syndrome (NMS) – potentially fatal symptom complex — can develop during treatment with any neuroleptics, including olanzapine. However, to date, there are no data confirming a reliable association of olanzapine intake with the development of this condition.Clinical manifestations of NMS include a significant increase in body temperature, muscle rigidity, changes in mental status, and vegetative disorders (unstable pulse or blood pressure, tachycardia, cardiac arrhythmias, and increased sweating). Additional signs may include increased CPK levels, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of neuroleptic malignant syndrome or a significant increase in body temperature without other symptoms of NMS require the withdrawal of all neuroleptics, including olanzapine.

In comparative studies, olanzapine treatment was significantly less frequently associated with the development of dyskinesia requiring drug correction than the use of typical and other atypical antipsychotics. However, the risk of tardive dyskinesia should be considered during long-term neuroleptic therapy. If signs of tardive dyskinesia develop, a dose adjustment of the neuroleptic agent is recommended. It should be borne in mind that when switching to olanzapine, symptoms of tardive dyskinesia may develop due to simultaneous discontinuation of previous therapy.

The efficacy of olanzapine in elderly patients with dementia-related psychosis has not been established. In this category of patients in placebo-controlled clinical trials, the death rate in the olanzapine group was higher than in the placebo group (3.5% vs. 1.5%, respectively). Risk factors that may predispose this group of patients to higher mortality with olanzapine treatment include age >80 years, sedation, concomitant use with benzodiazepines, or the presence of lung pathology (for example, pneumonia with or without aspiration).

There is insufficient data to establish differences in the incidence of cerebrovascular disorders and/or mortality (compared to placebo), and in the risk factors in this group of patients when taking olanzapine orally and with intravenous injections.

In some cases, olanzapine use, usually in the early stages of therapy, was accompanied by a transient, asymptomatic increase in the levels of hepatic transaminases (AST and ALT) in the blood serum. Rare cases of hepatitis have been reported. Special precautions should be taken when increasing serum AST and/or ALT levels in patients with hepatic insufficiency, with a limited functional reserve of the liver, or in patients receiving treatment with potentially hepatotoxic drugs. If AST and/or ALT levels increase during treatment with olanzapine, careful monitoring of the patient is required and, if necessary, dose reduction.

There is a higher prevalence of diabetes mellitus in patients with schizophrenia. As with some other antipsychotic medications, very rare cases of hyperglycemia, diabetes mellitus, exacerbation of pre-existing diabetes, ketoacidosis, and diabetic coma have been reported. No causal relationship has been established between antipsychotic medications and these conditions. Careful 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 who are exposed to factors that reduce the threshold of convulsive readiness. Convulsive seizures were rare in these patients treated with olanzapine.

Cerebrovascular adverse reactions (e. g. stroke, transient ischemic attack), including fatal outcomes, have been reported in olanzapine studies in elderly patients with dementia-related psychosis. In placebo-controlled studies, a higher incidence of cerebrovascular adverse events was observed in patients in the olanzapine group compared to the placebo group (1.3% vs. 0.4%, respectively).

All patients with cerebrovascular disorders had previous risk factors for developing cerebrovascular adverse reactions (for example, a previously reported case of cerebrovascular adverse reaction or transient ischemic attack, arterial hypertension, smoking), as well as concomitant diseases and/or taking medications that were associated with cerebrovascular adverse reactions over time. Olanzapine is not indicated for the treatment of patients with dementia-related psychosis.

As with other antipsychotics, caution should be exercised when using olanzapine in the following patient groups::

– with a reduced number of leukocytes and/or neutrophils in the peripheral blood due to various causes;

– with signs of suppression/toxic impairment of bone marrow function under the influence of drugs in the anamnesis;

– with suppression of bone marrow function due to concomitant disease, radiotherapy or chemotherapy in the anamnesis;

– 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 has rarely been associated with anticholinergic side effects in clinical trials. However, clinical experience with olanzapine in patients with concomitant diseases is limited, so caution is recommended when prescribing olanzapine to patients with clinically significant prostatic hypertrophy, paralytic intestinal obstruction, angle-closure glaucoma and similar conditions.

Taking into account the main effect of olanzapine on the central nervous system, caution should be exercised when using olanzapine in combination with other centrally acting drugs, as well as alcohol.

Influence on the ability to drive motor vehicles and manage mechanisms

Patients taking olanzapine should exercise caution when driving mechanical vehicles, including motor vehicles, as olanzapine may cause drowsiness.

Form of production

Dispersible tablets

Storage conditions

Store in a dry place, protected from light, at a temperature of 15-30 °C

Shelf life

2 years

Active ingredient

Olanzapine

Conditions of release from pharmacies

By prescription

Dosage form

Tablets