ATC code:N NERVOUS SYSTEM AGENTS; N05 PSYCHOLEPTICS; N05A ANTIPSYCHOTICS; N05A H Diazepines, oxazepines, thiazepines and oxepines; N05A H03 Olanzapine
Country of manufacture:Hungary
Diabetics:With caution
Delivery
USPS across the USA
Canada Post across Canada
Payment
Egolanza film-coated tablets 10 mg No. 28
1 132.40 грн.
Description
Instructions for Egolanza film-coated tablets 10 mg No. 28
Composition
active substance: 1 film-coated tablet contains 5 mg or 10 mg, or 15 mg, or 20 mg of olanzapine (equivalent to 7.03 mg or 14.06 mg, or 21.09 mg, or 28.12 mg of olanzapine dihydrochloride trihydrate, respectively);
shell composition: opadry Y-1-7000 white (hypromellose, titanium dioxide (E 171), macrogol 400), hypromellose, quinoline yellow (E 104).
Dosage form
Film-coated tablets.
Main physicochemical properties:
5 mg: yellow, oblong, biconvex, film-coated tablets, odorless or almost odorless, with a score on one side, engraved with a stylized letter "E" and the number "402" on the other side;
10 mg: yellow, round, biconvex, film-coated tablets, odorless or almost odorless, engraved with a stylized letter "E" and the number "404" on one side;
15 mg: yellow, round, biconvex, film-coated tablets, odorless or almost odorless, engraved with a stylized letter "E" and the number "405" on one side;
20 mg: yellow, round, biconvex, film-coated tablets, engraved with a stylized letter "E" and the number "406" on one side.
Pharmacotherapeutic group
Antipsychotics. ATX code N05A H03.
Pharmacological properties
Pharmacodynamics
Olanzapine is an antipsychotic, antimanic, mood-stabilizing drug with a broad spectrum of pharmacological action due to its effects on various receptors.
In preclinical studies, olanaspine has been shown to have affinity for several receptors (Ki; <100 nM) – serotonin 5HT2A/2C, 5-HT3, 5-HT6; dopamine D1, D2, D3, D4, D5; cholinergic muscarinic M1-M5 receptors; α1 adrenergic receptor and histamine H1 receptor.
In behavioral studies of animals treated with olanzapine, olanzapine has been shown to antagonize both serotonin 5HT receptors and dopamine and cholinergic receptors. Olanzapine has a higher binding affinity for serotonin 5HT2 receptors than for dopamine D2 receptors in both in vitro and in vivo models. Electrophysiological studies have shown that olanzapine selectively reduces the excitability of mesolimbic (A10) dopaminergic neurons, with little effect on striatal (A9) pathways involved in motor function. Olanzapine inhibits conditioned avoidance, suggesting antipsychotic activity at doses below those that produce catalepsy, a hallmark of motor side effects. Unlike some other antipsychotic drugs, olanzapine enhances responses to stimuli during anxiolytic testing.
A single oral dose of 10 mg olanzapine was found to have higher binding to 5HT2A receptors than to dopamine D2 receptors in healthy volunteers using positron emission tomography (PET). In addition, analysis of single-photon emission computed tomography (SPECT) images of patients with schizophrenia showed that olanzapine-responsive patients had lower binding to striatal D2 receptors than other antipsychotic- and risperidone-responsive patients compared with clozapine-responsive patients.
Clinical efficacy
In two of two placebo-controlled and two of three comparator-controlled studies involving over 2,900 patients with schizophrenia with positive and negative symptoms, olanzapine showed statistically significant improvements in both negative and positive symptoms.
In an international double-blind comparative study of 1481 patients with schizophrenia, schizoaffective disorder, and related disorders with varying degrees of depressive symptoms (16.6 points on the Montgomery-Asberg Depression Scale), a prospective secondary study from baseline to end of the assessment of mood changes found a statistically significant improvement (p = 0.001) after treatment with olanzapine (-6.0) compared with haloperidol (-3.1).
In a 12-month study of the prevention of recurrence of manic episodes in patients who achieved remission with olanzapine and were subsequently randomized to olanzapine or placebo, olanzapine demonstrated a statistically significant advantage over placebo on the endpoint of recurrence of bipolar disorder. Olanzapine also demonstrated a statistically significant advantage over placebo in preventing recurrence of mania or recurrence of depression.
In a subsequent 12-month study of the prevention of recurrence of manic episodes in patients who achieved remission with concomitant olanzapine and lithium and were subsequently randomized to receive olanzapine or lithium alone, olanzapine was not statistically superior to lithium on the endpoint of recurrence of bipolar disorder (olanzapine 30%, lithium 38.3%, p = 0.055).
In an 18-month study of concomitant treatment of manic or mixed episodes in patients stabilized on olanzapine with lithium or valproate as mood stabilizers, long-term concomitant treatment with olanzapine with lithium or valproate did not demonstrate a statistically significant advantage over lithium or valproate monotherapy in delaying relapse of bipolar disorder defined by syndromic (diagnostic) criteria.
Children.
Experience in adolescents (aged 13 to 17 years) is limited, based on short-term efficacy data for schizophrenia (6 weeks) and mania associated with bipolar disorder (3 weeks) in less than 200 adolescents. The starting dose of olanzapine was 2.5 mg and was increased to 20 mg/day. During treatment with olanzapine, adolescents gained significantly more weight than adults. Adolescents had higher levels of total cholesterol, low-density lipoprotein cholesterol, triglycerides, and prolactin compared to adults (see sections 4.4 and 4.8). Data on maintenance of treatment effect and long-term studies from open-label, uncontrolled clinical trials are limited (see sections 4.4 and 4.8).
Pharmacokinetics
Absorption
Olanzapine is well absorbed after oral administration, with peak plasma concentrations occurring 5-8 hours after oral administration. Food intake does not affect the absorption of olanzapine. The absolute bioavailability of oral versus intravenous olanzapine has not been established.
Distribution
The level of binding of olanzapine to plasma proteins was approximately 93% for concentrations ranging from 7 to 1000 ng/mL. Olanzapine binds primarily to albumin and α1-acid glycoprotein.
Biotransformation
Olanzapine is metabolized in the liver by conjugation and oxidation. The major circulating metabolite is the 10-N-glucuronide, which does not cross the blood-brain barrier. Cytochromes P450-CYP1A2 and P450-CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites, which exhibit significantly less pharmacological activity in vivo than olanzapine in animal studies. The predominant pharmacological activity is due to the parent olanzapine.
Breeding
After oral administration, the mean elimination half-life in healthy volunteers varied depending on age and gender.
In healthy elderly volunteers (aged 65 years and over), the mean elimination half-life was longer (51.8 vs. 33.8 hours) and clearance was reduced (17.5 vs. 18.2 L/hour) compared with younger volunteers. Pharmacokinetic variations observed in elderly subjects were within the range observed in younger subjects. In 44 patients aged 65 years and over with schizophrenia, doses of 5 to 20 mg/day had no effect on adverse reactions.
In women, the mean half-life was longer (36.7 vs. 32.3 hours) and plasma clearance was reduced (18.9 vs. 27.3 L/hour). However, olanzapine (5-20 mg) demonstrated a similar safety profile in both women (n = 467) and men (n = 869).
Patients with renal insufficiency
In patients with renal impairment (creatinine clearance <10 mL/min), there was no significant difference in mean elimination half-life (37.7 vs. 32.4 hours) and clearance (21.2 vs. 25.0 L/hour) compared to healthy volunteers. Mass balance analysis showed that approximately 57% of radiolabeled olanzapine was recovered in urine, primarily as metabolites.
Patients with hepatic insufficiency
In a study of the effect of hepatic impairment in 6 patients with clinically significant cirrhosis (Child-Pugh class A (n = 5) and B (n = 1), there was little effect on the pharmacokinetics of oral olanzapine (single dose 2.5-7.5 mg). Patients with mild to moderate hepatic impairment had slightly increased systemic clearance and a faster elimination half-life compared to patients without hepatic impairment (n = 3). There were more smokers among patients with cirrhosis (4/6; 67%) than among patients without hepatic impairment (0/3; 0%).
Patients who smoke
Olanzapine plasma clearance is lower in the elderly compared to the young, in women compared to men, and in non-smokers compared to smokers. However, the extent to which age, gender, or smoking status affect olanzapine plasma clearance and olanzapine half-life is small compared to the overall interindividual variability.
In studies involving European, Japanese, and Chinese patients, no differences in the pharmacokinetics of olanzapine were identified.
Children
The pharmacokinetics of olanzapine are similar in adolescents and adults. In clinical trials, the mean exposure to olanzapine was approximately 27% higher in adolescents. Demographic differences between adolescents and adults include lower mean body weight and fewer smokers among adolescent patients. These factors are likely to contribute to the higher mean exposure to olanzapine observed in adolescents.
Indication
Olanzapine is indicated for the treatment of schizophrenia.
Olanzapine is effective in maintaining the achieved clinical effect during long-term therapy in patients who have responded to initial therapy.
Olanzapine is indicated for the treatment of moderate to severe manic episodes.
Olanzapine is indicated for the prevention of recurrent attacks in patients with bipolar disorder who have responded to olanzapine treatment of mania.
Contraindication
Hypersensitivity to the active substance or to any of the excipients of the drug; known risk of angle-closure glaucoma.
Interaction with other medicinal products and other types of interactions
It is known that studies of interactions with other drugs have only been conducted with the participation of adults.
Interactions with potential impact on olanzapine
Since olanzapine is metabolized by the CYP1A2 isoenzyme, substances that specifically inhibit or induce this isoenzyme may affect the pharmacokinetics of olanzapine.
CYP1A2 inducers
The metabolism of olanzapine may be induced by smoking and the use of carbamazepine, which results in decreased olanzapine concentrations. A slight to moderate increase in olanzapine clearance has been observed. Clinical findings are limited, but clinical monitoring and, if necessary, an increase in the olanzapine dose is recommended (see section 4.2).
CYP1A2 inhibitors
Fluoxamine, a specific CYP1A2 inhibitor, significantly reduces the metabolism of olanzapine. This results in a mean increase in maximum concentration (Cmax) after administration of fluoxamine of 54% in non-smoking women and 77% in smoking men. The mean increase in the area under the pharmacokinetic curve (AUC) of olanzapine is 52% and 108%, respectively. Patients taking fluoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin, should be given reduced doses of olanzapine. A reduction in the dose of olanzapine should be considered if treatment with a CYP1A2 inhibitor is initiated.
Decreased bioavailability
The use of activated charcoal reduced the oral bioavailability of olanzapine by 50-60% and should be administered within 2 hours before or 2 hours after taking olanzapine.
Fluoxetine (CYP2D6 inhibitor), a single dose of antacids containing aluminum and magnesium, or cimetidine did not significantly affect the pharmacokinetics of olanzapine.
Potential for olanzapine to interact with other drugs
Olanzapine may antagonize the effects of direct and indirect dopamine agonists.
Olanzapine did not inhibit the major CYP450 isoenzymes (e.g. 1A2, 2D6, 2C9, 2C19, 3A4) in vitro. Therefore, no specific interactions are expected, as confirmed by in vivo studies, where no inhibition of olanzapine metabolism was observed with the following active substances: tricyclic antidepressants (which represent a predominantly CYP2D6 pathway), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4, 2C19).
No interactions of olanzapine were observed when used with lithium or biperiden.
Therapeutic monitoring of valproate plasma levels did not reveal the need for valproate dose adjustment when co-administered with olanzapine.
General activity regarding the central nervous system (CNS)
Olanzapine should be used with caution in patients taking ethanol or medications that may cause CNS depression.
The concomitant use of olanzapine with antiparkinsonian drugs is not recommended in patients with Parkinson's disease and dementia (see section "Special warnings and precautions for use").
QTc interval
Caution should be exercised when prescribing olanzapine with other drugs known to increase the QTc interval (see section 4.4).
Application features
Psychosis associated with dementia and/or behavioural disturbances. Olanzapine is not indicated for the treatment of psychosis associated with dementia and/or behavioural disturbances and is not recommended for use in these patients due to an increased risk of mortality and cerebrovascular events. In placebo-controlled clinical trials (6-12 weeks duration) in elderly patients (mean age 78 years) with psychosis associated with dementia and/or behavioural disturbances, the rate of deaths was 2-fold higher in patients treated with olanzapine than in patients treated with placebo (3.5% vs. 1.5%, respectively). The higher mortality was not related to the dose of olanzapine (mean daily dose was 4.4 mg) or to the duration of treatment. Risk factors that may increase mortality include age 65 years or older, dysphagia, sedation, malnutrition and dehydration, pulmonary disease (pneumonia with or without aspiration), and concomitant use of benzodiazepines. However, mortality was higher with olanzapine than with placebo, regardless of risk factors.
Cerebrovascular adverse reactions (e.g. stroke, transient ischemic attack), including fatal outcomes, have been reported in clinical trials. The incidence of cerebrovascular adverse reactions was 3-fold higher in patients treated with olanzapine than in patients treated with placebo (1.3% vs. 0.4%, respectively). All patients treated with olanzapine or placebo who experienced cerebrovascular adverse reactions had risk factors. Age ≥75 years and vascular/mixed dementia were identified as risk factors for cerebrovascular adverse reactions with olanzapine. The efficacy of olanzapine has not been established in these trials.
Parkinson's disease. Olanzapine is not recommended for the treatment of dopamine agonist-associated psychosis in patients with Parkinson's disease. In clinical trials, worsening of Parkinsonian symptoms and hallucinations were very common, more common than with placebo (see section 4.8); olanzapine was not more effective than placebo in the treatment of psychotic symptoms. In these trials, patients were required to continue on the lowest effective dose of their antiparkinsonian medication (dopamine agonist) and to continue on the same antiparkinsonian medication and dose throughout the study. Olanzapine was initiated at 2.5 mg/day and titrated to a maximum dose of 15 mg/day.
Neuroleptic malignant syndrome (NMS). NMS is a potentially fatal symptom complex described in association with antipsychotic drugs. Rare cases of NMS have been reported in association with olanzapine. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, loss of consciousness, and symptoms of cardiac instability (irregular pulse or blood pressure, tachycardia, increased sweating, and cardiac arrhythmia). Additional features may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Clinical manifestations of NMS or the presence of hyperthermia without clinical manifestations of NMS require immediate discontinuation of all antipsychotic drugs, including olanzapine.
Hyperglycemia and diabetes mellitus: Hyperglycemia and/or development of diabetes mellitus or worsening of pre-existing diabetes mellitus associated with ketoacidosis or diabetic coma, as well as fatal cases, have been reported uncommonly (see section 4.8). In some cases, prior weight gain has been reported, which may be a risk factor.
Appropriate clinical monitoring is recommended for patients with diabetes mellitus and those at risk for diabetes mellitus, including measuring blood glucose levels at baseline, after 12 weeks, and annually thereafter. Patients treated with antipsychotics, including olanzapine, should be observed for symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus and those at risk for diabetes should be monitored regularly for worsening of glucose control. Weight should be monitored regularly, e.g. at baseline, after 4 weeks, after 8 weeks, and after 12 weeks, and quarterly thereafter.
Anticholinergic activity: Although olanzapine has been shown to have anticholinergic activity in vitro, clinical studies have shown a low incidence of anticholinergic-related events. However, due to limited clinical experience with olanzapine in patients with comorbid conditions, caution should be exercised when prescribing olanzapine to patients with prostatic hypertrophy, paralytic ileus, or similar conditions.
Liver function tests. Transient, asymptomatic elevations of hepatic transaminases ALT and AST have been commonly observed with olanzapine, especially early in treatment. Olanzapine should be used with caution in patients with elevated ALT and/or AST, signs and symptoms of liver dysfunction, in patients with pre-existing conditions associated with hepatic impairment, and in patients receiving potentially hepatotoxic drugs. Olanzapine should be discontinued if hepatitis (including hepatocellular, cholestatic, or mixed liver injury) occurs.
Neutropenia: Olanzapine should be used with caution in patients with low white blood cell and/or neutrophil counts from any cause, in patients receiving medications that may cause neutropenia, in patients with a history of drug-induced bone marrow suppression/toxicity, in patients with bone marrow suppression due to underlying disease, radiation or chemotherapy, and in patients with hypereosinophilia and myeloproliferative disease. Neutropenia is a common adverse reaction when valproate and olanzapine are used concomitantly (see section 4.8).
Discontinuation of therapy: Acute symptoms, including excessive sweating, insomnia, tremor, irritability, nausea, or vomiting, have been reported very rarely (≥0.01% and 0.1%) upon abrupt discontinuation of therapy.
QT interval.
In clinical trials, clinically significant prolongation of the QTc interval (Friedrich QT correction (QTcF) ≥ 500 milliseconds (msec) at any time after initiation of therapy in patients with a baseline QTcF < 500 msec prior to initiation of therapy) was uncommon (0.1% to 1%) in patients treated with olanzapine. There was no significant difference in the incidence of associated cardiac adverse reactions compared to placebo. However, olanzapine should be used with caution in combination with drugs that may prolong the QTc interval, especially in elderly patients, patients with congenital long QT syndrome, congestive heart failure, cardiac hypertrophy, hypokalemia, or hypomagnesemia.
Thromboembolism: A temporal association between olanzapine treatment and venous thromboembolism has been reported infrequently (≥ 0.1% - < 1%). A causal relationship between olanzapine treatment and venous thromboembolism has not been established. However, given that patients with schizophrenia are often predisposed to thromboembolism, all possible risk factors, such as patient immobilization, should be considered and all necessary precautions taken.
General CNS effects: Given the predominant CNS effects of olanzapine, additional precautions should be taken when olanzapine is administered in combination with other centrally acting drugs, including alcohol. In vitro studies with dopamine antagonists have shown that olanzapine may antagonize the effects of direct and indirect dopamine agonists.
Seizures: Olanzapine should be used with caution in patients with a history of seizures or in patients with factors that lower the seizure threshold. Seizures have been reported uncommonly with olanzapine. In most of these cases, patients had a history of seizures or were at increased risk of seizures.
Tardive dyskinesia. In comparative clinical trials of 1 year or less duration, olanzapine was associated with a statistically significantly lower incidence of treatment-emergent dyskinesia. Because of the increased risk of tardive dyskinesia with long-term use of antipsychotics, coordinated dose reduction or discontinuation of the drug is necessary if a patient develops signs or symptoms of tardive dyskinesia. These symptoms may worsen over time or even recur after discontinuation of treatment.
Orthostatic hypotension: Orthostatic hypotension has been reported uncommonly in elderly patients in clinical trials. Periodic blood pressure monitoring is recommended in patients 65 years of age and older when using olanzapine.
Sudden Cardiac Arrest: Postmarketing reports of sudden cardiac death have been reported in patients taking olanzapine. In a retrospective observational cohort study, the risk of sudden cardiac death was approximately twofold increased in patients taking olanzapine compared with patients not taking antipsychotics. The risk with olanzapine is consistent with that with the atypical antipsychotics included in the pooled analysis.
Olanzapine is not recommended for use in children and adolescents. In studies of patients aged 13-17 years, various adverse reactions were observed: weight gain, changes in metabolic parameters and increased prolactin levels (see sections 5.1 and 5.2).
Lactose. The drug contains lactose monohydrate, so it should not be used in patients with hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.
Use during pregnancy or breastfeeding
Pregnancy
There are no adequate and well-controlled studies of olanzapine in pregnant women. Patients should inform their physician if they are pregnant or intend to become pregnant while taking olanzapine. Because there is limited experience with olanzapine in pregnant women, olanzapine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus.
Neonates exposed to antipsychotic drugs (including olanzapine) during the third trimester of pregnancy are at risk of adverse reactions, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration after birth. Agitation, hypertension, hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders have been reported. Therefore, neonatal monitoring is necessary.
Breastfeeding period
In a study of healthy, breast-feeding women, olanzapine was detected in breast milk. The mean no-risk infant dose (mg/kg) was estimated to be 1.8% of the maternal dose (mg/kg). Patients are advised not to breast-feed their infants while taking olanzapine.
Fertility
The effect on fertility is unknown.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of olanzapine on the reaction rate when driving vehicles or operating other mechanisms have not been conducted. Since olanzapine may cause drowsiness and dizziness, patients should be warned about the dangers associated with the operation of machinery, including motor vehicles.
Method of administration and doses
Adults
Schizophrenia: The recommended starting dose of olanzapine is 10 mg once daily.
Manic episodes: The recommended starting dose of olanzapine as monotherapy is 15 mg/day or 10 mg/day in combination therapy (see section 5.1).
Prevention of recurrence in patients with bipolar disorder. The recommended starting dose is 10 mg daily. Patients with bipolar disorder who have been treated with olanzapine for the treatment of manic episodes should continue to receive olanzapine at the same dose for the prevention of recurrence. If a new manic, depressive or mixed episode occurs, treatment should be continued (with dose adjustment if necessary) together with maintenance therapy for the treatment of mood symptoms, if clinically indicated.
Treatment of schizophrenia, manic episodes and prevention of relapse in bipolar disorder. The daily dose is determined based on clinical status in the range of 5 to 20 mg per day. Increases in the recommended initial dose should be carried out at intervals of at least 24 hours only after clinical examination. Olanzapine should be used regardless of food intake, since food intake does not affect the absorption of the drug. When discontinuing the drug, therapy should be discontinued gradually.
Elderly patients: A lower starting dose (5 mg/day) is usually not necessary. A lower starting dose should be considered for patients aged 65 years and older if clinically indicated (see section 4.4).
Patients with renal and/or hepatic impairment. A lower initial dose (5 mg/day) may be considered in such patients. In the presence of moderate hepatic impairment (cirrhosis, Child-Pugh class A or B), the initial dose should be 5 mg, and the dose should be increased with caution.
Patients who smoke: No dose adjustment is required based on smoking status.
Smoking may stimulate the metabolism of olanzapine. Clinical monitoring is recommended and, if necessary, an increase in the olanzapine dose may be considered (see section 4.5).
A lower starting dose may be considered in patients with a combination of factors (female gender, older age, non-smoking) that may reduce the metabolism of olanzapine. Dose escalation in these patients, if indicated, should be done conservatively (see sections 4.5 and 5.2).
Children
Olanzapine is not recommended for use in children under 18 years of age due to insufficient data on safety and efficacy. In short-term studies, adolescents were observed to have increased body weight, prolactin and lipid levels compared to adults (see sections 4.4, 4.8 and 5.1).
Overdose
Symptoms: Very common (>10% of cases) are tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and a reduced level of consciousness ranging from sedation to coma.
Other significant complications of overdose include delirium, seizures, coma, possible NMS, respiratory depression, aspiration, hypertension or hypotension, cardiac arrhythmia (<2% of overdoses), and cardiopulmonary shock. Fatalities have been reported with acute overdoses of 450 mg, but survival has been reported with acute overdoses of 2 g of olanzapine orally.
Treatment. There is no specific antidote for olanzapine. Induction of vomiting is not recommended. Standard overdose procedures are recommended (e.g. gastric lavage, administration of activated charcoal). Co-administration of activated charcoal has been shown to reduce the oral bioavailability of olanzapine by 50-60%.
Symptomatic treatment and monitoring of vital functions should be instituted as clinically indicated, including treatment of hypotension and circulatory failure, and respiratory support. Epinephrine, dopamine, and other sympathomimetics with beta-agonist properties should not be used, as beta-stimulation may exacerbate hypotension. Cardiovascular monitoring is necessary for the detection of possible arrhythmias. Close medical supervision and monitoring should continue until the patient has fully recovered.
Side effects
Brief description of the safety profile
Adults
The most common adverse reactions (seen in ≥1% of patients) associated with the use of olanzapine in clinical studies were: drowsiness, weight gain, eosinophilia, increases in prolactin, cholesterol, glucose and triglycerides in the blood (see section "Special instructions for use"), glycosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia (see section "Special instructions for use"), dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic increases in hepatic transaminases (see section "Special instructions for use"), rash, asthenia, fatigue, hyperthermia, arthralgia, increases in alkaline phosphatase, gamma-glutamyltransferase, uric acid, creatine phosphokinase and edema.
Tabulated list of adverse reactions
The table summarizes the main adverse reactions and laboratory findings identified during clinical trials and based on post-marketing experience.
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
The frequency of adverse reactions is classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency unknown (frequency cannot be estimated from the available data).
Very often
Often
Infrequently
Rarely
Frequency unknown
From the side of the hematopoietic and lymphatic systems
