Carbamazepine-astrapharm
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARBAZEPIN-ASTRAFARM (CARBAMAZEPINE-ASTRAFARM)
Composition:
Active substance: carbamazepine;
1 tablet contains|contains| carbamazepine| 200 mg;
Excipients: microcrystalline cellulose, povidone, magnesium stearate, sodium croscarmellose.
Pharmaceutical form. Tablets|tablets|.
Main physico-chemical|physico-chemical| properties: white or almost white tablets, round-shaped, with a biconvex surface and a score line on one side.
Pharmacotherapeutic group.
Antiepileptic drugs. ATC code N03A F01.
Pharmacological Properties.
Pharmacodynamics.
As an anticonvulsant agent, carbamazepine is effective in partial seizures (simple and complex), with or without secondary generalization, generalized tonic-clonic seizures, as well as in combinations of these seizure types.
The mechanism of action of carbamazepine has been only partially elucidated. Carbamazepine stabilizes membranes of overexcited nerve fibers, inhibits the occurrence of repetitive neuronal discharges, and reduces synaptic transmission of excitatory impulses. It has been established that the primary mechanism of action of the drug is prevention of the generation of sodium-dependent action potentials in depolarized neurons through blockade of sodium channels. The anticonvulsant effect of the drug is mainly due to reduced release of glutamate and stabilization of neuronal membranes, whereas the antimanic effect may be attributed to inhibition of dopamine and norepinephrine metabolism.
When carbamazepine is used as monotherapy in patients with epilepsy (especially in children), psychotropic effects have been observed, which partially manifest as a positive influence on symptoms of anxiety and depression, as well as reduced irritability and aggressiveness. According to several studies, the impact of carbamazepine on cognitive function and psychomotor performance was dose-dependent and either questionable or negative. However, in other studies, a positive effect of carbamazepine on parameters related to attention, learning ability, and memory has been noted.
As a neurotropic agent, carbamazepine is effective in certain neurological disorders. For example, it prevents painful attacks in idiopathic and secondary trigeminal neuralgia. Furthermore, the drug should be used to alleviate neuropathic pain in various conditions, including spinal cord tabes, post-traumatic paresthesias, and postherpetic neuralgia. In alcohol withdrawal syndrome, the drug increases the seizure threshold (which is reduced in this condition) and reduces the severity of clinical manifestations such as agitation, tremor, and gait disturbances. In patients with central diabetes insipidus, the drug reduces diuresis and thirst.
It has been confirmed that as a psychotropic agent, carbamazepine is effective in affective disorders, specifically: for treatment of acute manic states, and for maintenance therapy of bipolar affective (manic-depressive) disorders (as monotherapy or in combination with neuroleptics, antidepressants, or lithium salts).
Pharmacokinetics.
Absorption. After oral administration, carbamazepine is almost completely absorbed, although somewhat slowly. Following a single dose of a conventional tablet, maximum plasma concentration (Cmax) is reached within 12 hours. There are no clinically significant differences in the extent of absorption of the active substance after administration of different oral dosage forms of the drug. After a single 400 mg oral dose of carbamazepine, the mean Cmax of unchanged active substance reaches approximately 4.5 µg/mL.
The bioavailability of various oral formulations of carbamazepine ranges between 85–100%.
Food intake does not significantly affect the rate or extent of carbamazepine absorption.
Steady-state plasma concentrations are achieved within 1–2 weeks, depending on individual metabolic characteristics (autoinduction of hepatic enzyme systems by carbamazepine, heteroinduction by other concomitantly administered drugs), as well as the patient's condition, drug dosage, and duration of treatment. There are considerable interindividual differences in steady-state concentrations within the therapeutic range: in most patients, these values range from 4 to 12 µg/mL (17–50 µmol/L). Concentrations of carbamazepine-10,11-epoxide (a pharmacologically active metabolite) reach nearly 30% compared to carbamazepine concentrations.
The bioavailability of different carbamazepine formulations may vary; to avoid reduced bioavailability, risk of seizures, or excessive adverse effects, it may be advisable not to switch from one formulation to another.
Distribution. With complete absorption of carbamazepine, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg. Carbamazepine crosses the placental barrier. Plasma protein binding of carbamazepine is 70–80%. The concentration of unchanged drug in cerebrospinal fluid and saliva reflects the fraction unbound to plasma proteins (20–30%). The concentration of carbamazepine in breast milk is 25–60% of its plasma level.
Metabolism. Carbamazepine is metabolized in the liver primarily via the epoxide pathway, resulting in the formation of main metabolites – the 10,11-trans-diol derivative and its glucuronic acid conjugate. The main isoenzyme responsible for biotransformation of carbamazepine into carbamazepine-10,11-epoxide is cytochrome P450 3A4. These metabolic reactions also produce a "minor" metabolite – 9-hydroxymethyl-10-carbamoylacridan. After a single oral dose of carbamazepine, approximately 30% of the active substance is excreted in urine as end products of epoxide metabolism. Other important pathways of carbamazepine biotransformation lead to the formation of various monohydroxylated derivatives, as well as the N-glucuronide of carbamazepine, formed with the participation of uridyl diphosphate-glucuronosyltransferase (UGT2B7).
Elimination. After a single oral dose, the mean elimination half-life of unchanged carbamazepine is approximately 36 hours; after repeated administration, it is on average 16–24 hours (due to autoinduction of hepatic monoxygenase systems), depending on duration of treatment. In patients who are concurrently taking other drugs that induce the same hepatic enzyme system (e.g., phenytoin, phenobarbital), the elimination half-life of carbamazepine is on average 9–10 hours.
The mean elimination half-life of the 10,11-epoxide metabolite from plasma is approximately 6 hours after a single oral dose of the epoxide.
After a single 400 mg oral dose of carbamazepine, 72% of the administered dose is excreted in urine and 28% in feces. Nearly 2% of the administered dose is excreted in urine as unchanged drug, and approximately 1% as the pharmacologically active metabolite 10,11-epoxide.
Pharmacokinetic characteristics in specific patient populations
Children. Due to faster elimination of carbamazepine in children, higher doses (mg/kg body weight) may be required to maintain therapeutic concentrations compared to adults.
Elderly patients. There are no data indicating that the pharmacokinetics of carbamazepine differ in elderly patients compared to younger adults.
Patients with renal or hepatic impairment. Data on the pharmacokinetics of carbamazepine in patients with renal or hepatic dysfunction are currently unavailable.
Clinical characteristics.
Indications.
- Epilepsy:
- complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization;
- generalized tonic-clonic seizures;
- mixed forms of seizures.
CARBAMAZEPINE-ASTRAFARM may be used both as monotherapy and as part of combination therapy.
- Acute manic states; maintenance therapy in bipolar affective disorders to prevent exacerbations or to reduce clinical manifestations of an episode.
- Alcohol withdrawal syndrome.
- Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical forms).
- Idiopathic glossopharyngeal neuralgia.
Contraindications.
Hypersensitivity to carbamazepine or to structurally related medicinal products (such as tricyclic antidepressants), or to any other component of the drug.
Atrioventricular block.
History of bone marrow depression.
Hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria) in medical history.
Concomitant use with monoamine oxidase inhibitors (MAO inhibitors).
Interaction with other medicinal products and other types of interactions.
Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing the formation of the active metabolite of carbamazepine—10,11-epoxide. Concomitant use of CYP3A4 inhibitors may increase plasma concentrations of carbamazepine, which in turn may lead to the development of adverse reactions. Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, potentially reducing plasma concentrations of carbamazepine and its therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, leading to increased plasma levels of carbamazepine.
Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II hepatic enzyme systems; therefore, it may reduce plasma concentrations of other drugs primarily metabolized by CYP3A4 through induction of their metabolism.
Carbamazepine may increase the metabolism of certain hormonal contraceptives (via CYP3A4 induction), such as oral and subdermal implanted contraceptives, resulting in significantly lower hormone plasma concentrations. This may lead to contraceptive failure or breakthrough bleeding. Alternative methods to oral and subdermal implanted contraceptives, which are significantly affected by CYP3A4 induction, should be considered; or alternatively, consider replacing carbamazepine with another medicinal product.
Human microsomal epoxide hydrolase is the enzyme responsible for the formation of 10,11-trans-dihydrodiol derivatives from carbamazepine-10,11-epoxide. Concomitant use of inhibitors of human microsomal epoxide hydrolase may lead to increased plasma concentrations of carbamazepine-10,11-epoxide.
Medicinal products that may increase plasma levels of carbamazepine
Since increased plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), dosage adjustment of CARBAMAZEPINE-ASTRAFARM and/or monitoring of its plasma levels are required when used concomitantly with the following medicinal products.
Analgesics, anti-inflammatory agents: dextropropoxyphene, ibuprofen.
Androgens: danazol.
Antibiotics: macrolide antibiotics (e.g., erythromycin, troleandomycin, josamycin, clarithromycin, ciprofloxacin).
Antidepressants: desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.
Antiepileptic agents: stiripentol, vigabatrin.
Antifungal agents: azoles (e.g., itraconazole, ketoconazole, fluconazole, voriconazole). Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.
Antihistamines: loratadine, terfenadine.
Antipsychotic agents: olanzapine, loxapine, quetiapine.
Antituberculosis agents: isoniazid.
Antiviral agents: HIV protease inhibitors (e.g., ritonavir).
Carbonic anhydrase inhibitors: acetazolamide.
Cardiovascular agents: diltiazem, verapamil.
Gastrointestinal agents: cimetidine, omeprazole.
Muscle relaxants: oxybutynin, dantrolene.
Antiplatelet agents: ticlopidine.
Other substances: grapefruit juice, nicotinamide (in adults, only at high doses).
Medicinal products that may increase plasma levels of the active metabolite carbamazepine-10,11-epoxide
Since increased plasma levels of carbamazepine-10,11-epoxide may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), the dose of CARBAMAZEPINE-ASTRAFARM should be appropriately adjusted and/or its plasma levels monitored when used concomitantly with the following medicinal products.
Antiepileptic agents: progabide, valproic acid, valnoctamide, valpromide, primidone, brivaracetam.
Medicinal products that may reduce plasma levels of carbamazepine
Dose adjustment of CARBAMAZEPINE-ASTRAFARM may be necessary when used concomitantly with the following medicinal products.
Antiepileptic agents: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic carbamazepine concentrations, it is recommended to adjust phenytoin plasma concentrations to 13 µg/mL prior to initiating carbamazepine therapy), fosphenytoin, primidone, and clonazepam (although data are conflicting).
Antineoplastic agents: cisplatin or doxorubicin.
Antituberculosis agents: rifampicin.
Bronchodilators or antiasthmatic agents: theophylline, aminophylline.
Dermatological agents: isotretinoin.
Interaction with other substances: herbal medicinal products containing St. John’s wort (Hypericum perforatum).
Mefloquine may exhibit antagonistic properties towards the antiepileptic effect of CARBAMAZEPINE-ASTRAFARM. Therefore, the dose of CARBAMAZEPINE-ASTRAFARM should be adjusted accordingly.
Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; therefore, plasma concentrations of carbamazepine should be monitored.
Effect of CARBAMAZEPINE-ASTRAFARM on plasma levels of concomitantly administered medicinal products
Carbamazepine may reduce plasma levels of certain drugs and diminish or nullify their effects. Dose adjustment of the following medicinal products may be necessary according to clinical requirements.
Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long-term concomitant use of carbamazepine with paracetamol (acetaminophen) may be associated with hepatotoxicity), phenazone (antipyrine), tramadol.
Antibiotics: doxycycline, rifabutin.
Anticoagulants: oral anticoagulants (e.g., warfarin, phenprocoumon, dicoumarol, acenocoumarol).
Antidepressants: bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline, clomipramine).
Antiemetics: aprepitant.
Antiepileptic agents: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Both increased and decreased plasma levels of phenytoin have been reported under the influence of carbamazepine, as well as isolated cases of increased plasma levels of methadone.
Antifungal agents: itraconazole, voriconazole, ketoconazole. Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.
Anthelmintic agents: praziquantel, albendazole.
Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.
Neuroleptic agents: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone.
Antiviral agents: HIV protease inhibitors (e.g., indinavir, ritonavir, saquinavir).
Anxiolytics: alprazolam, midazolam.
Bronchodilators or antiasthmatic agents: theophylline.
Contraceptives: hormonal contraceptives (alternative methods of contraception should be considered).
Cardiovascular agents: calcium channel blockers (dihydropyridine group), e.g., felodipine, isradipine, digoxin, quinidine, propranolol, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.
Corticosteroids: particularly prednisolone, dexamethasone.
Agents used for erectile dysfunction treatment: tadalafil.
Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.
Thyroid agents: levothyroxine.
Interaction with other agents: products containing estrogens and/or progestogens (alternative methods of contraception should be considered); buprenorphine, gestrinone, tibolone, toremifene, mianserin, sertraline.
Combinations requiring special consideration
Concomitant use of carbamazepine and levetiracetam may increase carbamazepine toxicity.
Concomitant use of carbamazepine and isoniazid may increase isoniazid hepatotoxicity.
Concomitant use of carbamazepine with lithium preparations or metoclopramide, as well as carbamazepine with neuroleptics (haloperidol, thioridazine), may increase adverse neurological effects (even at therapeutic plasma levels in the case of the latter combination).
Combined therapy with CARBAMAZEPINE-ASTRAFARM and certain diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.
Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g., pancuronium). Increased doses of these agents may be required, and patients need careful monitoring due to the possibility of faster-than-expected termination of neuromuscular blockade.
Carbamazepine, like other psychotropic agents, may reduce tolerance to alcohol; therefore, patients are advised to abstain from alcohol consumption.
Contraindicated interaction
Since carbamazepine is structurally similar to tricyclic antidepressants, CARBAMAZEPINE-ASTRAFARM is not recommended for concomitant use with MAO inhibitors; treatment with an MAO inhibitor must be discontinued at least 2 weeks (or earlier, if clinically appropriate) before starting carbamazepine.
Effect on serological tests
Carbamazepine may yield false-positive results in HPLC (high-performance liquid chromatography) assays for determination of perphenazine concentration.
Carbamazepine and 10,11-epoxide may yield false-positive results in immunoassays using fluorescence polarization methodology for determination of tricyclic antidepressant concentrations.
Special precautions for use.
CARBAMAZEPINE-ASTRAFARM should be prescribed only under medical supervision, after careful assessment of the benefit/risk ratio, and with strict monitoring of patients with cardiac, hepatic, or renal disorders, patients with a history of hematological adverse reactions to other drugs, and patients with interrupted courses of carbamazepine therapy.
General urine analysis and blood urea nitrogen levels should be performed at the beginning and periodically during therapy.
CARBAMAZEPINE-ASTRAFARM exhibits mild anticholinergic activity; therefore, patients with elevated intraocular pressure should be warned and advised about possible risk factors.
One should bear in mind the possibility of activation of latent psychoses, and in elderly patients — possible activation of confusion and anxious agitation.
The drug is generally ineffective in absence seizures (petit mal seizures) and myoclonic seizures. There are isolated reports indicating that seizure exacerbation may occur in patients with atypical absences.
Hematological effects. Agranulocytosis and aplastic anemia have been associated with the use of the drug; however, due to the extremely low incidence of these conditions, it is difficult to assess the actual risk of developing such conditions during treatment with CARBAMAZEPINE-ASTRAFARM. The overall risk in untreated patients is 4.7 cases per 1,000,000 per year for agranulocytosis and 2 cases per 1,000,000 per year for aplastic anemia.
Patients should be informed about early signs of toxicity and symptoms of possible hematological disorders, as well as symptoms of dermatological and hepatic reactions. Patients should be warned that if any of the following reactions occur — fever, sore throat, skin rash, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura — they should immediately consult a physician.
If leukocyte or platelet counts significantly decrease during therapy, the patient's condition should be closely monitored, and regular complete blood counts should be performed. Treatment with CARBAMAZEPINE-ASTRAFARM should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical symptoms such as fever or sore throat. The use of CARBAMAZEPINE-ASTRAFARM should be discontinued upon signs of bone marrow suppression.
Transient or persistent reduction in platelet or white blood cell counts has been reported in association with the use of CARBAMAZEPINE-ASTRAFARM. However, in most cases, these effects were transient and did not indicate the development of aplastic anemia or agranulocytosis. Blood tests, including platelet count (and possibly reticulocyte count and hemoglobin level), should be performed before starting therapy and periodically during treatment.
Serious dermatological reactions. Serious dermatological reactions, including toxic epidermal necrolysis (TEN) or Lyell's syndrome, and Stevens-Johnson syndrome (SJS), occur very rarely with the use of CARBAMAZEPINE-ASTRAFARM. Patients with serious dermatological reactions may require hospitalization, as these conditions can be life-threatening and fatal. Most cases of SJS/TEN occur within the first few months of treatment with CARBAMAZEPINE-ASTRAFARM. If signs indicating serious dermatological reactions (e.g., SJS, Lyell's syndrome/TEN) develop, the use of CARBAMAZEPINE-ASTRAFARM should be immediately discontinued and alternative therapy initiated.
Pharmacogenomics.
There is increasing evidence of the influence of different HLA alleles on a patient's susceptibility to immune-related adverse reactions.
Association with (HLA)-B*1502
Retrospective studies in Han Chinese patients have demonstrated a strong correlation between skin reactions (SJS/TEN) associated with carbamazepine and the presence of human leukocyte antigen (HLA) allele (HLA)-B*1502 in these patients. A higher frequency of SJS (rare rather than very rare) has been reported in certain Asian countries (e.g., Taiwan, Malaysia, and the Philippines), where the (HLA)-B*1502 allele is prevalent in the population. The frequency of carriers of this allele among the Asian population is over 15% in the Philippines, Thailand, Hong Kong, and Malaysia, approximately 10% in Taiwan, nearly 4% in Northern China, about 2% to 4% in South Asia (including India), and less than 1% in Japan and Korea. The prevalence of the (HLA)-B*1502 allele is negligible among European and African populations, Native Americans, and Latin American populations.
For patients considered genetically at risk, testing for the presence of the (HLA)-B*1502 allele should be performed before initiating treatment with CARBAMAZEPINE-ASTRAFARM. If the patient tests positive for the (HLA)-B*1502 allele, treatment with CARBAMAZEPINE-ASTRAFARM should not be initiated, except when no other treatment options are available. Patients who have been tested and found negative for (HLA)-B*1502 have a low risk of developing SJS, although such reactions may still very rarely occur.
Currently, due to lack of data, it is not precisely known whether all individuals of Southeast Asian origin are at risk.
The (HLA)-B*1502 allele may be a risk factor for SJS/TEN in Chinese patients receiving other antiepileptic drugs that may be associated with SJS/TEN. Therefore, the use of other drugs potentially associated with SJS/TEN should be avoided in patients carrying the (HLA)-B*1502 allele, if alternative therapy is available. Genetic screening is generally not recommended for patients of ethnicities with a low frequency of the (HLA)-B*1502 allele. Screening is generally not recommended for patients already receiving CARBAMAZEPINE-ASTRAFARM, as the risk of SJS/TEN is largely confined to the first few months, regardless of the presence of the (HLA)-B*1502 allele in the patient's genes.
In Caucasian patients, there is no association between the (HLA)-B*1502 allele and the development of SJS.
Association with HLA-A*3101
Human leukocyte antigen may be a risk factor for skin adverse reactions such as SJS, TEN, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and maculopapular rash. If testing reveals the presence of the HLA-A*3101 allele, the use of CARBAMAZEPINE-ASTRAFARM should be avoided.
Limitations of genetic screening
Results of genetic screening should not replace appropriate clinical monitoring and management of patients. Other potential factors, such as antiepileptic drug dosage, adherence to therapy, and concomitant medications, may also play a role in the development of these severe skin adverse reactions. The impact of other diseases and the level of dermatological monitoring has not been studied.
Other dermatological reactions
Transient and non-life-threatening mild dermatological reactions, such as isolated macular or maculopapular exanthema, may also occur. These usually resolve within a few days or weeks, either with continued dosing or after dose reduction. Since early signs of more serious dermatological reactions may be difficult to distinguish from mild transient reactions, patients should be closely monitored so that the drug can be immediately discontinued if the reaction worsens with continued use.
The presence of the HLA-A*3101 allele is associated with less severe skin adverse reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or mild rashes (maculopapular eruptions). However, the presence of (HLA)-B*1502 has not been established as a predictor of the aforementioned skin reactions.
Hypersensitivity. CARBAMAZEPINE-ASTRAFARM may provoke hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), multiple delayed hypersensitivity reactions with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, altered liver function tests, and vanishing bile duct syndrome (including destruction and disappearance of intrahepatic bile ducts), which may manifest in various combinations. Other organs may also be affected (lungs, kidneys, pancreas, myocardium, colon).
The presence of the HLA-A*3101 allele in patients is associated with less severe skin adverse reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or mild rashes (maculopapular eruptions).
Patients with hypersensitivity reactions to carbamazepine should be informed that approximately 25–30% of such patients may also have hypersensitivity reactions to oxcarbazepine (Trileptal®).
Cross-hypersensitivity may occur with the use of carbamazepine and phenytoin.
If signs indicating hypersensitivity appear, the use of CARBAMAZEPINE-ASTRAFARM should be immediately discontinued.
Seizures. CARBAMAZEPINE-ASTRAFARM should be used with caution in patients with mixed seizure types, including absences (typical or atypical). Under such circumstances, the drug may provoke seizures. If seizures are provoked, the use of CARBAMAZEPINE-ASTRAFARM should be immediately discontinued.
An increase in seizure frequency may occur when switching from oral formulations to suppositories.
Liver function. Liver function should be assessed at baseline and during therapy, especially in patients with a history of liver disease and in elderly patients. In case of acute worsening of liver function or in patients with active liver disease, the drug should be immediately discontinued.
Some laboratory parameters used to assess liver function may exceed normal limits in patients taking carbamazepine, particularly gamma-glutamyl transferase (GGT). This is likely due to induction of hepatic enzymes. Enzyme induction may also lead to a moderate increase in alkaline phosphatase levels. Such an increase in hepatic metabolic activity is not an indication for discontinuation of carbamazepine.
Severe hepatic reactions due to carbamazepine use are very rare. In case of signs of liver dysfunction or active liver disease, the patient should be urgently evaluated, and treatment with CARBAMAZEPINE-ASTRAFARM should be suspended until test results are obtained.
Renal function. Assessment of renal function and blood urea nitrogen levels is recommended at the beginning and periodically during the course of therapy.
Hyponatremia. Cases of hyponatremia have been reported with the use of carbamazepine. In patients with pre-existing renal dysfunction associated with low sodium levels, or in patients receiving concomitant medications that reduce sodium levels (such as diuretics or drugs associated with inappropriate antidiuretic hormone secretion), serum sodium levels should be measured before treatment. Subsequently, sodium levels should be measured every 2 weeks, then monthly during the first 3 months of treatment, or as clinically necessary. This is particularly important for elderly patients. In such cases, water intake should be limited.
Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations; therefore, an increase in the dose of thyroid hormone replacement therapy may be necessary for patients with hypothyroidism.
Anticholinergic effects. CARBAMAZEPINE-ASTRAFARM exhibits moderate anticholinergic activity. Therefore, patients with elevated intraocular pressure or urinary retention should be closely monitored during therapy.
Psychiatric effects. One should bear in mind the possibility of activation of latent psychosis, and in elderly patients — confusion or agitation.
Suicidal thoughts and behavior. There have been several reports of suicidal thoughts and behavior in patients receiving antiepileptic drugs. Data from clinical trials of antiepileptic drugs showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude an increased risk of suicidal thoughts and behavior with carbamazepine.
Therefore, patients should be monitored for suicidal thoughts and behavior, and appropriate treatment should be initiated if necessary. Patients (and caregivers) should be advised to seek medical advice if signs of suicidal thoughts or behavior occur.
Endocrine effects. Due to hepatic enzyme induction, carbamazepine may reduce the therapeutic effect of estrogen and/or progesterone-containing drugs. This may lead to reduced contraceptive efficacy, symptom recurrence, breakthrough bleeding, or spotting. Women receiving CARBAMAZEPINE-ASTRAFARM who require hormonal contraception should use a preparation containing at least 50 mcg of estrogen, or alternative non-hormonal contraceptive methods should be considered for such patients.
Monitoring of plasma drug levels. Although the correlation between dosage and plasma carbamazepine levels, as well as between plasma carbamazepine levels and clinical efficacy and tolerability, is not well established, monitoring plasma drug levels may be useful in the following cases: sudden increase in seizure frequency, assessment of patient compliance, during pregnancy, in pediatric treatment; in suspected malabsorption, suspected toxicity, and when multiple drugs are used.
Dose reduction and discontinuation of the drug. Sudden discontinuation of CARBAMAZEPINE-ASTRAFARM may provoke seizures. If abrupt discontinuation of the drug is necessary, patients with epilepsy should be transitioned to a new antiepileptic drug while continuing appropriate medication (e.g., intravenous, rectal diazepam, or intravenous phenytoin).
Dose reduction and withdrawal syndrome. Sudden discontinuation of the drug may provoke seizures; therefore, carbamazepine should be discontinued gradually over 6 months. If immediate discontinuation is necessary, transition to a new antiepileptic drug should be performed while continuing appropriate medication.
Women of childbearing age
Carbamazepine may harm the fetus when used during pregnancy.
Pregnancy registries and epidemiological data indicate a potential association between carbamazepine use during pregnancy and serious congenital malformations, including neural tube defects and malformations of other organ systems (e.g., craniofacial defects and cardiovascular malformations). These data suggest that the prevalence of teratogenic effects associated with antiepileptic drugs may be higher with combination therapy compared to monotherapy. (See section "Use during pregnancy or breastfeeding")
Unless a careful evaluation of alternative treatment options concludes that benefits outweigh risks, carbamazepine should not be used in women of childbearing age.
Women of childbearing age should be fully informed about the potential risk to the fetus if they take carbamazepine during pregnancy.
Before initiating carbamazepine treatment, a pregnancy test should be considered in women of childbearing potential.
Women of childbearing age should use effective contraception during treatment and for two weeks after discontinuation of treatment. Due to enzyme induction, carbamazepine may impair the therapeutic effect of hormonal contraceptives; therefore, women of childbearing age should consult their physician about using other effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or breastfeeding").
Women of childbearing age should consult their physician if they plan pregnancy to discuss transitioning to alternative treatment before conception and discontinuation of contraception (see section "Use during pregnancy or breastfeeding").
Women of childbearing age should be advised to seek medical advice immediately if they become pregnant or suspect they may be pregnant while taking carbamazepine.
Use during pregnancy or breastfeeding.
Pregnancy
General risks associated with antiepileptic drugs
All women of childbearing age receiving antiepileptic therapy, especially those planning pregnancy and pregnant women, should receive medical advice regarding the potential risk to the fetus from seizures and antiepileptic drugs.
Abrupt discontinuation of antiepileptic drugs should be avoided, as this may lead to seizures, which may have serious consequences for the woman and the unborn child.
If possible, monotherapy is preferred for the treatment of epilepsy during pregnancy, as therapy with multiple antiepileptic drugs may be associated with a higher risk of congenital malformations.
Risks associated with carbamazepine
Carbamazepine crosses the placental barrier. Prenatal exposure to carbamazepine may increase the risk of congenital malformations and other adverse developmental outcomes. The impact of carbamazepine during pregnancy is associated with a 2–3 times higher frequency of serious malformations compared to the general population, where the frequency is 2–3%. Such malformations as fetal neural tube defects, craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, hypoplasia of fingers, and other anomalies affecting various fetal organ systems have been reported in mothers who used carbamazepine during pregnancy. Specialized prenatal monitoring for these malformations is recommended. Neurodevelopmental disorders have been reported in children born to women with epilepsy who used carbamazepine alone or in combination with other antiepileptic drugs during pregnancy. Studies on the risk of neurodevelopmental disorders in children exposed to carbamazepine during pregnancy are conflicting, and the risk cannot be excluded.
Unless a careful evaluation of alternative treatment options concludes that benefits outweigh risks, carbamazepine should not be used during pregnancy. The woman should be fully informed and understand the risks of taking carbamazepine during pregnancy.
Data suggest that the risk of malformations with carbamazepine use may be dose-dependent. If, after careful benefit/risk assessment, no suitable alternative treatment is available and carbamazepine therapy is continued, the drug should be used as monotherapy at the lowest effective dose. Monitoring of plasma drug levels is also recommended. Plasma concentrations can be maintained in the lower part of the therapeutic range (4–12 mcg/mL), provided seizure control is maintained.
It has been reported that some antiepileptic drugs, including carbamazepine, reduce serum folate levels. This deficiency may increase the frequency of congenital malformations in children born to mothers with epilepsy. Folic acid supplementation is recommended before and during pregnancy. To prevent coagulation disorders in the newborn, vitamin K1 is also recommended for the mother during the last weeks of pregnancy and for the newborn.
If a woman plans pregnancy, all efforts should be made before conception and discontinuation of contraception to transition to appropriate alternative treatment. If a woman becomes pregnant while taking carbamazepine, she should be referred to a specialist to reassess the treatment method and consider alternative options.
Women of childbearing age
Carbamazepine should not be used in women of childbearing age, except when the potential benefit outweighs the risks compared to alternative treatment options. The woman should be fully informed and understand the potential risk to the fetus if she takes carbamazepine during pregnancy; therefore, pregnancy planning in advance is important. Before initiating carbamazepine treatment, a pregnancy test should be considered in women of childbearing age.
Women of childbearing age should use effective contraception during and for two weeks after discontinuation of treatment. Due to enzyme induction, carbamazepine may impair the therapeutic effect of hormonal contraceptives (see section "Interaction with other medicinal products and other forms of interaction"), so women of childbearing age should consult their physician about using other effective contraceptive methods. At least one effective method of contraception (e.g., intrauterine) or two additional forms of contraception, including a barrier method, should be used. The choice of contraceptive method should consider individual circumstances, with patient involvement in the discussion.
In animal studies, administration of carbamazepine at clinically relevant doses during pregnancy resulted in developmental toxicity in the fetus, including increased incidence of fetal malformations.
Children born to mothers with epilepsy are predisposed to developmental disorders, including congenital malformations. It has been reported that carbamazepine, like most antiepileptic drugs, increases the frequency of these disorders, although convincing evidence from controlled monotherapy studies with carbamazepine is lacking. Also reported are intrauterine developmental disorders and congenital malformations associated with the use of CARBAMAZEPINE-ASTRAFARM, including spina bifida and other congenital anomalies, such as craniofacial defects, cardiovascular malformations, hypospadias, and developmental anomalies of various organ systems.
The following should be considered:
- use of CARBAMAZEPINE-ASTRAFARM in pregnant women with epilepsy requires special attention;
- if a woman receiving carbamazepine becomes pregnant, plans pregnancy, or during pregnancy there is a need to use CARBAMAZEPINE-ASTRAFARM, the potential benefit of the drug should be carefully weighed against the possible risk (especially in the first trimester);
- whenever possible, CARBAMAZEPINE-ASTRAFARM should be prescribed as monotherapy in women of childbearing age;
- the lowest effective doses should be prescribed, and plasma carbamazepine levels should be monitored;
- patients should be informed about the possible increased risk of congenital malformations and should be offered prenatal screening;
- effective antiepileptic therapy should not be interrupted during pregnancy, as disease exacerbation may endanger the health of both mother and child.
Monitoring and prevention. Folate deficiency may occur during pregnancy. Antiepileptic drugs may increase the risk of folate deficiency; therefore, additional folic acid supplementation is recommended before and during pregnancy.
Newborns. To prevent coagulation disorders in newborns, vitamin K1 is recommended for mothers during the last weeks of pregnancy and for newborns.
There have been several reports of seizures and/or respiratory depression in newborns, as well as several cases of vomiting, diarrhea, and/or poor appetite in newborns, associated with the use of carbamazepine and other anticonvulsant drugs.
Breastfeeding. Carbamazepine passes into breast milk (25–60% of plasma concentration). The benefits of breastfeeding versus the remote possibility of adverse effects in the infant should be carefully weighed. Mothers receiving CARBAMAZEPINE-ASTRAFARM may breastfeed provided that the infant is monitored for possible adverse reactions (e.g., excessive drowsiness, allergic skin reactions).
Fertility
Very rare cases of impaired fertility in men and/or abnormalities in spermatogenesis parameters have been reported.
Ability to influence reaction speed when driving or operating machinery.
The ability of a patient taking CARBAMAZEPINE-ASTRAFARM to react quickly (especially at the beginning of therapy or during dose titration) may be impaired due to dizziness and drowsiness; therefore, patients should exercise caution when driving a vehicle or operating machinery.
Method of administration and dosage.
CARBAMAZEPINE-ASTRAFARM tablets are taken orally; the daily dose is usually divided into 2 or 3 doses. The drug can be taken during, after meals, or between meals with a small amount of liquid, e.g., a glass of water.
Before starting treatment, patients who are potentially carriers of the HLA-A*3101 allele based on ancestry should, if possible, undergo testing for the allele, as its presence may provoke severe adverse reactions, such as skin reactions.
Epilepsy
Treatment is initiated with a low daily dose, gradually increasing the dose, which should be adjusted according to the needs of each patient.
Determining the plasma carbamazepine level may be helpful in selecting the optimal dose.
Especially in combination therapy, therapeutic doses should be calculated based on plasma carbamazepine levels and efficacy.
Adults. The recommended initial dose is 100–200 mg once or twice daily.
The dose is then gradually increased to achieve optimal effect; the usual daily dose is often 800–1200 mg. Some patients may require a dose of CARBAMAZEPINE-ASTRAFARM up to 1600 mg or even 2000 mg daily.
Elderly patients. In elderly patients, the dose of CARBAMAZEPINE-ASTRAFARM should be carefully titrated due to possible drug interactions.
Children. Treatment may be initiated with 100 mg/day; the dose should be gradually increased by 100 mg weekly.
The usual dose is 10–20 mg/kg body weight per day (administered in several doses).
| Child's age |
Daily dose |
| 5-10 years |
400-600 mg (in 2-3 doses) |
| 10-15 years |
600-1000 mg (in 2-5 doses) |
For children aged 15 years and older, the dosage is the same as for adults.
If possible, CARBAMAZEPINE-ASTRAFARM should be administered as monotherapy; however, when used concomitantly with other medicinal products, the same gradual dose escalation regimen is recommended.
When initiating treatment with CARBAMAZEPINE-ASTRAFARM in addition to ongoing antiepileptic therapy, the dose should be gradually increased without altering the dose of the current antiepileptic drug(s), or with dose adjustments if necessary.
Acute manic states and maintenance therapy in bipolar affective disorders
Dosage range – approximately 400 to 1600 mg per day; usually 400 to 600 mg per day, divided into 2–3 doses. In acute manic states, a relatively rapid dose increase is recommended, whereas for optimal tolerability during maintenance therapy in bipolar disorders, a gradual increase in small doses is advised.
Alcohol withdrawal syndrome
Average dose – 200 mg three times daily. In severe cases, the dose may be increased during the first few days (e.g., up to 400 mg three times daily). In severe alcohol withdrawal, treatment should be initiated with a combination of CARBAMAZEPINE-ASTRAFARM and sedative-hypnotic agents (e.g., clomethiazole, chlordiazepoxide), following the dosage recommendations outlined above. After completion of the acute phase, treatment with CARBAMAZEPINE-ASTRAFARM may continue as monotherapy.
Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical). Idiopathic glossopharyngeal neuralgia
The initial dose of CARBAMAZEPINE-ASTRAFARM is 200–400 mg per day (100 mg twice daily for elderly patients). The dose should be slowly increased until pain subsides (usually up to 200 mg three or four times daily). For most patients, a dose of 200 mg three or four times daily is sufficient to maintain a pain-free state. In some cases, a daily dose of up to 1600 mg of CARBAMAZEPINE-ASTRAFARM may be required. After pain relief is achieved, the dose should be gradually reduced to the minimum effective maintenance dose.
Children.
Due to a faster elimination of carbamazepine, children may require higher doses of the drug (on a mg/kg basis) compared to adults.
Treatment of bipolar disorder and pain in trigeminal neuralgia
The safety and efficacy of carbamazepine have not been established in pediatric patients.
Treatment of epilepsy
The safety and efficacy of carbamazepine have been established in pediatric patients for the treatment of partial seizures, generalized tonic-clonic seizures, and mixed seizure patterns [see sections "Indications" and "Dosage and administration"]. CARBAMAZEPINE-ASTRAFARM tablets may be administered to children aged 5 years and older.
Overdose.
Symptoms. Symptoms occurring in overdose typically reflect impairment of the central nervous, cardiovascular, and respiratory systems.
Central nervous system: CNS depression; disorientation, depressed level of consciousness, drowsiness, excitation, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (early), hyporeflexia (later); seizures, psychomotor disturbances, myoclonus, hypothermia, mydriasis.
Respiratory system: Respiratory depression, pulmonary edema.
Cardiovascular system: Tachycardia, arterial hypotension, occasionally arterial hypertension, conduction disturbances with widening of the QRS complex; syncope associated with cardiac arrest, accompanied by loss of consciousness.
Gastrointestinal tract: Vomiting, gastric stasis, reduced colonic motility.
Musculoskeletal system: Isolated cases of rhabdomyolysis associated with the toxic effect of carbamazepine have been reported.
Urinary system: Urinary retention, oliguria or anuria; fluid retention; hyperhydration due to the antidiuretic hormone-like effect of carbamazepine.
Laboratory abnormalities: Hyponatremia, possible metabolic acidosis, hyperglycemia, elevated muscle fraction of creatine phosphokinase.
Treatment. There is no specific antidote. Initial treatment should be based on the patient's clinical condition; hospitalization is indicated. Plasma carbamazepine concentration should be measured to confirm poisoning and assess the degree of overdose.
Gastric evacuation, gastric lavage, and administration of activated charcoal are recommended. Late gastric evacuation may lead to delayed absorption and recurrence of intoxication symptoms during recovery. Symptomatic and supportive treatment should be provided in an intensive care unit, including cardiac function monitoring and careful correction of electrolyte imbalances.
Special recommendations. In case of arterial hypotension, intravenous administration of dopamine or dobutamine is indicated; in case of cardiac arrhythmias, treatment should be individually tailored; in case of seizures, benzodiazepines (e.g., diazepam) or other anticonvulsants such as phenobarbital (with caution due to increased risk of respiratory depression) or paraldehyde should be administered; in case of hyponatremia (water intoxication), fluid intake should be restricted, and cautious slow intravenous infusion of 0.9% sodium chloride solution should be given. These measures may help prevent cerebral edema.
Hemoperfusion using charcoal sorbents is recommended. Forced diuresis and peritoneal dialysis have been reported as ineffective.
Recurrence of overdose symptoms on the 2nd and 3rd days after ingestion should be anticipated due to delayed absorption of the drug.
Adverse reactions.
Very common or common undesirable effects may occur at the beginning of treatment with CARBAMAZEPINE-ASTRAFARM, when using too high an initial dose, or when treating elderly patients; these include effects on the central nervous system (CNS) (dizziness, headache, ataxia, somnolence, general weakness, diplopia), gastrointestinal tract (nausea, vomiting), or allergic skin reactions.
Dose-dependent adverse reactions usually resolve within a few days either spontaneously or after temporary dose reduction. The development of adverse CNS reactions may result from relative overdose or significant fluctuations in the plasma concentration of the active substance. In such cases, monitoring of the active substance plasma levels is recommended, and the daily dose should be divided into smaller doses (e.g., 3–4 doses).
Adverse drug reactions observed during clinical trials are listed according to the MedDRA organ system classification. Within each organ system class, adverse reactions are categorized by frequency, with the most frequent reactions listed first. Within each frequency group, adverse drug reactions are presented in order of decreasing severity. Additionally, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
| From blood and lymphatic system |
|
| very common |
leukopenia |
| common |
thrombocytopenia, eosinophilia |
| uncommon |
leukocytosis, lymphadenopathy |
| very rare |
agranulocytosis, aplastic anemia, pancytopenia, pure red cell aplasia, anemia, megaloblastic anemia, reticulocytosis, hemolytic anemia |
| frequency unknown |
bone marrow suppression |
| From immune system |
|
| uncommon |
delayed multiorgan hypersensitivity disorder with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests and vanishing bile duct syndrome (destruction and disappearance of bile ducts), various combinations; other organs may also be involved (e.g., liver, lungs, kidneys, pancreas, myocardium, colon) |
| very rare |
anaphylactic reaction, edema, angioneurotic edema, hypogammaglobulinemia |
| frequency unknown** |
drug rash with eosinophilia and systemic symptoms (DRESS) |
| Infections and infestations |
|
| frequency unknown** |
reactivation of human herpesvirus type 6 infection |
| From endocrine system |
|
| common |
edema, fluid retention, weight gain, hyponatremia and reduced blood osmolality due to antidiuretic hormone (ADH)-like effect, which in rare cases may lead to water intoxication accompanied by lethargy, vomiting, headache, confusion, neurological disturbances |
| very rare |
galactorrhea, gynecomastia |
| Metabolism and nutrition disorders |
|
| rare |
folate deficiency, decreased appetite |
| very rare |
acute porphyria (acute intermittent porphyria and variegate porphyria), non-acute porphyria (late cutaneous porphyria) |
| frequency unknown** |
hyperammonemia |
| From mental disorders |
|
| rare |
hallucinations (visual or auditory), depression, aggression, agitation, restlessness, confusion |
| very rare |
activation of psychosis |
| From nervous system |
|
| very common |
ataxia, dizziness, somnolence |
| common |
diplopia, headache |
| uncommon |
abnormal involuntary movements (e.g., tremor, asterixis, dystonia, tics), nystagmus |
| rare |
dyskinesia, eye movement disorders, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia and paralysis |
| very rare |
malignant neuroleptic syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia |
| frequency unknown** |
sedation, memory impairment |
| From eye organs |
|
| common |
accommodation disorders (e.g., blurred vision) |
| very rare |
lens opacities, conjunctivitis |
| From ear and labyrinth disorders |
|
| very rare |
hearing disturbances, e.g., tinnitus, hyperacusis, hypoacusis, altered pitch perception |
| From cardiac disorders |
|
| rare |
cardiac conduction disturbances |
| very rare |
arrhythmia, atrioventricular block with syncope, bradycardia, congestive heart failure, exacerbation of ischemic heart disease |
| Vascular disorders |
|
| rare |
hypertension or hypotension |
| very rare |
circulatory collapse, embolism (e.g., pulmonary artery thromboembolism), thrombophlebitis |
| From respiratory system, thoracic organs and mediastinum |
|
| very rare |
lung hypersensitivity characterized by, for example, fever, dyspnea or pneumonia |
| From gastrointestinal system |
|
| very common |
vomiting, nausea |
| common |
dry mouth, rectal irritation may occur when using suppositories |
| uncommon |
diarrhea, constipation |
| rare |
abdominal pain |
| very rare |
pancreatitis, glossitis, stomatitis |
| frequency unknown** |
colitis |
| Hepatobiliary disorders |
|
| rare |
cholestatic, parenchymal (hepatocellular) or mixed type hepatitis, vanishing bile duct syndrome, jaundice |
| very rare |
liver failure, granulomatous liver disease |
| From skin and subcutaneous tissue |
|
| very common |
urticaria, which may be severe allergic dermatitis |
| uncommon |
exfoliative dermatitis |
| rare |
systemic lupus erythematosus, pruritus |
| very rare |
Stevens-Johnson syndrome*, toxic epidermal necrolysis, photosensitivity reaction, erythema multiforme, nodular erythema, pigmentary disturbances, purpura, acne, hyperhidrosis, alopecia, hirsutism |
| frequency unknown** |
acute generalized exanthematous pustulosis (AGEP)**, lichenoid keratosis, onychomadesis |
| Musculoskeletal, connective tissue and bone disorders |
|
| rare |
muscle weakness |
| very rare |
bone metabolism disorders (decreased plasma calcium and 25-hydroxycholecalciferol in blood), leading to osteomalacia/osteoporosis, arthralgia, myalgia, muscle spasms |
| frequency unknown** |
fracture |
| From renal and urinary system |
|
| very rare |
tubulointerstitial nephritis, renal failure, renal function impairment (e.g., albuminuria, hematuria, oliguria and urea/nitrogen blood levels), urinary retention, urinary frequency |
| From reproductive system |
|
| very rare |
sexual disorders/erectile dysfunction; abnormal spermatogenesis (with reduced number and/or motility of spermatozoa) |
| General disorders and administration site conditions |
|
| very common |
fatigue |
| Laboratory findings |
|
| very common |
elevation of gamma-glutamyltransferase (due to hepatic enzyme induction), usually not clinically significant |
| common |
increased blood alkaline phosphatase levels |
| uncommon |
elevated transaminases |
| very rare |
increased intraocular pressure, increased blood cholesterol levels, increased high-density lipoprotein levels, increased blood triglyceride levels; thyroid function test abnormalities: decreased L-thyroxine levels (free thyroxine, thyroxine, triiodothyronine) and increased thyroid-stimulating hormone in blood, usually without clinical manifestations, increased blood prolactin |
| frequency unknown** |
decreased bone mineral density |
| Injury, poisoning and procedural complications |
|
| frequency unknown** |
falls (associated with carbamazepine treatment due to ataxia, dizziness, somnolence, arterial hypotension, confusion, sedation) |
* Rarely reported in some Asian countries. See also section "Special precautions".
**Additional adverse drug reactions from spontaneous reports (frequency unknown).
Adverse reactions based on spontaneous reports (frequency unknown)
The following adverse reactions have been reported during post-marketing use of the medicinal product from spontaneous reports and literature sources. As the reports are spontaneous, it is not possible to determine the exact number of affected patients or reliably estimate the frequency of occurrence of adverse reactions; therefore, their frequency is classified as "frequency unknown".
Infections and infestations: reactivation of human herpesvirus type 6.
Blood and lymphatic system disorders: bone marrow failure.
Nervous system disorders: sedative effect, memory impairment.
Gastrointestinal disorders: colitis.
Immune system disorders: drug reaction with eosinophilia and systemic symptoms (DRESS).
Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis, lichenoid keratosis, onychomadesis.
Musculoskeletal and connective tissue disorders: fractures.
Investigations: decreased bone mineral density.
Shelf life.
3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach and sight of children.
Packaging.
10 tablets per blister; 2 or 5 blisters per carton.
Prescription status.
Prescription only.
Manufacturer.
ASTRAFARM LLC, Ukraine.
Manufacturer's address and place of business.
6 Kyivska Street, Vyshneve, Kyiv-Sviatoshyn district, 08132, Ukraine.