Zipreksa

Zipreksa – the antipsychotic means applied at treatment of schizophrenia and bipolar affective disorders.

Form of release and structure

• Tablets, film coated: round, white color, on one of the parties the identification text, depending on the content of active agent is printed: 2,5 mg - "LILLY 4112", 5 mg - "LILLY 4115", 7,5 mg - "LILLY 4116", 10 mg - "LILLY 4117" (on 7 pieces in blisters, on 1, 2, 4, 8 blisters in a cardboard pack);
• Lyophilisate for preparation of solution for intramuscular introduction (in oil): the condensed mass or powder of yellow color (on 10 mg in bottles, on 1 bottle in a cardboard pack).

Structure of 1 tablet:

• Active ingredient: olanzapine – 2,5 mg, 5 mg, 7,5 mg or 10 mg;
• Auxiliary components: hydroxypropyl cellulose (hypro rod), кросповидон, monohydrate of lactose, magnesium stearate, microcrystallic cellulose;
• Cover: methylhydroxypropyl cellulose (gipromelloza), mix of white dye, karnaubsky wax (for polish), blue food ink (for drawing an identification text).

Structure of 1 bottle of lyophilisate:

• Active ingredient: olanzapine – 10 mg;
• Auxiliary components: tartaric acid, monohydrate of lactose.

Indications to use

Tablets, film coated

• Bipolar affective disorder: Zipreksa in monotherapy or in a combination with Valproatum or lithium is applied to treatment of the mixed or acute maniacal episodes at bipolar affective disorder with psychotic manifestations and bystry change of phases, or without them; it is also shown to patients with bipolar disorder at whom olanzapine was effective for treatment of a maniacal phase for prevention of a recurrence;
• Schizophrenia: therapy of aggravations; the supporting and prolonged antirecurrent treatment, both schizophrenia, and other psychotic frustration with the expressed symptomatology (negative (including emotional flatness, depletion of the speech, decrease in social activity) and/or productive (including hallucinations, nonsense, automatism)) and the accompanying affective frustration.

Olanzapine in a combination with fluoxetine is shown for treatment of the depressions connected with bipolar disorder.

Lyophilisate for preparation of solution for introduction in oil
Injection administration of olanzapine is recommended for bystry stopping of psychomotor excitement (agitation) at patients with bipolar affective disorder and schizophrenia.

Contraindications

The diagnosed hypersensitivity to any of Zipreksa's components.

Route of administration and dosage

Tablets, film coated
Pill is taken inside, irrespective of meal.

The daily dose is selected individually and depends on a clinical condition of the patient. It is necessary to increase a dose over standard gradually (maintaining an interval at 24 o'clock at least), and only after carrying out the corresponding clinical inspection.

The recommended dosing mode:

• Schizophrenia and similar psychotic frustration: an initial dose of drug (it – standard) – 10 mg of 1 times a day; therapeutic doses – from 5 to 20 mg a day;
• Acute mania at bipolar disorder: an initial dose of drug (it – standard) – 15 mg of 1 times a day; therapeutic doses – from 5 to 20 mg a day.

With heavy degree of a renal failure the initial dose of olanzapine – 5 mg a day is recommended to elderly people, patients with a liver failure of moderate severity.

Also decrease in an initial dose of Zipreksa is shown at a combination of the following factors: female patients, non-smoking, patients of senile age – in connection with possible delay of metabolism of active ingredient.

Lyophilisate for preparation of solution for introduction in oil
The solution prepared from lyophilisate is entered intramusculary. It is not necessary to administer the drug subcutaneously or intravenously.

Use of olanzapine in the form of an injection is necessary for bystry stopping of a condition of agitation at patients with bipolar affective disorder and schizophrenia.

The recommended initial dose – 10 mg (a single injection in oil). Further, taking into account a clinical condition of the patient not earlier than in 2 hours, it is allowed to make the second injection – to 10 mg. At least 4 hours later after the second injection it is allowed to make a third – to 10 mg. Safety of a dose more than 30 mg a day was not estimated in clinical trials.

In the presence of indications for therapy continuation intramuscular injections of Zipreksa need to be cancelled and passed in case of clinical expediency to oral administration of olanzapine in a dose from 5 to 20 mg.

The single intramuscular injection of drug in a dose of 2,5-5 mg is recommended to elderly people or patients with other clinical risk factors.

Lyophilisate is allowed to be dissolved exclusively sterile water for injections.

It is not necessary to mix olanzapine in one syringe with lorazepam, diazepam and a haloperidol as are possible lengthening of time of dissolution, precipitation and/or weakening of effect of olanzapine.

For preparation of solution for contents of a bottle it is necessary to add 2,1 ml of sterile water for injections:

1. Solution has to be yellow color, transparent;
2. It is necessary to use solution within 1 hour after preparation;
3. The unused rest should be merged;
4. Before introduction it is necessary to check solution on presence of mechanical impurities (if the container and solution allow to make it).

The olanzapine dose in mg corresponding to the volume of the used solution for an injection in oil:

• All contents of a bottle – 10 mg;
• 1,5 ml – 7,5 mg;
• 1 ml – 5 mg;
• 0,5 ml – 2,5 mg.

The overdose of olanzapine is very often shown by tachycardia, excitement/aggression, a dysarthria, various extrapyramidal disorders and disturbances of awareness of various degrees of severity (from sedation to a coma). Can be other clinically significant effects: malignant antipsychotic syndrome, delirium, spasms, respiratory depression, aspiration, decrease or increase in the arterial pressure (AP), arrhythmia, and also cardiac standstill and breath. The minimum registered olanzapine dose in case of acute overdose with a lethal outcome – 450 mg, maximum at overdose with survival (a favorable outcome) – 1500 mg.

The specific antidote at drug does not exist. It is not necessary to provoke vomiting. It is allowed to carry out procedures, standard at overdose: reception of absorbent carbon, gastric lavage.

The symptomatic treatment corresponding to a clinical condition of the patient and control of functions of vitals is recommended (including maintenance of respiratory function, therapy of a vascular collapse and lowering of arterial pressure). It is impossible to apply a dopamine, Epinephrinum and other sympathomimetics, agonists of β-adrenoceptors, as stimulation of these receptors can strengthen a lowering of arterial pressure.

Side effects

The side effects connected using olanzapine according to clinical trials:

• Very often (> 1/10): drowsiness and increase in body weight, poorly expressed tranzitorny increase in concentration of prolactin in plasma (to 34% of cases) *;
• Often (<1/10-≥ 1/100): dizziness, an adynamy, an akathisia, increase in appetite, peripheral hypostases, orthostatic hypotension, locks, dryness in a mouth;
• Seldom (<1/1000-> 1/10 000): tranzitorny symptomless increase in hepatic indicators of ALT (alaninaminotranspherase) and nuclear heating plant (aspartate aminotransferase) in blood serum;
• In isolated cases (<1/10 000): increase in concentration of glucose in a blood plasma of ≥200 mg/dl (suspicion on a diabetes mellitus), increase in concentration of glucose in a blood plasma from ≥160 mg/dl to <200 mg/dl (suspicion on a hyperglycemia) at basic level of glucose of ≤140 mg/dl.

Note:

* – The maximum values of concentration of prolactin on average do not reach the upper bound of norm and statistically authentically do not differ from placebo; clinical symptoms and signs of a giperprolaktinemiya, such as gynecomastia, increase in mammary glands and a galactorrhoea, are noted seldom; in most cases normalization of level of prolactin happens without Zipreksa's cancellation.

In clinical trials with the assistance of 1185 patients (N=1185) increase in level of triglycerides on average on 20 mg/dl from basic was noted.

By results of placebo - controlled researches (N=2528) cholesterol level on average increased by 0,4 mg/dl from basic.

Isolated cases of a symptomless eosinophilia were celebrated.

Aggregated data about the main side effects and frequency of their manifestation (by results of clinical tests and/or to data of the post-registration period at treatment by various dosage forms of Zipreksa):

• Organism in general: very often – increase in weight ^tela1; often – ^asteniya2; infrequently – raised ^{svetochuvstvitelnost2};
• Cardiovascular system: often – orthostatic ^gipotenziya1; infrequently – ^{bradikardiya2};
• Alimentary system: often – ^zapory2, dryness in ^rtu2, increase ^appetita2; very seldom – ^gepatit3;
• Metabolic disturbances: often – peripheral ^oteki2; very seldom – diabetic ^koma3, diabetic ^{ketoatsidoz3,5}, ^{giperglikemiya3}, ^{gipertriglitseridemiya3,6};
• Nervous system: very often – disturbance ^pokhodki4, ^sonlivost2; often – ^akatiziya2, ^{golovokruzheniye2}; seldom – convulsive ^pripadki3;
• Skin and appendages: seldom – ^syp3;
• Urinogenital system: very seldom – ^priapizm3;
• Clinical biochemistry: very often – increase ^prolaktina1; often – increase ^{in ALT1}, increase ^{in ACT1}, isolated cases of increase in concentration of glucose of ≥160 mg / дл-<200 mg/dl (suspicion on a hyperglycemia) ¹, isolated cases of increase in concentration of glucose of ≥200 mg/dl (suspicion of diabetes) ¹;
• Hematology: often – ^{eozinofiliya1}; seldom – ^leykopeniya3; very seldom – ^{trombotsitopeniya3}.

Notes

1 – Assessment of indicators from the database of clinical trials.

2 – The side effects registered in the database of clinical trials.

3 – The side effects registered spontaneously during the post-market researches.

4 – The side effects found during clinical trials in patients with dementia of altsgeymerovsky type.

5 – Diabetic acidosis on classification in the dictionary of symbols of coding for adverse reactions (COSTART).

6 – A lipidemia on COSTART classification.

Gradation of frequency depending on quantity of noted episodes: very often (> 1/10); often (<1/10,> 1/100); infrequently (<1/100,> 1/1000); seldom (<1/1000,> 1/10 000); very seldom (<1/10 000).

Special instructions

Therapy by any neuroleptics, including olanzapine, can become the reason of development of the malignant antipsychotic syndrome (MAS) – potentially fatal symptom complex. Clinical manifestations of ZNS: substantial increase of body temperature, change of the mental status, muscle tension, vegetative disturbances (unstable the ABP, pulse, cardiac arrhythmias, tachycardia, the increased sweating). Can be additional confirmation of ZNS: increase in level of a kreatinfosfokinaza, myoglobinuria (рабдомиолиз), acute renal failure. Such clinical manifestations of ZNS, or essential temperature increase without other symptoms, demand cancellation of all neuroleptics, including olanzapine.

During the comparative researches for more than 6 weeks therapy by olanzapine was followed by development of the dyskinesia demanding medicamentous correction than treatment a haloperidol authentically less often. At the same time it is necessary to consider risk of late dyskinesia in case of long therapy by neuroleptics. In case of development of symptoms of late dyskinesia the dose decline or cancellation of olanzapine is recommended. After drug withdrawal can accrue or demonstrate symptoms of late dyskinesia.

In some cases Zipreksa's use, as a rule, at the beginning of therapy, was followed by symptomless, tranzitorny increase in levels of hepatic transaminases (ALT and nuclear heating plant). Extra care at such increase should be observed the patient with a liver failure, with a limited functional reserve of a liver, or in case of therapy by potentially hepatotoxic drugs. Increase in the ALT and/or nuclear Heating Plant levels during treatment demands careful observation of the patient and, if necessary, dose declines.

With care drug in the presence of data in the anamnesis on epileptic seizures, or sick, subject to influence of the factors reducing a threshold of convulsive readiness is used. Convulsive attacks at such patients during therapy by olanzapine were observed seldom.

It is also necessary to show care at: the lowered quantity of neutrophils and/or leukocytes; signs of toxic disturbance / oppression of function of marrow under the influence of medicines in the anamnesis; the oppression of function of marrow caused by associated diseases; radiotheraphy or chemotherapy in the anamnesis; hypereosinophilia; myeloproliferative diseases.

By results of clinical trials a recurrence of a klozapinzavisimy neutropenia or agranulocytosis at use of olanzapine for patients with existence of data on these frustration in the anamnesis is not celebrated.

During conduct of clinical trials Zipreksa's use by side effects of anticholinergic character was followed seldom. However, in the presence of associated diseases, clinical experience of use of olanzapine is limited therefore it is necessary to show care at clinically significant prostatauxe, paralytic impassability of intestines, closed-angle glaucoma and similar states.

In vitro olanzapine acts as the antagonist to a dopamine and, as well as other neuroleptics, is theoretically capable to suppress action of agonists of a dopamine and levodopa.

Considering the main action on the central nervous system (CNS), it is necessary to be careful, using drug in combination with other medicines of the central action and etanolsoderzhashchy substances.

Effect of olanzapine for injections in oil in an age group of patients up to 18 years was not studied.

Olanzapine is capable to cause drowsiness therefore in the course of therapy by Zipreksa it is recommended to observe the increased care, managing mechanical means, including the car.

Medicinal interaction

At simultaneous use of Zipreksa with some medicines can arise following effects:

• Absorbent carbon: at oral administration of olanzapine reduces its bioavailability to 50-60%;
• Antacids: aluminum - or magniysoderzhashchy, Cimetidinum – use in a single dose does not break Zipreksa's bioavailability in the form of tablets;
• Valproic acid: clinically significant pharmacokinetic interaction with olanzapine is improbable;
• Substances/drugs, metaboliziruyemy with participation of CYP1A2, such as theophylline: their pharmacokinetics generally does not change as olanzapine is not potential inhibitor of activity CYP1A2;
• Known potential CYP1A2 inhibitors: can reduce clearance of olanzapine;
• Isoenzymes _{of P450 cytochrome} (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A): olanzapine is potentially not capable to suppress their activity (according to the researches in vitro with use of microsomes of a liver of the person);
• Imipraminum or its metabolite desipramine (CYP2D6, CYP3A, CYP1A2), warfarin (CYP2C19), theophylline (CYP1A2) or diazepam (CYP3A4, CYP2C19): metabolism of the specified substances is not oppressed (according to clinical trials, at their introduction with a single dose of olanzapine);
• The inhibitors or inductors of isoenzymes _{of P450 cytochrome} showing specific activity concerning CYP1A2: can change olanzapine metabolism;
• Carbamazepine and smoking of the patient: increase clearance of olanzapine (increasing activity of CYP1A2);
• Lithium, Biperidinum: signs of medicinal interaction are not revealed;
• Lorazepam: at administration of lorazepam in oil in a dose of 2 mg 1 hour later after an injection of olanzapine in oil in a dose of 5 mg of considerable influence on pharmacokinetics of olanzapine and the general or not conjugated lorazepam it was not noted, but such combination of injections increases the drowsiness noted at use of each of drugs separately;
• The drugs capable to lower the ABP the mechanisms other than adrenergic antagonism α-1: decrease in the ABP and/or bradycardia at intramuscular administration of olanzapine, thanks to its activity as adrenergic antagonist α-1 is possible;
• Fluvoksamin (CYP1A2 inhibitor): reduces clearance of olanzapine, increasing average value its _Cmax: at non-smoking women for 54%, at the smoking men for 77%; average AUC value: for 52% and 108% respectively. Olanzapine in small doses should be accepted the patient receiving treatment fluvoksaminy;
• Fluoxetine (at a single dose of 60 mg or 60 mg daily within 8 days): causes increase in the maximum concentration of olanzapine on average by 16% and also on average for 16% – decrease in its clearance. It is not recommended to change an olanzapine dose at its appointment in a combination with fluoxetine;
• Ethanol: changes of pharmacokinetics of ethanol against the background of steady concentration of olanzapine were not noted, but at such combination strengthening of pharmacological effect of olanzapine, for example, sedative is possible.

Terms and storage conditions

To store in the protected from light, dry place unavailable to children at temperature of 15-30 °C. Not to freeze lyophilisate.

Period of validity – 3 years.

The prepared solution should be used within an hour.