Ziprexa - instructions for use, dose, side effects, contraindications

tablet core excipients: lactose monohydrate 102.15 mg, giprolose (hydroxypropylcellulose: hydroxypropylcellulose extra thin 30:70) 5.20 mg, crospovidone 6.50 mg, microcrystalline cellulose 13.00 mg, magnesium stearate (vegetable) 0.65 mg;

tablet coating aids: hypromellose 2.60 mg, dye white mixture YS-1-18027-A (hypromellose, titanium dioxide, macrogol 400, polysorbate 80) 5.30 mg, carnauba wax wax, blue food inks (shellac, ethanol, isopropanol, butanol, propylene glycol, aqueous ammonia, indigocarmine) traces.

For a dosage of 5 mg

Active ingredient: olanzapine 5.00 mg;

tablet core excipients: lactose monohydrate 156.00 mg, giprolose (hydroxypropyl cellulose: hydroxypropylcellulose extra thin 30:70) 8.00 mg, crospovidone 10.00 mg, microcrystalline cellulose 20.00 mg, magnesium stearate (vegetable) 1.00 mg;

auxiliary substances of the coating of tablets: Hypromellose 4.00 mg, dye white mixture YS-1-18027-A (hypromellose, titanium dioxide, macrogol 400, polysorbate 80) 8.16 mg, carnauba wax wax, blue food inks (shellac, ethanol, isopropanol, butanol, propylene glycol , ammonia water, indigo carmine) traces.

For a dosage of 7.5 mg

Active ingredient: olanzapine 7.50 mg;

tablet core excipients: lactose monohydrate 234.0 mg, giprolose (hydroxypropylcellulose: hydroxypropylcellulose extra thin 30:70) 12.00 mg, crospovidone 15.00 mg, microcrystalline cellulose 30.00 mg, magnesium stearate (vegetable) 1.50 mg;

tablet coating aids: hypromellose 6.00 mg, dye white mixture YS-1-18027-A (hypromellose, titanium dioxide, macrogol 400, polysorbate 80) 12,24 mg, carnauba wax wax, blue food inks (shellac, ethanol, isopropanol, butanol, propylene glycol, aqueous ammonia, indigocarmine) traces.

For a dosage of 10 mg

Active ingredient: olanzapine 10.00 mg;

tablet core excipients: lactose monohydrate 312.0 mg, giprolose (hydroxypropylcellulose: hydroxypropylcellulose extra thin 30:70) 16.00 mg, crospovidone 20.0 mg, microcrystalline cellulose 40.00 mg, magnesium stearate (vegetable) 2.00 mg;

auxiliary substances of the coating of tablets: Hypromellose 8.00 mg, dye white mixture YS-1-18027-A (hypromellose, titanium dioxide, macrogol 400, polysorbate 80) 16.32 mg, carnauba wax wax, blue food inks (shellac, ethanol, isopropanol, butanol, propylene glycol , ammonia water, indigo carmine) traces.

In the case of Lilly SA, Spain, the formulation is indicated in the accompanying instructions only for 5 mg and 10 mg.

Description:

Round white tablets covered with a film sheath, printed with the appropriate identification on one side: for tablets of 2.5 mg - LILLY 4112, for tablets 5 mg - LILLY 4115, for tablets 7.5 mg - LILLY 4116, for tablets 10 mg - LILLY 4117.

In the case of Lilly SA, Spain, the description in the attached instructions is only for 5 mg and 10 mg.

Pharmacotherapeutic group:Antipsychotic agent (antipsychotic)

ATX: & nbsp

N.05.A.H.03 Olanzapine

Pharmacodynamics:

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, 5HT₆, dopamine D₁, D₂, D₃, D₄, D₅, muscarinic M_1-5, adrenergic α₁ and histamine H₁receptors. 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 with respect to serotonin 5HT₂receptors, in comparison with dopamine D₂receptors. 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 causing catalepsy (a disorder reflecting a side effect on the motor function). Unlike other neuroleptics, olanzapine increases the anti-anxiety effect during the "anxiolytic" test. Olanzapine provides statistically significant reduction as productive (delirium, hallucinations, etc.), and negative disorders.

Pharmacokinetics:

After oral administration olanzapine well absorbed and its maximum concentration in the plasma is achieved after 5-8 hours. Absorption of olanzapine is not dependent on food intake. In studies with different doses ranging from 1 mg to 20 mg, it is shown that the plasma concentrations of olanzapine vary linearly and in proportion to the dose. Olanzapine metabolized in the liver as a result of conjugation and oxidation.

The main circulating metabolite is 10-N-glucuronide, which theoretically does not penetrate the blood-brain barrier. Isozymes CYP1A2 and CYP2D6 cytochrome P450 are involved in the formation of 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. In healthy volunteers, after oral administration, the mean half-life was 33 hours (21-54 hours for 5-95%), and the average clearance of olanzapine in plasma was 26 l / h (12-47 l / h for 5-95%). The pharmacokinetic parameters of olanzapine vary depending on smoking, sex and age (see table):

Characteristics of 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 due to each of these factors is significantly inferior to the degree of difference between these indicators among individuals.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. 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 persons of European, Japanese and Chinese origin, no differences in the pharmacokinetics of olanzapine associated with race were established. The activity of the cytochrome P450 CYP2D6 isoenzyme does not affect the metabolism of olanzapine.

Indications:

Schizophrenia in adults. Olanzapine is indicated for the treatment of exacerbations, sustained and prolonged anti-relapse therapy in patients with schizophrenia and other similar psychotic disorders.

Bipolar affective disorder in adults. Olanzapine in the form of monotherapy or in combination with lithium or valproate is indicated for the treatment of acute manic or mixed episodes in bipolar affective disorder with / without psychotic manifestations and with / without rapid phase change. Olanzapine It is shown to prevent relapse in patients with bipolar disorder who have olanzapine was effective in treating the manic phase. In combination with fluoxetine olanzapine is indicated for the treatment of depressive conditions associated with bipolar disorder.

Contraindications:

Established hypersensitivity to any of the components of the drug.

Contraindicated for persons under 18 years.

Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.

Pregnancy and lactation:

Pregnancy

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 of the onset or planning of pregnancy during treatment with olanzapine, they need to inform their physician.

In newborns whose mothers took antipsychotics (including olanzapine) in the third trimester of pregnancy, there is a risk of developing unwanted reactions, including extrapyramidal disorders and withdrawal symptoms, different in severity and duration. Cases of development of excitation, hypertension, hypotension, tremor, drowsiness, respiratory distress syndrome and eating disorders have been reported. In this regard, the newborns must be under observation.

Breast-feeding

The study found that olanzapine penetrates into breast milk. The average dosage 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:

The recommended therapeutic dose of olanzapine is from 5 mg to 20 mg per day. The daily dose must be selected individually depending on the clinical condition of the patient.

Olanzapine can be taken regardless of food intake.

Schizophrenia in adults. The recommended initial dose of olanzapine is 10 mg once daily.

Acute mania in bipolar disorder in adults. The recommended initial dose of olanzapine is 15 mg once daily as monotherapy or 10 mg once daily in combination with lithium or valproate.

Supportive therapy for bipolar disorder in adults. The recommended initial dose of olanzapine is 10 mg once daily. Patients who received olanzapine for the treatment of acute mania, it is recommended to continue supporting therapy in the same dose.

Depression in bipolar disorder in adults. Olanzapine in combination with fluoxetine should be prescribed 1 time per day, regardless of food intake. The initial dose is 5 mg of olanzapine and 20 mg of fluoxetine. If necessary, you can change the dosage of both olanzapine and fluoxetine.

General rules for the choice of a daily oral dose for special therapeutic groups

Reduction of the initial dose to 5 mg per day is recommended for elderly patients or patients with other clinical risk factors, including severe renal failure or moderate-level liver failure. A reduction in the initial dose may be recommended for patients with a combination of factors (female, elderly, non-smokers) who can slow the metabolism of olanzapine.Studies of monotherapy olanzapine in persons under the age of 13 years have not been conducted.

Side effects:

The most frequent (≥1%), side effects associated with taking olanzapine during clinical trials were drowsiness, weight gain, eosinophilia, increased concentrations of prolactin, cholesterol, glucose, triglycerides, glucosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia, dyskinesia , orthostatic hypotension, anticholinergic effects, transient asymptomatic increase in liver aminotransferase activity, rash, asthenia, fatigue, fever, arthralgia, increased alkaline phosphate activity ataxia, high activity of gamma-glutamyltransferase, high concentration of uric acid, increased activity of creatine phosphokinase, edema.

The table below shows the main side effects and their frequency recorded during clinical trials and / or post-marketing period with the following frequency: very often (≥ 10%), often (<10% and ≥ 1%), infrequently (<1% and ≥ 0.1%), rarely (<0.1% and ≥ 0.01%), very rarely (<0.01%), the frequency is unknown (the frequency can not be determined from the available data).

System / Side Effect	Frequency
	Often (≥ 10%)	often (<10% and ≥ 1%)	infrequently (<1% and ≥ 0.1%)	rarely (<0.1% and ≥0.01%)	rarely (< 0,01%)	frequency is unknown (frequency can not be determined from available data)
Violations of the blood and lymphatic system
¹Eosinophilia		X
¹ Leukopenia, including neutropenia		X
³Thrombocytopenia				X
Metabolic disorders
³Development or decompensation of diabetes mellitus, in some cases accompanied by ketoacidosis and diabetic coma, including fatal cases			X
³Hyperglycaemia				X
²Peripheral edema		X
¹³Increase glucose concentrations		X
^14,15Increase concentrations triglycerides		X
³Hypothermia				X
Disturbances from the nervous system
^2,13Akathisia		X
²Amnesia			X
^2,9Dizziness		X
³Convulsions in patients with a history of seizures or in the presence of risk factors for seizures			X
²Drowsiness	X
¹²Parkinsonism		X
¹²Dyskinesia		X
³Late dyskinesia			X
³Dystonia (including the oculogic crisis)			X
Dysatria			X
Malignant neuroleptic syndrome				X
Violations from the heart and blood vessels
²Bradycardia			X
Interval lengthening QT_C			X
¹Orthostatic hypotension	X
Ventricular tachycardia / ventricular fibrillation, sudden death				X
³ Venous thromboembolism, including pulmonary embolism and deep vein thrombosis			X
Disturbances from the respiratory system
²Nose bleed			X
Disorders from the gastrointestinal tract
²Bloating			X
²Increased appetite		X
³ Pancreatitis				X
Weakly expressed transient anticholinergic effects, including constipation and dry mouth		X
Disturbances from the liver and bile ducts
³Hepatitis (including hepatocellular, cholestatic or mixed)				X
³ Jaundice					X
Disturbances from the skin and subcutaneous tissues
Rash		X
Alopecia			X
Disruptedfrom the musculoskeletal and connective tissues
³Rhabdomyolysis				X
²Arthralgia		X
Infringements from kidney and urinary tracttheir ways
³ Priapism				X
³ Urinary incontinence			X
³ Delayed urination			X
Difficult start urination			X
Pregnancy, postpartum and perinatal complications
The withdrawal syndrome is newborns whose mothers took olanzapine						X
Violations of the genitals and mammary gland
Erectile dysfunction		X
Reduction of libido in men and women		X
Amenorrhea			X
Increase mammary gland			X
Galactorrhea in women			X
Gynecomastia in men			X
General disordersa and violations at the site of administration
^3,6Allergic reaction			X
²Asthenia		X
^3,7Reaction to cancellation					X
²Fever		X
²Photosensitivity			X
^1,9 Weight gain	X
^1,10Weight gain ≥7% of the initial value	X
^1,11Weight gain> 15% of the initial value		X
^2,9Fatigability		X
Laboratory and instrumental data
¹ Increased activity alanine aminotransferase in serum		X
¹Increase in activity of aspartate aminotransferase in serum		X
¹ Increased activity alkaline phosphatase		X
³ Increase in the concentration of total bilirubin			X
^1,9 Increased prolactin	X
³ Increase in activity of creatine phosphokinase		X
^3,8Hypercholesterolemia					X
¹An increase in the concentration of total cholesterol from normal fasting values (<5.17 mmol / l) to elevated (> 6.2 mmol / L)		X
^1,10Increaseconcentrationscholesterolfrom(≥ 5.17- <6.2 mmol / l) to elevated levels (≥ 6.2 mmol / l)	X
^3,5,8Hypertriglyceridemia					X
¹ Glucosuria		X
¹ High activity gamma-glutamyl transferase		X
¹High concentration of uric acid		X

¹Evaluation of indicators from the database of clinical studies.

² Side effects recorded in the database of clinical trials.

³Side effects recorded spontaneously in post-registration studies.

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

⁵In the classification COSTART is referred to as hyperlipidemia.

⁶For example, an anaphylactic reaction, angioedema, pruritus or urticaria.

⁷With a sharp abolition, the development of such symptoms as sweating, insomnia, tremor, anxiety, nausea and vomiting was observed.

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

⁹Statistically significant differences in groups with three different doses were recorded in a single 8-week, randomized, double-blind, fixed-dose study compared with oral olanzapine 10, 20, 40 mg / day in patients with schizophrenia and schizoaffective disorder.

¹⁰The average duration before the appearance of the phenomenon is 8 weeks.

¹¹The average duration before the onset of the phenomenon is 12 weeks.

¹² In clinical trials, the incidence of parkinsonism and dystonia in patients taking olanzapine, were more frequent, but the difference with the placebo group was not statistically significant. In patients who took olanzapine, cases of development of parkinsonism, akathisia, dystonia, were observed less often than in patients receiving titrated doses of haloperidol.In view of the lack of detailed information about the presence of acute and late dyskinesias in patients with an anamnesis, at present It is impossible to conclude that olanzapine to a lesser degree causes the development of late dyskinesias or other late extrapyramidal syndromes.

¹³ There was an increase in glucose concentration from normal fasting values (<5.56 mmol / l) to elevated (≥ 7 mmol / L). Change in glucose concentration from fasting borderline≥ 5.56 - <7 mmol / l) to elevated (≥ 7 mmol / l) was very frequent.

¹⁴ The average increase in fasting lipids (cholesterol, low-density lipoprotein (LDL), triglycerides) was more pronounced in patients without initial signs of lipid metabolism disorders.

¹⁵ There was an increase in the concentration of triglycerides from normal fasting values (<1.69 mmol / l) to elevated (≥ 2.26 mmol / l).

The change in the concentration of triglycerides from the fasting borderline≥ 1.69 - <2.26 mmol / l) to elevated (≥ 2.26 mmol / l) was very frequent.

Body mass

In clinical studies, the average increase in body weight was higher in patients taking olanzapine, than in the placebo group.A clinically significant increase in body weight was observed in all body mass index (BMI) categories.

In long-term clinical trials (duration not less than 48 weeks), both the mean increase in body weight and the percentage of recipients olanzapine of patients with a clinically significant increase in body weight were higher than those from short-term studies. Cases of persistent weight gain of patients more than 25% of the original value were very frequent (≥10%).

Glucose

In clinical studies (up to 52 weeks), a greater average increase in glucose concentration was observed with olanzapine compared with placebo. In patients with signs of an underlying disorder of glucose metabolism (including patients with diabetes mellitus or the presence of signs of hyperglycemia), there was a more pronounced increase in the concentration of glucose and HbAlc compared with placebo. The number of patients whose glucose concentration increased from the normal or threshold value at the time of initiation of therapy to high increased with time. According to the results of the analysis of patients'who completed a 9-12 month course of olanzapine therapy, after approximately 6 months of treatment, the increase in mean blood glucose concentration was reduced.

Lipids

In clinical trials of up to 12 weeks in patients who received olanzapine, there was a more pronounced mean increase in total cholesterol, low-density lipoprotein (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.

Concerning high-density lipoprotein (HDL) concentrations in the fasting state, there were no statistically significant differences between olanzapine and placebo treatment groups.

In long-term clinical trials (lasting at least 48 weeks), the incidence of increasing total cholesterol, LDL, triglycerides from normal or threshold to high, and the frequency of HDL cholesterol change from normal or threshold to low was higher than in short-term studies.According to the results of the analysis of patients who completed the 12-month course of olanzapine therapy, the average concentration of cholesterol (not on an empty stomach) did not increase after 4-6 months.

Prolactin

During controlled clinical trials (up to 12 weeks) an increase in the concentration of prolactin was recorded in 30% of patients taking olanzapine, compared with 10.5% in the placebo group. In most patients, the increase was insignificant. In patients with schizophrenia, menstrual irregularities, potentially associated with increased prolactin concentrations, were frequent (<10% to ≥1%), whereas violations of sexual function and side effects from the breast - infrequent (from <1% to ≥0.1%). In patients receiving therapy for other psychiatric disorders, cases of impaired sexual function, potentially associated with increased prolactin concentrations, occurred frequently (<10% to ≥1%), while side effects from the breast and menstrual disorders - infrequently (from <1% to ≥0,1 %).

Aminotransferase of the liver

Sometimes there was a transient, asymptomatic increase in the activity of aminotransferases of the liver: alanine aminotransferase (ALT) and aspartate aminotransferase (ACT).

Eosinophilia

Sometimes asymptomatic eosinophilia was observed.

Undesirable effects in special therapeutic groups of patients

Very frequent (≥ 10%), the undesirable effect of olanzapine in clinical studies in patients with psychosis against dementia was 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 psychosis induced by admission drug (dopamine receptor agonist) in Parkinson's disease, increased symptoms of parkinsonism was 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 valproate, very frequent (≥ 10%), unwanted effects were weight gain, dry mouth, increased appetite, tremor and frequent (<10% and ≥ 1%) - speech disorder.

Overdose:

Overdose 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, hypertension or hypotension, arrhythmias (<2% overdose), and cardiac arrest and respiratory arrest. The minimum dose for acute overdose with a lethal outcome was 450 mg, the maximum dose for an acute overdose with a favorable outcome (survival) is 2000 mg.

Medical assistance for overdose

There is no specific antidote for olanzapine. It is not recommended to provoke vomiting. Standard procedures for overdose can be shown (gastric lavage, the appointment of activated charcoal). Co-administration of activated carbon showed a decrease in bioavailability of olanzapine when ingested by 50-60%. Symptomatic treatment is shown in accordance with the clinical condition and control over the functions of vitalorgans, 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 inhibitors or inducers of cytochrome P450 isoenzymes exhibiting specific activity for the isoenzyme CYP1A2. The clearance of olanzapine is increased in smokers and in patients taking carbamazepine (in connection with an increase in the activity of the isoenzyme CYP1A2). Known potential inhibitors of the CYP1A2 isoenzyme may reduce the clearance of olanzapine. Olanzapine It is not a potential inhibitor of the activity of the CYP1A2 isoenzyme. so when taking olanzapine, pharmacokinetics of medicines, such as theophylline, mainly metabolized with the participation of the isoenzyme CYP1A2, does not change.

In clinical studies, it was shown that a single 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 (isoenzymes CYP3A4, CYP2C19).

There were no signs of drug interaction when olanzapine was used in combination with lithium or biperidin.

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

The effect of drugs on the absorption of oral olanzapine was studied. A single dose of an aluminum or magnesium-containing antacid or cimetidine did not interfere with the bioavailability of olanzapine when taken orally. Simultaneous use of activated carbon reduced the bioavailability of olanzapine when ingested by 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, an inhibitor of the isoenzyme CYP1A2, reduces the clearance of olanzapine.The result is an average increase FROM_mOh (maximum concentration) of olanzapine with the administration of fluvoxamine 54% in nonsmoking women and 77% in male smokers, the average increase in AUC (area under the curve) of olanzapine is 52% and 108%, respectively. Small doses of olanzapine should be given to patients who are jointly receiving fluvoxamine treatment.

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

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.

Caution should be exercised when using olanzapine in patients who consume alcohol or who receive medications that cause central nervous depression system.

The combined use of olanzapine with anti-Parkinsonics in patients with Parkinson's disease and dementia is not recommended.

Caution should be exercised when using olanzapine in conjunction with drugs that can prolong the QTc interval.

Special instructions:

Clinical improvement with antipsychotic medications can take from a few days to several weeks and requires careful monitoring of the patient.

Suicide

The risk of a suicide attempt by patients with schizophrenia and bipolar disorder of the first type is due to the aforementioned diseases. In this regard, against the background of pharmacotherapy requires careful monitoring of those patients who have a risk of suicide is particularly high. When prescribing olanzapine, one should strive to minimize the number of tablets taken by the patient, so as to reduce the risk of overdose.

Malignant neuroleptic syndrome

Malignant neuroleptic syndrome (CNS) can develop in the treatment of any neuroleptic, including olanzapine. Clinical manifestations of malignant neuroleptic syndrome include a significant increase in body temperature, rigidity of muscles,change in mental status and autonomic disorders (unstable pulse or blood pressure, tachycardia, arrhythmias, increased sweating). Additional signs may include an increase in the activity of creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of malignant neuroleptic syndrome or a significant unexplained increase in body temperature without other symptoms of malignant neuroleptic syndrome require withdrawal 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, an increased 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.

Psychosis associated with dementia and / or behavioral disorders

Olanzapine is not indicated for the treatment of psychosis associated with dementia and / or behavioral disorders and is not recommended for use in this group of patients due to high mortality and risk of cerebral circulation. In placebo-controlled studies (6-12 weeks) in elderly patients (mean age 78 years) with psychosis associated with dementia and / or behavioral disorders, there was a twice higher incidence of death in patients in the olanzapine group compared with placebo group (3.5% and 1.5%, respectively). A higher mortality rate is not associated with a dose of olanzapine (average dose of 4.4 mg) or duration of treatment. Risk factors that may affect the predisposition of this group of patients to a higher mortality in olanzapine therapy include age ≥ 65 years of age, dysphagia, sedation, malnutrition (depletion), dehydration, combined use with benzodiazepines, or the presence of lung pathology (eg, pneumonia with or without aspiration).

Cerebrovascular adverse events (eg, stroke, transient ischemic attack), including death, were noted in the same studies of olanzapine in elderly patients. In the placebo-controlled studies, there was a three-fold higher incidence of cerebrovascular adverse events in patients in the olanzapine group than in the placebo group (1.3% vs. 0.4%, respectively). All patients with cerebrovascular disorders had previous risk factors for developing cerebrovascular adverse events: age ≥75 years old, vascular or mixed dementia, a previously noted case of cerebrovascular undesirable phenomenon or transient ischemic attack, arterial hypertension, smoking, as well as concomitant diseases and / or medications, associated with cerebrovascular undesirable events. In the course of these studies, the efficacy of olanzapine has not been established.

Parkinson's disease

It is not recommended to use olanzapine in the treatment of psychoses induced by dopamine receptor agonists in Parkinson's disease.

In clinical studies in patients with psychosis induced by the drug (dopamine receptor agonist) in Parkinson's disease, increased symptoms of parkinsonism and hallucinations were noted very often (≥10%) and with a higher frequency than in the placebo group. Efficacy in the treatment of psychotic symptoms of olanzapine in patients with Parkinson's disease did not exceed the placebo. In these clinical trials, patients had to use anti-Parkinsonian drugs (dopamine agonists) at the lowest effective dose and continue to take them at the same dose throughout the study. The initial dose of olanzapine was 2.5 mg per day and could be increased to 15 mg per day as recommended by the physician.

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 parameters of hepatic aminotransferases (aspartate aminotransferase and alanine aminotransferase) in blood serum. There were rare cases of hepatitis. In very rare cases, hepatic cholestasis and other associated liver damage were noted. Particular caution is needed when increasing the activity of aspartate aminotransferase and / or alanine aminotransferase in the blood serum in patients with insufficient liver function, with limited functional reserve of the liver or in patients,receiving treatment with potentially hepatotoxic drugs.

Hyperglycemia and diabetes mellitus

Patients with schizophrenia have a higher prevalence of diabetes. As with some other antipsychotic drugs, there have been cases of hyperglycemia, diabetes, exacerbation of pre-existing diabetes, ketoacidosis, and diabetic coma. Clinical monitoring of patients with diabetes and patients with risk factors for diabetes is recommended in accordance with the following guidelines: measurement of the initial blood glucose concentration, 12 weeks after the start of olanzapine and subsequently annually. In patients taking antipsychotic drugs, including Ziprex®, it is necessary to check the presence of signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, weakness). Patients with diabetes mellitus or risk factors for diabetes mellitus need regular monitoring of blood glucose concentration. It is necessary to conduct regular control of body weight: before the treatment, 4, 8 and 12 weeks after the start of taking olanzapine and subsequently every 3 months.

Change in lipid profile

In placebo-controlled trials in patients who received olanzapine, undesirable changes in the lipid spectrum were observed (see "Side effect"), especially in patients with dyslipidemia and in patients with risk factors for developing a disorder of lipid metabolism. In patients taking antipsychotics, including the Ziprex® drug, the lipid profile should be checked regularly according to the recommendations: before the treatment, 12 weeks after the start of olanzapine and subsequently every 5 years.

Sudden cardiac death

According to the results of post-marketing observations of olanzapine, sudden deaths were recorded. A retrospective observational study revealed an approximately two-fold increase in the risk of sudden death in the olanzapine group compared to the group of patients who did not receive antipsychotics. In this study, these results for olanzapine were comparable to those for other atypical antipsychotics included in the analysis. Spontaneous reports of sudden death during post-marketing observations were rare.

Convulsions

Olanzapine should be used with caution in patients with a history of seizures or exposed to factors that reduce the threshold of convulsive readiness. Cases of seizures were rarely seen in patients taking olanzapine, and in most of these cases, a history of patients had seizures or risk factors for the development of seizures.

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; sypereosinophilia or myeloproliferative disease.

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

Abolition of therapy

In the case of a single-step cancellation of olanzapine, seldom (≥ 0.01% and <0.1%) reported the rapid development of sweating, insomnia, tremors, anxiety, nausea and vomiting.

Duration of the QT interval

In clinical studies, a clinically significant prolongation of the QT interval (QT interval with Fderia [QTcF] correction> 500 ms in patients with baseline QTcF <500 ms) was noted infrequently in clinical studies in patients receiving olanzapine, in the absence of significant differences with placebo in the frequency of occurrence of adverse events from the heart. However, as with other antipsychotics, caution should be exercised in prescribing olanzapine in combination with drugs that can prolong the QT interval, especially in elderly patients, with congenital QT interval prolongation, congestive heart failure, myocardial hypertrophy, hypokalemia, and hypomagnesemia .

Total activity in relation to the central nervous system (CNS)

Taking into account 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.

Postural hypotension

Postural hypotension was rarely observed in clinical studies of olanzapine in the elderly. Just as with the use of other antipsychotics, in the case of olanzapine, patients older than 65 years are advised to periodically monitor blood pressure.

Thromboembolism

Infrequently (≥ 0.1% and <1%) reported cases of a temporary relationship between the development of venous thromboembolism and olanzapine therapy. The presence of a causal relationship between the administration of olanzapine and venous thromboembolism has not been established. However, given that patients with schizophrenia often have acquired risk factors for venous thromboembolism, an overall assessment of all possible risk factors for the development of this complication, including immobilization of patients, and take the necessary preventive measures.

Lactose

Ziprex® tablets contain lactose in their composition. Patients with rare hereditary intolerance to galactose, lactase deficiency and glucose-galactose malabsorption should not be taken olanzapine.

Anticholinergic activity

Although olanzapine exhibited anticholinergic activity in in vitro studies; in clinical trials, olanzapine therapy was rarely accompanied by anticholinergic side effects. However, the clinical experience with olanzapine in patients with concomitant diseases is limited, so 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 exhibits antagonism against dopamine and, like other antipsychotics, theoretically can suppress the action of levodopa and dopamine agonists.

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

Patients receiving olanzapine, Care should be taken when driving vehicles and machinery, since olanzapine may cause drowsiness.

Form release / dosage:

In the case of Eli Lilly and Company Limited, UK, it is stated:

Tablets, film-coated, 2.5 mg, 5 mg, 7.5 mg and 10 mg.

In the case of the production of Lilly SA, Spain or Lilly del Caribe Inc., Puerto Rico, it is indicated:

Tablets, film-coated, 5 mg and 10 mg.

Packaging:

In the case of Eli Lilly and Company Limited, UK, it is stated:

7 tablets in a blister of aluminum, sealed with aluminum foil with vinyl coating.

For 1 (7 tablets), 2 (14 tablets), 4 (28 tablets) or 8 blisters (56 tablets) together with instructions for use are placed in a pack of cardboard.

Tablets with a dosage of 5 mg and 10 mg of 14 tablets in a pack of cardboard are for use only as samples.

In the case of the production of Lilly SA, Spain or Lilly del Caribe Inc., Puerto Rico, it is indicated:

7 tablets in a blister of aluminum, sealed with aluminum foil with vinyl coating.

For 4 blisters together with instructions for use are placed in a pack of cardboard.

Storage conditions:

At a temperature of 15-30 ° C in a dry and dark place.

Keep out of the reach of children.

Shelf life:

In the case of Eli Lilly and Company Limited, UK indicates:

2 years for a dosage of 2.5 mg.

3 years for the dosage of 5 mg, 7.5 mg and 10 mg.

Do not use after expiry date.

In the case of the production of Lilly SA, Spain or Lilly del Caribe Inc., Puerto Rico, it is indicated:

3 years.

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:П N014208 / 01

Date of registration:02.04.2008 / 03.09.2014

Expiration Date:Unlimited

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

Manufacturer: & nbsp

ELI LILLY & Company, Limited United Kingdom

LILLY, S.A. Spain

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

Information update date: & nbsp14.10.2017

Illustrated instructions

Instructions

Ziprex® (Zyprexa®)