Instructions for Olasin tablets 5 mg No. 28
Composition
active ingredient: olanzapine;
1 tablet contains 5 mg or 10 mg of olanzapine;
Excipients: calcium carbonate DC CS90 (calcium carbonate, pregelatinized corn starch, corn starch); lactose monohydrate; crospovidone (type A); aspartame; magnesium stearate.
Dosage form
Orodispersible tablets.
Main physicochemical properties:
5 mg tablets: round, yellow to pale yellow, biconvex tablets, engraved with "5" on one side.
10 mg tablets: round, yellow to pale yellow, biconvex tablets, engraved with "10" on one side.
Pharmacotherapeutic group
Antipsychotic drugs.
ATX code N05A H03.
Pharmacological properties
Pharmacodynamics.
Olanzapine is an antipsychotic, antimanic and mood-stabilizing drug with a broad spectrum of pharmacological effects mediated by a variety of receptors. Olanzapine has been shown in clinical studies to bind to serotonin 5HT2A/2C, 5HT3, 5HT6, dopamine D1, D2, D3, D4, D5, muscarinic M1-M5, adrenergic α1 receptors and histamine H1 receptors. Olanzapine has been shown to antagonize both serotonin 5HT, dopamine and cholinergic receptors in behavioral studies in animals treated with olanzapine. Olanzapine has a higher level of binding to serotonin 5HT2 receptors than to 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, while showing little effect on striatal (A9) pathways involved in motor function. Olanzapine inhibits the conditioned avoidance reflex, which indicates its antipsychotic activity at doses lower than those that cause catalepsy, which is a sign of motor side effects. Unlike some other antipsychotic drugs, olanzapine increases responses to stimuli in an anxiolytic test.
A single dose of 10 mg olanzapine was found to have higher binding to 5HT2A receptors than to dopamine D2 receptors in volunteers using positron emission tomography (PET). In addition, analysis of single-photon emission computed tomography (SPECT) images of patients with schizophrenia showed that olanzapine-sensitive patients had lower binding to striatal D2 receptors than other antipsychotic- and risperidone-sensitive patients compared with clozapine-sensitive patients.
Clinical efficacy.
It is known that in two of two placebo-controlled and two of three comparator-controlled studies involving more than 2,900 patients with schizophrenia with positive and negative symptoms, olanzapine showed statistically significant improvements in both negative and positive symptoms.
It is known that in an international double-blind comparative study involving 1484 patients with schizophrenia, schizoaffective disorder, and related disorders with varying degrees of impairment associated with depressive symptoms (16.6 points on the Montgomery-Asberg Depression Scale), a prospective secondary study from the beginning to the 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 patients with manic or mixed episodes in bipolar disorder, olanzapine was superior to placebo and divalproex in reducing manic symptoms over 3 weeks. Olanzapine was also comparable to haloperidol in terms of the proportion of patients in symptomatic remission from mania and depression at 6 and 12 weeks of treatment. In a study, olanzapine 10 mg added to lithium or valproate for 2 weeks resulted in a significant reduction in manic symptoms compared with lithium or valproate alone after 6 weeks.
It is known that 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 receive olanzapine or placebo, olanzapine demonstrated a statistically significant advantage over placebo in 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.
It is known that in an 18-month study of concomitant treatment of manic or mixed episodes, patients were stabilized with olanzapine, lithium or valproate was used as a mood stabilizer, long-term concomitant treatment with olanzapine with lithium or valproate did not establish a statistically significant advantage over lithium or valproate monotherapy and the postponement of relapses of bipolar disorders defined according to 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 than adults. Data on maintenance of treatment effect and long-term studies are limited.
Pharmacokinetics.
Absorption.
The drug is well absorbed after oral administration, Cmax in blood plasma is reached after 5-8 hours. The absorption of olanzapine is not affected by food intake. The absolute bioavailability of the oral form of olanzapine compared with intravenous administration has not been established.
Distribution.
The level of binding of olanzapine to plasma proteins was approximately 93% for concentrations ranging from 7 ng/mL 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. Cytochrome P450 isoenzymes CYP1A2 and 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 of olanzapine in volunteers varied depending on age and gender.
In healthy elderly volunteers (65 years of age and older), the mean elimination half-life was longer (51.8 vs. 33.8 hours) and plasma clearance was reduced (17.5 vs. 18.2 l/h) compared to younger volunteers. The pharmacokinetic variability observed in elderly volunteers is within the range observed in younger volunteers. In 44 schizophrenic patients >65 years of age, dosing from 5 to 20 mg/day was not associated with any distinctive adverse event profile.
In women compared to men, the mean half-life was longer (36.7 vs. 32.3 hours) and plasma clearance was reduced (18.9 vs. 27.3 L/h). However, olanzapine (5–20 mg) showed a comparable safety profile in both women (N = 467) and men (N = 869).
Patients with renal failure.
In patients with renal impairment (creatinine clearance < 10 mL/min) compared to healthy volunteers, there was no significant difference in mean elimination half-life (37.7 vs. 32.4 hours) or plasma clearance (21.2 vs. 25.0 L/h). Studies have shown that approximately 57% of radiolabeled olanzapine is present in the urine, primarily as metabolites.
Patients with liver failure.
It is known that in a study of the effect of hepatic insufficiency in 6 patients with clinically significant cirrhosis (Child-Pugh class A (n = 5) and B (n = 1)), a minor effect on the pharmacokinetics of oral olanzapine (single dose 2.5-7.5 mg) was found: Patients with mild to moderate hepatic impairment had slightly increased systemic clearance and a faster elimination time compared to patients with no hepatic impairment (n = 3). In patients with mild hepatic impairment who were smokers, the mean elimination half-life was longer (4/6; 67%) compared to patients without hepatic impairment who were non-smokers (0/3; 0%).
Patients who smoke.
In non-smokers compared to smokers (men and women), the mean half-life was longer (38.6 vs. 30.4 hours) and plasma clearance was reduced (18.6 vs. 27.7 L/h).
Olanzapine plasma clearance is lower in elderly patients compared to young patients, in women compared to men, and in non-smokers compared to smokers. However, the magnitude of the influence of factors such as age, gender, and smoking status on olanzapine plasma clearance and half-life is likely to be small compared to the overall interindividual variability.
It is known that no differences in the pharmacokinetics of olanzapine were found in studies involving European, Japanese, and Chinese patients.
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 effective in maintaining clinical improvement during long-term therapy in patients with an initial response to treatment.
Olanzapine is indicated for the treatment of moderate to severe manic episode.
In patients with bipolar disorder whose manic episode responds to olanzapine treatment, the drug should be used to prevent relapse.
Contraindication
Hypersensitivity to the active substances or to any of the inactive ingredients of the medicinal product. 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 that have a potential impact on olanzapine.
Since olanzapine is metabolized by the CYP1A2 isoenzyme, substances that specifically induce or inhibit this isoenzyme may affect the pharmacokinetics of olanzapine.
CYP1A2 inducers.
The metabolism of olanzapine may be induced by smoking and 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 are recommended.
CYP1A2 inhibitors.
Fluvoxamine, a specific CYP1A2 inhibitor, significantly reduces the metabolism of olanzapine. This results in a mean increase in Cmax after fluvoxamine of 54% in non-smoking women and 77% in smoking men. The mean increase in olanzapine AUC is 52% and 108%, respectively. Patients taking fluvoxamine or any other CYP1A2 inhibitors, such as ciprofloxacin, should be given a reduced dose of olanzapine. A reduced dose of olanzapine should be considered if treatment with a CYP1A2 inhibitor is initiated.
Reduced bioavailability.
Administration of activated charcoal reduced the oral bioavailability of ingested olanzapine by 50–60% and should be administered within 2 hours before or 2 hours after olanzapine administration.
Fluoxetine (a CYP2D6 inhibitor), a single dose of antacids containing aluminum and magnesium, or cimetidine did not significantly affect the pharmacokinetics of olanzapine.
Olanzapine may affect other medicines.
Olanzapine may antagonize the effects of direct and indirect dopamine agonists.
Olanzapine did not inhibit the major cytochrome P450 isoenzymes (e.g. CYP1A2, CYP2D6, CYP2C9, CYP2C19, CYP3A4) 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 (mainly represented by the CYP2D6 isoenzyme), warfarin (CYP2C9), theophylline (CYP1A2) or diazepam (CYP3A4 and CYP2C19).
No interactions of olanzapine were observed when administered 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 CNS activity
Olanzapine should be used with caution in patients taking ethanol or drugs that may cause central nervous system (CNS) depression.
Concomitant use of olanzapine with antiparkinsonian drugs is not recommended in patients with Parkinson's disease and dementia.
QTc interval.
Caution should be exercised when prescribing olanzapine with other drugs with a known risk of prolonging the QTc interval.
Application features
During treatment with antipsychotics, clinical improvement may take from a few days to a few weeks. During this period, patients should be closely monitored.
Psychosis associated with dementia and/or behavioral disorders.
Cerebrovascular adverse reactions (stroke, transient ischemic attack), including fatal outcomes, were observed in clinical trials. The incidence of cerebrovascular adverse reactions was 3-fold higher in patients treated with olanzapine compared to 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 psychosis associated with dopamine agonists. Concomitant use of olanzapine and antiparkinsonian medicinal products is not recommended in patients with Parkinson's disease and dementia. In clinical trials, worsening of Parkinson's disease symptoms and hallucinations were very common, more frequently than with placebo; olanzapine was not more effective than placebo in the treatment of psychotic symptoms. From the outset of these studies, patients were required to continue on the lowest effective dose of antiparkinsonian medicinal products (dopamine agonists) and to continue on the same antiparkinsonian medicinal products and doses throughout the study. Olanzapine was initiated at a dose of 2.5 mg/day and titrated to a maximum of 15 mg/day.
Neuroleptic malignant syndrome. Neuroleptic malignant syndrome (NMS) is a potentially fatal symptom complex described in association with antipsychotic drugs. Rare cases of NMS have been reported with olanzapine. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, loss of consciousness, and symptoms of cardiac instability (irregular pulse or blood pressure changes, 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. Pre-existing weight gain, which may be a risk factor, has been reported occasionally.
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 signs and 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, 8 weeks, and 12 weeks, and quarterly thereafter.
Lipid changes: Undesirable changes in lipid levels may occur in patients treated with olanzapine. Lipid changes should be managed appropriately in patients with dyslipidemia and in patients with risk factors for lipid disorders. Patients treated with antipsychotics, including olanzapine, should have their blood lipid levels monitored regularly, for example at baseline, after 12 weeks, and every 5 years thereafter.
Anticholinergic activity: In vitro clinical studies have shown a low incidence of anticholinergic effects. 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.
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 event when valproate is used concomitantly with olanzapine.
Discontinuation of therapy: Acute symptoms have been reported rarely (≥ 0.01% and 0.1%) upon abrupt discontinuation of therapy, including excessive sweating, insomnia, tremor, irritability, nausea, or vomiting.
QT interval: In clinical studies, olanzapine did not cause long-term prolongation of the absolute QT and QTc intervals. However, as with other antipsychotics, caution should be exercised when olanzapine is administered in combination with drugs that may prolong the QTc interval, especially in the elderly, 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 with other centrally acting drugs, including alcohol. Olanzapine exhibits dopamine antagonism in vitro and may theoretically antagonize the effects of levodopa and dopamine agonists, as with other antipsychotics.
Seizures. Olanzapine should be used with caution in patients with a history of seizures or in patients susceptible to 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 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, a 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 reappear after treatment is discontinued.
Orthostatic hypotension: Orthostatic hypotension has been reported uncommonly in elderly patients in clinical trials. As with other antipsychotics, periodic blood pressure monitoring is recommended in patients aged 65 years and older when olanzapine is used.
Sudden Cardiac Death: Cases of sudden cardiac death have been reported in postmarketing experience. In a retrospective observational cohort study, the risk of sudden cardiac death was approximately twofold increased in patients treated with olanzapine compared with patients not taking antipsychotics. The risk with olanzapine is consistent with that with the atypical antipsychotics included in the pooled analysis.
Children.
Olanzapine is not recommended for the treatment of children and adolescents.
Studies in patients aged 13–17 years have shown various adverse reactions, including weight gain, changes in metabolic parameters, and increased prolactin levels. The outcomes associated with these adverse events have not been studied and remain unknown.
The medicine contains lactose, therefore it should not be prescribed to patients with hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.
Aspartame: This medicine contains aspartame, a source of phenylalanine. It is harmful for people with phenylketonuria.
Use during pregnancy or breastfeeding
Pregnancy
Neonates exposed to antipsychotics (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, close monitoring of the neonate 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 if they are 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 speed 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 mechanisms, 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.
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 should be determined based on clinical status in the range of 5 to 20 mg per day. Increases in the recommended initial dose should be made at intervals of at least 24 hours only after clinical examination.
Olanzapine should be used without regard to meals, as food intake does not affect the absorption of the drug. When discontinuing the drug, therapy should be discontinued gradually.
Olanzapine orodispersible tablets should be placed in the mouth where they disperse rapidly in saliva and can be easily swallowed. It is difficult to remove the whole tablet from the mouth. Because the orodispersible tablets are fragile, they should be taken immediately after opening the blister. Alternatively, they may be dispersed in a glass of water or other suitable beverage (orange juice, apple juice, milk or coffee) immediately before use.
Olanzapine orodispersible tablets are bioequivalent to olanzapine film-coated tablets and have the same rate and extent of absorption. Olanzapine orodispersible tablets can be used as an alternative to olanzapine film-coated tablets.
Special population groups
Elderly patients: A lower starting dose (5 mg/day) is usually not necessary. A lower starting dose should be considered for patients over 65 years of age if clinically indicated.
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.
Smokers. No dose adjustment is necessary based on smoking status. The metabolism of olanzapine may be induced by smoking. Clinical monitoring is recommended and an increase in the olanzapine dose may be considered if necessary.
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 increases in these patients, if indicated, should be made gradually and with caution.
Children: Olanzapine is not recommended for use in children and adolescents below 18 years of age due to insufficient data on safety and efficacy. In short-term studies, weight gain, changes in prolactin and lipid levels were observed in adolescent patients compared to adults.
Overdose
Other significant complications of overdose include delirium, seizures, coma, possible neuroleptic malignant syndrome, 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. Drugs that induce vomiting are not recommended. Standard overdose procedures are recommended (e.g. gastric lavage, activated charcoal). Coadministration 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
The most common adverse reactions (occurring in ≥ 1% of patients) associated with the use of olanzapine in clinical trials were: somnolence, weight gain, eosinophilia, increases in prolactin, cholesterol, glucose and triglycerides, glycosuria, increased appetite, dizziness, akathisia, parkinsonism, leukopenia, neutropenia, dyskinesia, orthostatic hypotension, anticholinergic effects, transient asymptomatic elevations of hepatic transaminases, rash, asthenia, fatigue, hyperthermia, arthralgia, increases in alkaline phosphatase, gamma-glutamyltransferase, uric acid, creatine phosphokinase and edema.
The main adverse reactions and their frequencies identified in clinical trials and/or from post-marketing experience are summarized below.
Very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), frequency unknown (frequency cannot be estimated from the available data).
From the side of the hematopoietic and lymphatic system: often - eosinophilia, leukopenia10, neutropenia10; rarely - thrombocytopenia11.
Immune system disorders: uncommon – hypersensitivity11.
Metabolism and digestive disorders: very common - weight gain1; common - increased cholesterol2,3, increased glucose4, increased triglycerides2,5, glycosuria, increased appetite; uncommon - development or exacerbation of diabetes associated with ketoacidosis or coma, including fatal outcomes11; rare - hypothermia12.
Nervous system disorders: very common: drowsiness; common: dizziness, akathisia6, parkinsonism6, dyskinesia6; uncommon: history of or risk factors for epileptic seizures11, dystonia (including ocular symptoms)11, tardive dyskinesia11,
amnesia9, dysarthria, stuttering11, restless legs syndrome11; rarely – neuroleptic malignant syndrome12, withdrawal syndrome7,12.
Respiratory, thoracic and mediastinal disorders: uncommon – epistaxis9.
From the side of the cardiac system: infrequently - bradycardia, prolongation of the QTc interval; rarely - ventricular tachycardia/fibrillation, sudden death11.
Vascular disorders: very common: orthostatic hypotension10; uncommon: thromboembolism (including pulmonary embolism and deep vein thrombosis).
Gastrointestinal: common: mild, transient anticholinergic effects, including constipation and dry mouth; uncommon: abdominal distension9, salivary hypersecretion11; rare: pancreatitis11.
Hepatobiliary system: often - transient, asymptomatic fluctuations in the levels of hepatic transaminases (ALT and AST), especially at the beginning of treatment; rarely - hepatitis (including hepatocellular, cholestatic or mixed liver damage)11.
Skin and subcutaneous tissue disorders: common: rash; uncommon: photosensitivity reactions, alopecia; frequency unknown: drug reaction with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal and connective tissue disorders: common: arthralgia9; rare: rhabdomyolysis11.
Renal and urinary disorders: uncommon – urinary incontinence, urinary retention, difficulty urinating11.
Pregnancy, puerperium and perinatal period: frequency unknown - withdrawal syndrome in newborns.
From the reproductive system and mammary glands: often - erectile dysfunction in men, decreased libido in women and men; infrequently - amenorrhea, breast enlargement, galactorrhea in women,
