Ziprexa Adera - instructions for use, doses, side effects, contraindications

carmellose sodium 7.5 mg, mannitol 50.0 mg, polysorbate 80 1.0 mg, 10% hydrochloric acid solution and / or 10% sodium hydroxide solution q.s. to establish a pH of 5.0-8.0, water for injection q.s. up to 1 ml.

Description:

The powder is yellow.

When mixed with a solvent, a yellow suspension forms.

Pharmacotherapeutic group:antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.H.03 Olanzapine

Pharmacodynamics:

It is believed that the effectiveness of the drug in schizophrenia is mediated by a combination of antagonism of dopamine and serotonin type 2 (5HT₂).

Olanzapine is an antipsychotic agent (neuroleptic) with a broad pharmacological spectrum of influence on a number of receptor systems.

In preclinical studies, the affinity of olanzapine for serotonin 5-HT_{2A / C}, 5HT₃, 5NT₆; dopamine D₁, D₂, D₃, D₄, D₅; muscarinic M₁-₅; adrenergic α₁- and histamine H_1-receptors.In animal experiments, the presence of antagonism of olanzapine with respect to 5HT, dopamine and cholinergic receptors was detected. In conditions in vitro and in vivo olanzapine has a more pronounced affinity and activity for serotonin 5HT₂ receptors, in comparison with 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) neural pathways involved in the regulation of motor functions. Olanzapine reduces the conditioned protective reflex (a test characterizing antipsychotic activity) at doses lower than the doses that cause catalepsy (a disorder reflecting a secondary effect on motor function). Unlike other neuroleptics, olanzapine increases the anti-anxiety effect during the "anxiolytic" test.

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

Pharmacokinetics:

Suction and distribution. The release of olanzapine from olanzapine pamoate to prepare a suspension for injection is slow, and the delayed absorption process maintains the systemic concentration of olanzapine in the plasma during the time between injections. Typical systemic concentrations - peak in the first week after the injection and the lowest value - just before the next injection. Throughout the interval between injections (2-4 weeks), generally stable concentrations of olanzapine in the plasma are maintained. Fluctuations in the concentration of olanzapine in plasma between peak and minimum values are comparable with similar fluctuations after oral administration once a day.

Binding to plasma proteins. At a plasma concentration of 7 to 1000 ng / ml, about 93% of olanzapine binds to plasma proteins. Olanzapine mainly binds to albumin and α₁acid glycoprotein. In a study involving Europeans, Japanese and Chinese, there is no difference in the pharmacokinetics of olanzapine associated with race. The activity of the cytochrome P450 CYP2D6 isoenzyme does not affect the level of olanzapine metabolism.

Proportionality of the dose and compliance with the dose after ingestion. Olanzapine pamoate for the preparation of a suspension for injection provides doses of olanzapine 150, 210, 300 and 405 mg. Injection of a higher dose leads to a proportional dose of increases in systemic exposure. A dose-proportional exposure for olanzapine pamoate for the preparation of a suspension for injection corresponds to that for a dose of olanzapine ingested. The dose of olanzapine pamoate 300 mg (once every two weeks) provides a dose of 20 mg per day, and a dose of olanzapine pamoate 150 mg once every two weeks provides a dose of 10 mg per day. It has been shown that these doses of olanzapine pamoate to prepare an injection suspension maintain equilibrium concentrations of olanzapine for a long period of treatment that correspond to concentrations after ingestion of 10 or 20 mg of olanzapine once a day.

The pharmacokinetic effect of the transition to olanzapine pamoate for the preparation of a suspension for injection with olanzapine for oral administration. Transition from olanzapine for oral administration to olanzapine pamoate leads to a change in pharmacokinetics with controlled-time-withdrawal at controlled-rate-absorption.Transition to olanzapine pamoate may require treatment for a period of about 3 months to restore equilibrium conditions. Initial treatment of olanzapine with pamoate is recommended in a dose that is comparable to the dose of mg / day for oral administration. The plasma concentrations of olanzapine during the first interval between injections may be less than the concentrations maintained by the appropriate oral dose. Despite the fact that according to clinical studies these concentrations were lower, they remained within the therapeutically effective interval, and additional oral olanzapine intake was usually not required.

Metabolism. Olanzapine metabolized in the liver as a result of conjugation and oxidation. The main circulating metabolite is 10-N- Glucuronide, which does not theoretically penetrate the blood-brain barrier. Isozymes CYP1A2 and CYP2D6 cytochrome P450 are involved in education N-desmethyl and 2-hydroxymethyl metabolites of olanzapine. Both metabolites in animal studies had significantly less pharmacological activity in vivo, than olanzapine. The main pharmacological activity of the drug is due to the starting substance - olanzapine.

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

Characteristics patients	Half-life (hours)	Clearance in plasma (l / h)
Non-smokers	38,6	18,6
Smokers	30,4	27,7

Women	36,7	18,9
Men's	32,3	27,3

Elderly (65 years and over)	51,8	17,5
Younger than 65 years	33,8	18,2

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

Excretion. No significant differences between the mean half-life and clearance of olanzapine in plasma in patients with severe renal impairment as compared to individuals with normal renal function is not installed. About 57% of radiolabelled olanzapine is excreted in the urine, mainly in the form of metabolites.

In smokers with minor violations of liver function, the clearance of olanzapine is lower than that of non-smokers without impaired liver function.

Special populations. In general, the decision to use olanzapine pamoate in special populations should be well thought out.For patients who have not previously taken olanzapine, before prescribing olanzapine pamoate, individual tolerance should be established by administration of oral olanzapine. For impaired patients, patients with a predisposition to hypotensive reactions, for patients with a combination of factors that may lead to a slowdown in the metabolism of olanzapine (eg, non-smokers aged> 65 years) and for patients who may be sensitive to olanzapine in terms of pharmacodynamics, the recommended initial dose of olanzapine pamoate is 150 mg / 4 weeks. Increase in the dose in such patients should be done with caution (see section "Method of administration and dose"). All precautions described below must be observed.

Impaired renal function. As olanzapine is extensively metabolized before excretion and only 7% of the drug is excreted unchanged, renal dysfunction does not itself have a significant effect on the pharmacokinetics of olanzapine. The pharmacokinetic characteristics of olanzapine taken orally were similar in patients with severe renal dysfunction and in patients with normalfunction, which indicates that there is no need for dose adjustment in accordance with the degree of impaired renal function. Besides, olanzapine not output during dialysis. The effect of renal dysfunction on the excretion of metabolites has not been studied.

Impaired liver function. Although a decrease in olanzapine clearance can be expected if liver function is impaired, a study of the effect of liver function impairment in patients (n = 6) with clinically significant (Child-Pugh class A and B classes) cirrhosis showed little effect on the pharmacokinetics of olanzapine oral administration.

Elderly patients. In a study of 24 healthy volunteers, on average, the half-life with oral olanzapine was approximately 1.5 times higher in the elderly population (> 65), compared with the younger participants in the study (<65 years). When used in elderly patients, caution should be exercised, especially if other factors are present that may also affect the drug metabolism and / or pharmacodynamic sensitivity (see the "Application and dosage" section).

Floor. Both for oral olanzapine and for olanzapine pamoate, women had a higher average plasma concentration of olanzapine than men. However, no apparent differences between women and men were observed with regard to efficacy or adverse effects. No dosage adjustment is required based on the patient's sex.

Smoking. Both for oral olanzapine and olanzapine pamoate, studies have shown that olanzapine clearance is higher in smokers compared to non-smokers, although dose adjustment is usually not required.

Race. Oral administration of olanzapine in vivo showed that the pharmacological properties of the drug are similar in Japanese, Chinese and Europeans, especially when standardizing for body weight. Thus, based on race, dose adjustment is not required.

Combined Effects. The combined effects of age, smoking and sex factors can lead to significant differences in pharmacokinetics in different populations. For example, the clearance in young men who smoke can be 3 times higher than in older nonsmoking women.Patients with a combination of factors that may lead to a slowdown in the metabolism of olanzapine may require dose adjustment.

Indications:

Schizophrenia in adults. Olanzapine pamoate is an injectable form of olanzapine long-acting for treatment of acute and maintenance treatment of schizophrenia in adults.

Contraindications:

Hypersensitivity to any of the components of the drug.

Age to 18 years.

Carefully:

Hepatic failure, hyperplasia, prostate, breast, angle-closure glaucoma, epilepsy, myelosuppression (including leukopenia, neutropenia), myeloproliferative disorders, hypereosinophilic syndrome, a history of seizures, paralytic ileus, pregnancy. For more information, see "Special instructions".

Pregnancy and lactation:

Because of insufficient experience with olanzapine during pregnancy, the drug should be administered during pregnancy only if the potential benefit to the patient is significantly greater than the potential risk to the fetus. Patients should be warned that in the event or planning pregnancy during treatment with olanzapine, they should report this to your doctor.

Adequate and well-controlled studies of the effects of olanzapine on pregnant women have not been conducted. In clinical trials of olanzapine pamoate, 4 pregnancies were recorded, including 1 pregnancy, terminating in normal births, and 3 therapeutic abortions. Since research on reproductive function in animals can not always predict the reaction of the human reproductive system, the drug can be used during pregnancy only if the potential benefit exceeds the possible risk to the fetus.

The study found that olanzapine penetrates into breast milk. The average dose received by the child (mg / kg) when the mother's equilibrium concentration reached equilibrium was 1.8% of the mother's olanzapine dose (mg / kg). It is not recommended to breast-feed during therapy with olanzapine.

Dosing and Administration:

Only for intramuscular injection. Enter deep into the gluteus muscle.

Do not administer intravenously or subcutaneously.

The efficacy of olanzapine pamoate was demonstrated at a dose range of 150 mg to 300 mg administered every 2 weeks, and a dose of 405 mg administered every 4 weeks.

Before the treatment of olanzapine with pamoat in patients who had never taken oral olanzapine, it is recommended to test the tolerability of a sample with oral olanzapine.

Based on the recommended therapeutic doses for oral olanzapine from 10 mg to 20 mg per day, the following table shows the recommended dose matching between oral olanzapine and olanzapine pamoate. Recommended compliance of the doses between oral olanzapine (tablets) and olanzapine pamoate (powder for suspension for intramuscular administration).

The dose of oral olanzapine	The recommended initial dose of olanzapine pamoate	Supportive dose after 2 months of therapy with olanzapine pamoate
10 mg / day	210 mg / 2 weeks or 405 mg / 4 weeks	150 mg / 2 weeks or 300 mg / 4 weeks
15 mg / day	300 mg / 2 weeks	210 mg / 2 weeks or 405 mg / 4 weeks
20 mg / day	300 mg / 2 weeks	300 mg / 2 weeks

Doses of olanzapine pamoate exceeding 405 mg every 4 weeks or 300 mg every 2 weeks have not been studied in clinical trials. Additional treatment with oral neuroleptics is not required. However, according to clinical indications, patients can additionally receive neuroleptics for oral administration.

General recommendations for the choice of a dose of olanzapine pamoate for intramuscular administration for specific therapeutic groups

For weakened patients, for patients prone to hypotensive reactions, for patients with a different combination of factors that may slow the metabolism of olanzapine (for example, a nonsmoking woman aged> 65 years), or for patients who may be pharmacodynamically more sensitive to olanzapine, the recommended initial the dose is 150 mg / 4 weeks of olanzapine pamoate. In the presence of indications in these patients, you can carefully increase the dose.

Preparation for injection

Olanzapine pamoate for the preparation of a suspension for intramuscular administration has not been studied in combination with other parenteral preparations, therefore, the combined use of olanzapine pamoate to prepare a suspension for intramuscular administration with any other parenteral preparation is not recommended.

Instructions for the recovery and use of olanzapine pamoate for the preparation of a suspension for intramuscular administrationI

Only for intramuscular injections in the gluteus muscle. Do not administer intravenously or subcutaneously.

1. Selection and preparation material.

The package contains:

- flacon with olanzapine pamoate powder;

- fa lacon with 3 ml of solvent to prepare a suspension of olanzapine pamoate;

- aboutdyne syringe 3 cm³;

- tWith the needle.

Suspension of olanzapine pamoate should be prepared only with the supplied solvent.

During the preparation of the suspension, gloves are recommended, since olanzapine pamoate may have an irritant effect on the skin.

2. Determine the volume required for recovery.

To determine the volume of solvent required for the preparation of the suspension of olanzapine pamoate, refer to the table below. It is important to note that the vial contains more solvent than is necessary to obtain a solution of olanzapine pamoate.

Dose	Olanzapine base content in vial	The amount of solvent to be added
150 mg	210 mg	1.3 ml
210 mg	210 mg	1.3 ml
300 mg	300 mg	1.8 ml
405 mg	405 mg	2.3 ml

3. Recovery of olanzapine pamoate.

Loosen the powder, tapping the bottle lightly.

Remove the syringe from the package.

To type in a syringe the necessary volume of a solvent (item 2 "Determination of the volume required for recovery), attached to the package.

Introduce the solvent into the vial of powder.

Remove air by slightly pulling back the plunger of the syringe, in order to level the pressure in the vial.

Remove the needle from the vial by holding the bottle in an upright position to avoid leakage of the solution.

Tap the bottom of the vial over a non-solid surface (for example, by placing a soft cloth) to mix (see Figure 1).

The drug in the form of a suspension will be opaque, yellow in color. Visually check the contents of the bottle for the presence of lumps. The powder, which did not pass into the suspension, looks like a light yellow dry lump adhered to the bottom of the vial. If such lumps remain, you can re-mix the contents until the suspension becomes outwardly uniform in color and consistency (see Figure 2).

If foam forms, leave the vial at rest until disappearance of foam.

The recovered olanzapine pamoate remains stable in the vial during, 24 hours. If the drug is not used immediately, before using it it will be necessary to vigorously shake to re-form the suspension.

4. Introduction of olanzapine pamoate.

To verify the final volume of the suspension for intramuscular injection refer to the following table. The concentration of the suspension is 150 mg / ml.

Dose	The content of olanzapine - the base in the vial	The final volume for intramuscular introduction of
150 mg	210 mg	1.0 ml
210 mg	210 mg	1.4 ml
300 mg	300 mg	2.0 ml
405 mg	405 mg	2.7 ml

1. Connect the new needle to the syringe.

2. Slowly fill the syringe with the required amount of solution.

Some excess amount of the drug will remain in the vial.

3. Remove the needle from the syringe.

For the introduction, take a 38 mm needle 19G Hypodermic Needle-Pro with a protective cap. For obese patients, a 50 mm needle can be usedG or even larger (not in the kit). To prevent blockage of the needle, you need to use the size 19G or more.

4. Attach a new needle to the syringe before performing the injection to prevent the formation of lumps. After sampling the suspension of olanzapine pamoate from the vial, it should be injected immediately.

5. Select and prepare a place for injection in the buttock area.

Do not administer intravenously or subcutaneously!

6. After inserting the needle into the muscle, pull the plunger toward you for a few seconds to make sure that there is no blood in the syringe.If the blood appeared in the syringe, then the syringe along with the drug contained in it should be destroyed and a fresh solution prepared. The drug should be injected by pressing the plunger of the syringe with a constant force.

Place the injection should not be massaged!

7. Vials, needles and syringes should be appropriately destroyed after the injection. The bottle is intended for single use only.

Application features:

Patients who are first prescribed prolonged injection of olanzapine, before the start of treatment, it is useful to determine the tolerance of the drug by prescribing oral olanzapine. For weakened patients who are prone to hypotensive reactions, as well as patients in whom several factors contribute to a slowdown in olanzapine metabolism and an increase in pharmacodynamic sensitivity to it (female sex, age 65 years, non-smokers), the recommended initial dose is 150 mg / 4 weeks. In this case, the dose should be increased with caution.

In patients younger than 18 years of age, the use of a prolonged injection of olanzapine has not been studied.

Side effects:

Body mass

In clinical studies in adults, the mean increase in body weight was higher in patients who received olanzapine, compared with placebo. A clinically significant increase in body weight was observed in all body mass index (BMI) categories.

Glucose

In clinical studies in adults (up to 12 months), with a reception of olanzapine, there was a greater average increase in glucose concentration compared with placebo, decreasing an average of 6 months after the start of the drug.

Patients with signs of an initial disturbance of glucose metabolism (including patients with diabetes mellitus) experienced a more pronounced increase in glucose concentration and HbA1c compared with placebo.

Lipids

In clinical trials in adult patients who received olanzapine, there was a more pronounced mean increase in total cholesterol, LDL and fasting triglyceride compared with placebo.

The average increase in fasting lipids (total cholesterol, LDL, triglycerides) was more pronounced in patients without signs of an initial lipid metabolism disorder.

There were no statistically significant differences between the olanzapine and placebo treatment groups for fasting HDL cholesterol.

Prolactin

Concentrations of prolactin in plasma were elevated in 34% of patients who received olanzapine. This increase was insignificant and transient (the mean value at the endpoint was not higher than the upper limit of the norm and statistically significantly different from the value in the placebo group), and the clinical conditions associated with hyperprolactinemia (for example, gynecomastia, galactorrhea, breast enlargement) were rare. In most patients, rates returned to normal without discontinuing treatment.

Aminotransferase of the liver

Sometimes there was a transient, asymptomatic increase in the activity of liver aminotransferases: ALT and ACT.

Eosinophilia

Sometimes asymptomatic eosinophilia was observed.

Undesirable effects in special therapeutic groups of patients

Very frequent (≥10%) undesirable effects in the use of olanzapine in clinical studies in patients with psychosis in the background of dementia were a violation of gait and fall.

Frequent (<10% and ≥1%), unwanted effects with olanzapine in elderly patients with psychosis on the background of dementia were incontinence and pneumonia.

In clinical studies in patients with drug-induced psychosis (dopamine receptor agonists) for the treatment of Parkinson's disease, the increased symptoms of parkinsonism were noted very often (≥10%) and with a higher frequency than in the placebo group. Hallucinations were also noted very often (≥10%) and with a higher frequency than in the placebo group.

In patients with bipolar mania receiving olanzapine in combination with lithium or valproic acid, very frequent (≥10%), unwanted effects were weight gain, dry mouth, increased appetite, tremor and frequent (<10% and ≥1%) - speech disorder.

The following table shows the main side effects in adults and their frequency recorded during clinical trials and / or post-marketing periods.

System / Side Effect		Frequency
		≥10%		<10% and 1≥%	<1% and ≥0,1%	<0.1% and ≥ 0,01%	<0,01%	The frequency can not be reliably determined
Violations of the blood and lymphatic system
¹ Eosinophilia				X
³ Leukopenia, including neutropenia						X
³ Thrombocytopenia							X
Disorders from the metabolism and nutrition
^1,9,10 Weight gain		X
^1,11Weight gain ≥ 7% of the original		X
^1,12 Weight gain ≥ 15% of the original				X
³ Diabetic coma							X
^3,4 Diabetic ketoacidosis							X
³ Hyperglycaemia						X
^3,8 Hypercholesterolemia							X
^{H, 5.8} Hypertriglyceridemia							X
² Peripheral edema				X
¹Glucosuria				X
²Increased appetite				X
Disturbances from the nervous system
² Akathisia				X
² Parkinsonism				X
^2,9 Dizziness				X
³ Convulsive seizures						X
² Drowsiness		X
² Dyskinesia				X
Malignant neuroleptic syndrome								X
Dystonia (oculogic crisis)								X
Late dyskinesia								X
Heart Disease
² Bradycardia					X
Interval lengthening QT_C					X
Ventricular tachycardia / fibrillation, sudden cardiac death								X
Vascular disorders
¹ Orthostatic hypotension				X
³Venous thromboembolism, including pulmonary embolism and deep vein thrombosis							X
Disorders from the gastrointestinal tract
² Constipation				X
² Dry mouth				X
³ Pancreatitis							X
Disturbances from the liver and bile ducts
³Hepatitis						X
³Jaundice							X
Disturbances from the skin and subcutaneous tissues
³Alopecia							X
³Rash						X
Musculoskeletal system disorders
³ Rhabdomyolysis							X
Infringements from kidneys and urinary tract
³ Priapism							X
³ Urinary incontinence							X
³ Retention of urine							X
Pregnancy, postpartum and perinatal conditions
Abstinence syndrome of newborns								X
General disorders
^3,6 Allergic reaction							X
² Asthenia				X
^3,7 Reaction to cancellation							X
Fatigue				X
Edema				X
² Increased sensitivity to light					X
^2,9 Weakness				X
Hypothermia								X
Laboratory data
¹ Increased activity of alanine aminotransferase at blood serum				X
¹ Increase aspartate aminotransferase in serum				X
³ Increased activity of alkaline phosphatase							X
³ Increase in the concentration of total bilirubin							X
^1,10 Total fasting cholesterol: < 200 mg / dl up to > 240 mg / dL				X
¹ Total fasting cholesterol: > 200 mg / dL and < 240 mg / dl up to > 240 mg / dL		X
^1,10 Fasting triglycerides: < 150 mg / dl up to > 200 mg / dL				X
¹ Fasting triglycerides: > 150 mg / dL and < 200 mg / dl up to > 200 mg / dL		X
^1,9,10,14 Increased prolactin	X
¹ Fasting glucose: <100 mg / dl to> 126 mg / dL			X
¹ Fasting glucose: > 100 mg / dL and <126 mg / dl to> 126 mg / dL	X

¹Evaluation of indicators from the database of clinical studies.

²Side effects recorded in the database of clinical trials.

³Side effects recorded spontaneously in postmarketing studies.

⁴In the classification COSTART is referred to as diabetic acidosis.

⁵In the classification COSTART is referred to as hyperlipidemia.

⁶For example, anaphylactoid reaction, angioedema, itching or urticaria.

⁷That is, sweating, insomnia, anxiety, nausea, or vomiting.

⁸In isolated cases, the level of cholesterol S 240 mg / dl and triglyceride level ≥ 1000 mg / dl.

⁹According to a randomized double-blind 8-week study.

¹⁰According to a 24-week study in patients with schizophrenia.

¹¹The median duration of exposure is 8 weeks.

¹²The median duration of exposure is 12 weeks.

¹³With correction by sex.

¹⁴As a rule, in patients receiving olanzapine, clinical manifestations associated with the mammary gland and menstrual cycle (such as amenorrhea, breast enlargement, galactorrhea in women, gynecomastia / breast enlargement in men), were infrequent.

Overdose:

In pre-registration clinical trials of olanzapine pamoate in patients after injection of the drug, adverse reactions did not differ from those in olanzapine overdose: sedation (including coma) and / or delirium (see section Special instructions). Such adverse events occurred in <0.1% of injections and in approximately 2% of patients who received injections for up to 46 months.These events correlated with an involuntary rapid increase in serum olanzapine concentrations up to concentrations above the therapeutic range. With the rapid increase in serum olanzapine concentration in some patients with such undesirable effects, the precise mechanism of drug delivery into the bloodstream remained unknown.

Signs and Symptoms

Very frequent (frequency ≥ 10%) with symptoms of olanzapine overdose were tachycardia, agitation / aggressiveness, articulation disorder, various extrapyramidal disorders and disorders of consciousness of varying severity (from sedation to coma).

Other clinically relevant consequences of olanzapine overdose included delirium, seizures, malignant neuroleptic syndrome, respiratory depression, aspiration, increased or decreased blood pressure, cardiac arrhythmias (<2% of overdoses), and cardiac arrest and respiratory arrest. The minimum dose for acute overdose with a lethal outcome was 450 mg, the maximum dose for an overdose with a favorable outcome (survival) is 2 g.

Medical assistance for overdose

There is no specific antidote for olanzapine. Symptomatic treatment is shown in accordance with the clinical condition and control over 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 beta-adrenergic receptor agonists, since stimulation of these receptors can aggravate arterial hypotension.

Interaction:

The metabolism of olanzapine can be altered by the inhibitors or inducers of the isoenzyme CUR1A2. The clearance of olanzapine is increased in smokers and in patients taking carbamazepine (in connection with an increase in isoenzyme activity CYP1A2). Known potent inhibitors of isoenzyme CYP1A2 can reduce the clearance of olanzapine. Olanzapine It is not a potent inhibitor of isoenzyme activity CYP1A2, so when taking olanzapine, the pharmacokinetics of medicines, such as theophylline, mainly metabolized with the participation of isoenzyme CYP1A2, does not change.

In clinical trials,that a single administration of a dose of olanzapine against the background of therapy with the following drugs was not accompanied by a suppression of the metabolism of these drugs: imipramine or its metabolite desipramine (isozymes CYP2D6, CYP3A, CYP1A2), warfarin (isoenzyme CYP2C19), theophylline (isoenzyme CYP1A2) or diazepam (isozymes CYP3A4, CYP2C19 ). There were no signs of drug interaction when olanzapine was used in combination with lithium or biperidin. Also, the combined administration of diazepam with olanzapine increases the orthostatic hypotension that occurs when taking olanzapine, warfarin does not affect the pharmacokinetics of olanzapine.

Against the background of a stable concentration of olanzapine, there was no change in the pharmacokinetics of ethanol. However, taking ethanol with olanzapine may be accompanied by an increase in the pharmacological effects of olanzapine, for example, sedation.

A single intake of aluminum or magnesium containing an antacid or cimetidine did not interfere with the bioavailability of olanzapine when ingested.

Co-administration of activated carbon reduced the bioavailability of olanzapine when administered orally to 50-60%.

Fluoxetine (60 mg once or 60 mg daily for 8 days) causes an increase in the maximum concentration of olanzapine by an average of 16% and a decrease in the clearance of olanzapine by an average of 16%. The degree of influence of this factor is significantly inferior to 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, inhibitor of isoenzyme CYP1A2, decreases the clearance of olanzapine. The result is an average increase in C_mOh olanzapine with the administration of fluvoxamine by 54% in nonsmoking women and by 77% in male smokers. Average increase AUC olanzapine 52% and 108% respectively. Patients who receive treatment with fluvoxamine jointly should be given small doses of olanzapine.

In studies in vitro, using human liver microsomes, it is shown that olanzapine slightly suppresses the process of formation of valproate glucuronide (the main pathway of valproic acid metabolism). Valproic acid also slightly affects the metabolism of olanzapine in vitro. Therefore, clinically significant pharmacokinetic interaction between olanzapine and valproic acid is unlikely.

Due to the influence of olanzapine on the central nervous system, it should be combined with great caution with other drugs with central action and alcohol.

As olanzapine can cause hypotension, it can enhance the effect of certain antihypertensive drugs.

Olanzapine may be an antagonist of levodopa and dopamine agonists. Simultaneous administration of lorazepam (intramuscularly) has little effect on the pharmacokinetics of olanzapine, unconjugated lorazepam, or total lorazepam. However, simultaneous administration of lorazepam with olanzapine increases the drowsiness caused by each of these drugs.

Single doses of olanzapine do not affect the pharmacokinetics of imipramine and its active metabolite desipramine.

According to research in vitro, using human liver microsomes, olanzapine also demonstrated an extremely low potential in inhibiting the activity of the following cytochrome P450 isoenzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A.

Special instructions:

Malignant neuroleptic syndrome. Malignant neuroleptic syndrome (ZNS) is a potentially life-threatening symptom complex that can develop with the use of neuroleptics, including olanzapine.Clinical manifestations of malignant neuroleptic syndrome include a significant increase in body temperature, muscle rigidity, impaired mental status and manifestations of autonomic dysfunction (instability of heart rate and blood pressure, tachycardia, cardiac arrhythmias, profuse sweating). Additional signs may include an increase in the concentration of creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of malignant neuroleptic syndrome or the presence of fever of unknown origin without other symptoms of malignant neuroleptic syndrome require the abolition of all antipsychotics, including olanzapine.

Late dyskinesia. In comparative studies lasting more than 6 weeks, treatment with olanzapine was significantly less often accompanied by the development of dyskinesia requiring drug correction than haloperidol. However, the risk of tardive dyskinesia with prolonged therapy with neuroleptics should be considered. With the development of signs of tardive dyskinesia, a dose reduction or elimination of olanzapine is recommended.Symptoms of tardive dyskinesia may increase or manifest after the drug is discontinued.

Experience in elderly patients with psychosis on the background of dementia. The effectiveness of olanzapine in elderly patients with psychosis against a background of dementia is not established. In this category of patients in placebo-controlled clinical trials, the incidence of lethal cases in the olanzapine group was higher than in the placebo group (3.5% vs. 1.5%, respectively). Elderly patients with psychosis in the background of dementia who are receiving atypical antipsychotics are at increased risk of death compared with placebo. The main risk factors for increased mortality for this group of patients in the treatment with olanzapine are age> 80 years, sedation, combined use with benzodiazepines, or the presence of lung pathology (eg, pneumonia with or without aspiration).

Cerebrovascular adverse events, for example, stroke, transient ischemic attack, including death, were noted in studies of olanzapine in elderly patients with psychosis on the background of dementia. In placebo-controlled studies, a higher incidence of cerebrovascular unwantedof patients in the olanzapine group compared with placebo (1.3% vs. 0.4%, respectively). All patients with cerebrovascular disorders had previous risk factors for developing cerebrovascular adverse events (for example, the previously noted case of cerebrovascular undesirable phenomenon or transient ischemic attack, hypertension, smoking), as well as concomitant diseases and / or medications associated with cerebrovascular undesirable events.

Olanzapine is not recommended for the therapy of patients with psychosis on the background of dementia. Weight gain. Before starting olanzapine, "you need to take into account the potential increase in body weight." Patients taking olanzapine, it is necessary to control body weight.

Monotherapy with olanzapine in adults. Based on 13 placebo-controlled trials of olanzapine monotherapy, patients who took olanzapine, an average of 2.6 kg of body weight was added, and in the placebo group, 0.3 kg was lost with an average duration of therapy of 6 weeks; in 22.2% of patients taking olanzapine, the body weight increased by at least 7% from the baseline, in the placebo group by 3%; the average duration of therapy before weight gain was 8 weeks; 4.2% of those who received olanzapine patients were added at least 15% of body weight, in the placebo group - 0.3% of patients with an average duration of therapy before weight gain of 12 weeks. A clinically significant increase in body weight was observed in all the initial categories of the Body Mass Index (BMI). 0.2% of patients in the olanzapine group discontinued therapy due to weight gain, in the placebo group, 0%.

In long-term studies (minimum 48 weeks), the mean increase in body weight was 5.6 kg (median exposure 573 days, N= 2021). The proportion of patients whose body weight increased by at least 7%, 15% or 25% of the baseline value for a prolonged exposure was 64%, 32% and 12%, respectively. Of the patients receiving olanzapine for a minimum of 48 weeks, 0.4% discontinued therapy due to weight gain.

Increase the interval QTc. In clinical trials of oral olanzapine, a clinically significant lengthening of the interval QTc. According to clinical studies of intramuscular olanzapine or olanzapine pamoate, olanzapine did not cause a prolonged interval QT or QT_c.Tem not less than, olanzapine caution should be given to patients with congenital syndrome of elongated QT, congestive heart failure, hypertrophy of the myocardium, hypokalemia, hypomagnesemia, or with drugs that extend the interval QT.

Dysfunction of the liver. In some cases, the use of olanzapine, usually in the early stages of therapy, was accompanied by: a transient, asymptomatic increase in the parameters of hepatic aminotransferases (aspartate aminotransferase and alanine aminotransferase) in serum. There were rare cases of hepatitis.

In very rare cases, hepatic cholestasis and other mixed liver damage were noted. Particular caution is needed when increasing aspartate aminotransferase and / or alanine aminotransferase levels in blood serum in patients with hepatic insufficiency, with limited functional liver reserve, or in patients receiving potentially hepatotoxic drugs.

Hyperglycemia and diabetes mellitus. There is a higher prevalence of diabetes in patients with schizophrenia. As with some other antipsychotic drugs, there have been cases of hyperglycemia, diabetes, exacerbation of pre-existing diabetes, ketoacidosis, and diabetic coma.A thorough clinical monitoring of patients with diabetes and patients with risk factors for diabetes is recommended.

Change in lipid spectrum. In placebo-controlled trials in patients who received olanzapine, undesirable changes in the lipid spectrum were observed. Clinical observation is recommended (see "Side effect").

Epileptic seizures. Olanzapine should be administered with caution to patients with epileptic seizures in the history or exposed to factors that reduce the threshold of convulsive readiness. In such patients, seizures were rarely seen with olanzapine. Hematologic changes. As with other antipsychotics, caution should be exercised when olanzapine is used in patients with reduced leukocyte counts and / or neutrophils in peripheral blood due to various causes; with signs of oppression or toxic damage to bone marrow function under the influence of drugs in the anamnesis; with oppression of bone marrow function due to concomitant disease, radiotherapy or chemotherapy in history; with hypereosinophilia or myeloproliferative disease.

In clinical studies, the use of olanzapine in patients with clozapine-associated neutropenia or agranulocytosis in a history was not accompanied by recurrence of these disorders.

Accompanying illnesses. In clinical trials, olanzapine therapy was rarely accompanied by anticholinergic side effects. However, in view of the limited clinical experience of olanzapine in patients with concomitant disease, caution should be exercised in prescribing olanzapine to patients with clinically significant prostatic hypertrophy, paralytic intestinal obstruction, occlusive glaucoma, and similar conditions. Dopaminergic antagonism. In conditions in vitro olanzapine reveals antagonism against dopamine and, like other antipsychotics, theoretically can suppress the action of levodopa and dopamine agonists.

Total activity against the central nervous system. Given the main effect of olanzapine on the central nervous system, caution should be exercised when using olanzapine in combination with other central drugs and alcohol.

Orthostatic hypotension. Olanzapine can cause orthostatic hypotension, which is probably due to its antagonist α₁-adrenergic receptors. Olanzapine with extreme caution should be used in patients with diagnosed cardiovascular diseases (myocardial infarction or ischemia in anamnesis, heart failure or conduction disorder), diseases or pathologies predisposing to hypotension (dehydration, hypovolemia and treatment with antihypertensive drugs), in which loss of consciousness, hypotension and / or bradycardia can lead to medical complications. If such patients have never previously taken olanzapine, then before the start of olanzapine therapy with pamoate it is necessary to establish individual tolerability by prescribing oral olanzapine.

It is necessary to carefully prescribe the drug to patients taking other drugs that can provoke hypotension, bradycardia, oppression of the respiratory or central nervous system.

Suicide. In schizophrenia, suicide attempts are possible, therefore, during the period of drug therapy, patients with high suicidal risk should be closely monitored.

Convulsive seizures. Patients with a history of convulsive seizures or with diseases potentially reducing the threshold of convulsive readiness, such as dementia in Alzheimer's disease, olanzapine should be administered with caution.

Undesirable reactions after injection, including post-injection delirium and sedative syndrome. Pre-registration clinical trials reported the occurrence after the injection of olanzapine pamoate phenomena that were characterized by signs and symptoms of an overdose of olanzapine. These phenomena occurred in <0.1% of injections and approximately 2% of patients. In most patients, clinical signs and symptoms included sedation (from mild to severe to coma) and / or delirium (including confusion, disorientation, agitation, anxiety and cognitive impairment). Among other symptoms, extrapyramidal disorders, dysarthria, ataxia, aggressive tendencies in behavior, dizziness, weakness, increased muscle tone or convulsions (see the section "Overdose") were noted. In most cases, the first signs and symptoms associated with this phenomenon appeared within 1 hour after the injection.In all cases, the disappearance of all symptoms was reported within 24-72 hours after the injection. The probability of occurrence of this phenomenon is highest during the first hour from the moment of injection. Very rarely (<1 per 10,000 injections) postinjection syndrome occurred 1 hour after the appointment. It is recommended that health professionals discuss the described risk with patients each time they prescribe and administer olanzapine pamoate. Injections of olanzapine pamoate should be performed by a qualified medical professional. After each injection, the patient should be observed in a medical facility for at least 2 hours for signs and symptoms that are characteristic of an overdose of olanzapine. Immediately before leaving the patient from a medical facility, you should make sure that he is conscious, focused and does not have any symptoms and signs of an overdose. During the remainder of the day after the injection, patients should be advised to remain alert to the symptoms of post-injection adverse reactions. In addition, they should be able to get medical help if necessary.Patients should not drive vehicles and mechanisms.

If there is a suspicion of overdose, careful medical surveillance and monitoring should continue until the examination indicates symptom resolution. With the development of any signs and symptoms of post-injection syndrome, the recommended follow-up period (2 hours) should be extended in accordance with clinical necessity.

If parenteral administration of benzodiazepines is required for the treatment of post-injection adverse reactions, careful assessment of the patient's condition for excessive sedation and oppression of the functioning of the cardiac and respiratory systems is recommended.

Effect on the ability to drive transp. cf. and fur:

Patients receiving olanzapine, care should be taken when controlling mechanical means, including a vehicle, because olanzapine may cause drowsiness.

Patients who received an injection of a suspension of olanzapine pamoate should be advised not to drive the car and control mechanisms for the rest of the day after each injection.

Form release / dosage:

Powder for suspension for intramuscular injection 210 mg, 300 mg or 405 mg complete with a solvent.

Packaging:

1 bottle with powder, 1 bottle with 3 ml of solvent, a syringe and 3 needles are placed in a plastic container.

One container together with instructions for use in a pack of cardboard.

Storage conditions:

The preparation and solvent should be stored at a temperature of 15 ° C to 30 ° C. Do not store in the refrigerator. Do not freeze.

Keep out of the reach of children.

Shelf life:

A drug: 3 years.

Solvent: 2 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-001683

Date of registration:02.05.2012

Date of cancellation:2016-09-21

The owner of the registration certificate:Eli Lilly East SAEli Lilly East SA Switzerland

Manufacturer: & nbsp

ELI LILLY & Company USA

LILLY PHARMA Fertigung und Distribution, GmbH & Co. KG. KG Germany

Representation: & nbspELI LILLY EAST SA ELI LILLY EAST SA Switzerland

Information update date: & nbsp22.09.2016

Illustrated instructions

Instructions

Ziprex® Adera ™ (Zyprexa® Adera ™)