Carbamazepine-fs: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CARBAMAZEPINE-PS

Composition:

Active substance: carbamazepine;

One tablet contains 200 mg of carbamazepine;

Excipients: microcrystalline cellulose, gelatin, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white, round, biconvex tablets with a score line on one side.

Pharmacotherapeutic group. Antiepileptic drugs. Carboxamide derivatives.

ATC code N03AF01.

Pharmacological properties.

Pharmacodynamics.

As an anticonvulsant agent, carbamazepine is effective in partial seizures (simple and complex), with or without secondary generalization, and in generalized tonic-clonic seizures, as well as in combinations of these seizure types.

In clinical studies, when carbamazepine was used as monotherapy in patients with epilepsy (especially in children and adolescents), a psychotropic effect of the drug was observed, which was partially manifested by a positive influence on symptoms of anxiety and depression, as well as by reduced irritability and aggressiveness.

As a neurotropic agent, carbamazepine is effective in certain neurological disorders: it prevents painful attacks in idiopathic and secondary trigeminal neuralgia. In addition, carbamazepine is used to alleviate neuropathic pain in various conditions. In alcohol withdrawal syndrome, carbamazepine increases the seizure threshold (which is reduced in this condition) and reduces the severity of clinical manifestations such as excitability, tremor, and gait disturbances.

It has been confirmed that carbamazepine, as a psychotropic agent, is effective in affective disorders, specifically: for the 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 relatively slowly. After a single dose, maximum plasma concentration (Cmax) is reached within 12 hours.

Bioavailability of various oral dosage forms of carbamazepine has been shown to range between 85–100%.

Food intake does not significantly affect the rate or extent of carbamazepine absorption.

At doses up to 300 mg, approximately 75% of the total amount reaches the systemic circulation within 6 hours. Therefore, the maximum recommended daily dose for this dosage form is 250 mg four times daily.

Plasma concentrations. No clinically significant differences in the absorption extent of the active substance have been observed after administration of different oral dosage forms of the drug. After a single oral dose of a 400 mg carbamazepine tablet, the mean Cmax of unchanged active substance reaches approximately 4.5 µg/mL.

Significant interindividual variations in steady-state concentrations within the therapeutic range are observed: 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) are nearly 30% of carbamazepine concentrations.

Steady-state plasma concentration of the drug is achieved within 1–2 weeks, depending on individual metabolic characteristics (autoinduction of hepatic enzyme systems by carbamazepine, heteroinduction by other concurrently administered drugs), as well as the patient's condition, drug dosage, and duration of treatment.

Distribution. Plasma protein binding of carbamazepine ranges from 70–80%. Concentrations of unchanged carbamazepine in cerebrospinal fluid and saliva are proportional to the fraction of active substance not bound to plasma proteins (20–30%). Carbamazepine concentration in breast milk amounts to 25–60% of its plasma level. Carbamazepine crosses the placental barrier. Assuming complete absorption, the apparent volume of distribution is 0.8–1.9 L/kg.

Metabolism. Carbamazepine is metabolized in the liver, primarily via the epoxide pathway, forming several metabolites: 10,11-transdihydrodiol derivative and its glucuronic acid conjugates. The first step involves oxidation to carbamazepine-10,11-epoxide, primarily mediated by the cytochrome P450 3A4 isoenzyme. Human microsomal epoxide hydrolase is believed to be responsible for the formation of pharmacologically active carbamazepine-10,11-epoxide, which is almost completely transformed into the 10,11-transdihydrodiol derivative and its glucuronides. 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 biotransformation pathways lead to the formation of various monohydroxylated derivatives and the N-glucuronide of carbamazepine, formed with the participation of uridine diphosphate-glucuronosyltransferase (UGT2B7).

Carbamazepine induces its own metabolism.

Elimination. After a single dose, the elimination half-life (T1/2) of unchanged carbamazepine averages approximately 36 hours, while after repeated administration, it averages 16–24 hours (due to autoinduction of metabolic enzymes), depending on the duration of treatment. In patients concurrently taking other drugs that induce the same hepatic enzyme system (e.g., phenytoin, phenobarbital), the T1/2 of carbamazepine averages 9–10 hours.

The average T1/2 of the 10,11-epoxide metabolite in 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. Approximately 2% of the administered dose is excreted unchanged in urine, approximately 1% as the pharmacologically active 10,11-epoxide metabolite, and approximately 30% as carbamazepine-10,11-transdihydrodiol and other inactive metabolites.

Pharmacokinetic characteristics in specific patient populations.

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. Pharmacokinetic data on 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.
- The medicinal product Carbamazepine-FS can be used both as monotherapy and in combination therapy.
- The medicinal product Carbamazepine-FS is generally ineffective in absence seizures (a mild form of epileptic seizure) and myoclonic seizures (see section "Special precautions for use").
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 oxcarbazepine, or to structurally related medicinal products (e.g., tricyclic antidepressants), or to any other component of the product;
Atrioventricular block;
History of bone marrow suppression episodes;
History of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria);
In combination with monoamine oxidase inhibitors (MAOIs).

Interaction with other medicinal products and other forms of interaction.

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing the formation of the active metabolite of carbamazepine—10,11-epoxide. Concomitant administration of CYP3A4 inhibitors or epoxide hydrolase inhibitors with carbamazepine may increase plasma concentrations of carbamazepine, potentially leading to adverse reactions. Therefore, dosage adjustment of Carbamazepine-FS and monitoring of plasma levels are required.

Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, potentially reducing plasma carbamazepine concentrations and diminishing therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, leading to increased plasma levels of carbamazepine. Hence, dosage adjustment of Carbamazepine-FS may be necessary.

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II hepatic enzyme systems, and therefore may reduce plasma concentrations of other drugs primarily metabolized by CYP3A4 through induction of their metabolism.

Human microsomal epoxide hydrolase is the enzyme responsible for the formation of 10,11-trans-diol derivatives from carbamazepine-10,11-epoxide. Concomitant administration of inhibitors of human microsomal epoxide hydrolase (e.g., valproic acid) may lead to increased plasma concentrations of carbamazepine-10,11-epoxide.

Concomitant use of carbamazepine with direct oral anticoagulants (rivaroxaban, dabigatran, apixaban, edoxaban) may reduce plasma concentrations of direct oral anticoagulants and thus increase the risk of thrombosis. Therefore, if concomitant use is necessary, patients should be closely monitored for signs and symptoms of thrombosis.

Medicinal products that may increase carbamazepine plasma levels.

Since increased plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), dosage of Carbamazepine-FS should be appropriately adjusted and/or plasma levels monitored when co-administered 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.

Antiepileptics: 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: terfenadine.

Antipsychotics: olanzapine, loxapine, quetiapine.

Antituberculosis agents: isoniazid.

Antiviral agents: HIV protease inhibitors (e.g., ritonavir).

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular agents: diltiazem, verapamil.

Agents for gastrointestinal disorders: 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.

Elevated plasma levels of the active metabolite carbamazepine-10,11-epoxide may cause adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia, blurred vision, nystagmus). Therefore, dosage of Carbamazepine-FS should be appropriately adjusted and/or plasma levels monitored when co-administered with agents that increase plasma levels of this metabolite, such as: brivaracetam, loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, and valpromide.

Medicinal products that may decrease carbamazepine plasma levels.

Dosage adjustment of Carbamazepine-FS may be required when co-administered with the following medicinal products.

Antiepileptic agents: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin and 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 toward the antiepileptic effect of Carbamazepine-FS. Therefore, the dose of Carbamazepine-FS should be adjusted.

Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; plasma concentrations of carbamazepine should be monitored.

Effect of Carbamazepine-FS on plasma levels of concomitantly administered medicinal products.

Carbamazepine may reduce plasma levels of certain drugs and diminish or nullify their effects. Dosage adjustment of the following medicinal products may be necessary according to clinical requirements.

Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol, phenazone (antipyrine), tramadol.

Antibiotics: doxycycline, rifabutin.

Anticoagulants: oral anticoagulants (e.g., warfarin, phenprocoumon, dicoumarol, acenocoumarol, rivaroxaban, dabigatran, apixaban, edoxaban).

Antidepressants: bupropion, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline, clomipramine).

Antiemetics: aprepitant.

Antiepileptic agents: brivaracetam, clobazam, clonazepam, eslicarbazepine, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Reports exist both of increased and decreased plasma phenytoin levels due to carbamazepine, and isolated cases of increased plasma levels of mephenytoin. To avoid phenytoin toxicity and subtherapeutic carbamazepine concentrations, the recommended plasma concentration of phenytoin should not exceed 13 µg/mL prior to initiating carbamazepine therapy. Isolated reports describe increased plasma concentrations of mephenytoin during carbamazepine treatment, rarely leading to confusion and even coma.

Antifungal agents: itraconazole, voriconazole, ketoconazole.

Anthelmintic agents: albendazole, praziquantel.

Antineoplastic agents: cyclophosphamide, imatinib, lapatinib, temsirolimus.

Antipsychotics: aripiprazole, bromperidol, clozapine, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, ziprasidone.

Antiviral agents: HIV protease inhibitors (e.g., indinavir, ritonavir, saquinavir).

Anxiolytics: alprazolam, midazolam.

Bronchodilators or antiasthmatic agents: theophylline.

Contraceptives: hormonal contraceptives (alternative contraceptive methods should be considered).

Cardiovascular agents: calcium channel blockers (dihydropyridine group), e.g., felodipine, isradipine, digoxin, quinidine, propranolol, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.

Corticosteroids, including prednisolone, dexamethasone.

Agents used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, sirolimus, tacrolimus.

Thyroid agents: levothyroxine. Carbamazepine is expected to increase the elimination of thyroid hormones and increase the requirement for them in patients with hypothyroidism. Therefore, thyroid function should be monitored in patients receiving replacement therapy, both at the beginning and end of treatment with Carbamazepine-FS.

Dose adjustment of thyroid hormones may be necessary. Thyroid function may change, particularly when carbamazepine is used concomitantly with other anticonvulsants (e.g., phenobarbital).

Interaction with other agents: products containing estrogens and/or progestogens (alternative contraceptive methods should be considered); buprenorphine, gestrinone, tibolone, toremifene, mianserin, sertraline.

Combinations requiring special consideration.

Long-term concomitant use of carbamazepine and paracetamol (acetaminophen) may be associated with hepatotoxicity.

Concomitant administration of carbamazepine and levetiracetam may increase carbamazepine toxicity.

Concomitant use of carbamazepine and isoniazid may enhance isoniazid hepatotoxicity.

Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.

Concomitant use of carbamazepine with lithium or metoclopramide, as well as with antipsychotics (haloperidol, thioridazine), may enhance neurological adverse effects (even at therapeutic plasma levels in the latter case). Therefore, careful clinical monitoring is required. At least 8 weeks should elapse after discontinuation of prior antipsychotic treatment. Concomitant therapy should be avoided. Patients should be monitored for neurotoxic symptoms such as unsteady gait, ataxia, horizontal nystagmus, increased proprioceptive muscle reflexes, and muscle spasms (fasciculations).

Published data suggest that adding carbamazepine to ongoing antipsychotic therapy may increase the risk of neuroleptic malignant syndrome or Stevens-Johnson syndrome.

When isotretinoin (an acne treatment) is used concomitantly with carbamazepine, plasma levels of carbamazepine should be monitored.

Combination therapy with Carbamazepine-FS and certain diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.

Carbamazepine may reduce the efficacy of hormonal contraceptives, and breakthrough bleeding may occur during their use. Therefore, either the contraceptive should contain more than 50 µg of estrogen, or non-hormonal contraceptive methods should be recommended.

Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g., pancuronium). Higher doses of these agents may be required, and patients need careful monitoring due to the possibility of faster-than-expected reversal of neuromuscular blockade.

Like other psychotropic agents, carbamazepine may reduce tolerance to alcohol; therefore, patients are advised to abstain from alcohol consumption.

Carbamazepine may reduce plasma levels of bupropion and increase levels of its metabolite hydroxybupropion, thereby reducing the clinical efficacy and safety of bupropion.

Contraindicated interactions.

Since carbamazepine is structurally similar to tricyclic antidepressants, Carbamazepine-FS is contraindicated for concomitant use with monoamine oxidase inhibitors (MAOIs); treatment with an MAOI inhibitor must be discontinued before initiating Carbamazepine-FS (at least two weeks prior, or earlier if clinically appropriate).

Effect on serological tests.

Carbamazepine may produce false-positive results in HPLC (high-performance liquid chromatography) assays for perphenazine.

Carbamazepine and 10,11-epoxide may produce false-positive results in immunoassays using fluorescence polarization methodology for the detection of tricyclic antidepressants.

Special precautions for use.

Carbamazepine should be used only under medical supervision, only after an assessment of the benefit-risk ratio, and with careful monitoring of patients with cardiac, hepatic, or renal disorders, hematological adverse reactions to other drugs in their history, disturbances in sodium metabolism, and patients with interrupted courses of Carbamazepine-FS therapy.

It is recommended to perform a general urine analysis and determine blood urea nitrogen levels at the beginning and periodically during therapy.

Carbamazepine 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 triggering latent psychoses, and in elderly patients, the potential for triggering confusion and anxious agitation.

The drug is generally ineffective for absence seizures (petit mal seizures) and myoclonic seizures. Individual cases indicate that seizure exacerbation may occur in patients with atypical absence seizures.

Hematological effects.

The use of carbamazepine has been associated with the development of agranulocytosis and aplastic anemia; however, due to the extremely low frequency of these conditions, it is difficult to assess the actual risk associated with carbamazepine use. 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 dermatological and hepatic reactions. Patients should be warned that if reactions such as fever, angina, groin infection, skin rashes, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura occur, they should seek medical advice immediately.

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-FS should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical manifestations such as fever or sore throat. Carbamazepine-FS should be discontinued upon signs of bone marrow suppression.

Temporary or persistent reduction in platelet or white blood cell counts may occur periodically or frequently with carbamazepine use. However, most of these cases have been shown to be transient and do not indicate the development of aplastic anemia or agranulocytosis. A blood test, including platelet count (and possibly reticulocyte count, hemoglobin level, and serum iron 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 carbamazepine use. 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 carbamazepine treatment. It is estimated that these dermatological reactions occur in 1–6 of 10,000 new patients in countries with predominantly Caucasian populations. However, in patients from certain Asian countries, the risk may be approximately 10 times higher. If symptoms indicating serious dermatological reactions (e.g., SJS, Lyell's syndrome/TEN) develop, Carbamazepine-FS should be discontinued immediately and alternative therapy initiated.

Pharmacogenomics.

Increasing evidence suggests 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 carbamazepine-related skin reactions (SJS/TEN) and the presence of human leukocyte antigen (HLA) allele (HLA)-B*1502 in these patients. The prevalence of this HLA-B*1502 allele ranges from 2% to 12% in Han Chinese patients and is approximately 8% in Thai patients. A higher frequency of reported SJS cases (rare rather than very rare) is characteristic of certain Asian countries (e.g., Taiwan, Malaysia, and the Philippines), where the (HLA)-B*1502 allele is prevalent. The carrier frequency of this allele among the Asian population exceeds 15% in the Philippines and in certain Malaysian populations. Prevalence of 2% and 6% has been recorded in Korea and India, respectively. The prevalence of the (HLA)-B*1502 allele is negligible in European, African, Native American, and Latin American populations (<1%).

The allele prevalence stated in this document represents the percentage of chromosomes in specified populations carrying the corresponding allele. Thus, the percentage of patients carrying at least one copy of the allele on either of their two chromosomes (i.e., "carrier frequency") is nearly twice the allele prevalence. Therefore, the percentage of patients at risk is nearly twice the allele prevalence.

For patients considered genetically at risk, testing for the presence of the (HLA)-B*1502 allele should be performed before initiating Carbamazepine-FS therapy. If the patient's test for the (HLA)-B*1502 allele is positive, treatment with Carbamazepine-FS should not be initiated, except when no other therapeutic options are available. When assessing risk, it should be remembered that the HLA-B*1502 allele is also a risk factor for other antiepileptic drugs. Patients who have been tested and found negative for (HLA)-B*1502 have a low risk of developing SJS, although such reactions are still possible, albeit very rarely.

It has been established that identifying patients carrying the HLA-B*1502 allele and avoiding carbamazepine use in these Han Chinese patients reduces the incidence of carbamazepine-induced SJS/TEN.

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, 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 nationalities with a low frequency of the (HLA)-B*1502 allele. Screening is generally not recommended for patients already receiving Carbamazepine-FS, as the risk of SJS/TEN is significantly limited to the first few months of therapy, regardless of the presence of the (HLA)-B*1502 allele in the patient's genes.

Genetic screening results should not replace appropriate clinical monitoring, as many HLA-B*1502 carriers do not develop SJS/TEN, while other patients without genetic risk factors may develop SJS/TEN for other reasons. The situation is similar for carriers of the HLA-A*3101 allele receiving Carbamazepine-FS treatment. These patients do not necessarily develop SJS/TEN, DRESS, AGEP, or maculopapular rash. However, serious skin adverse reactions may occur in patients without the HLA-A*3101 allele for other reasons. To date, no studies have been conducted on how other factors (such as dosage, adherence, concomitant medications, and comorbidities) contribute to the development of these serious dermatological reactions.

In Caucasian patients, there is no association between the (HLA)-B*1502 allele and the occurrence of SJS.

Association with HLA-A*3101

Human leukocyte antigen may be a risk factor for skin adverse reactions such as SJS, TEN, drug rash 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-FS should be avoided.

Retrospective analysis data in Japanese patients and Northern European residents have demonstrated an association between severe skin reactions (Stevens-Johnson syndrome, Lyell's syndrome, drug rash with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, and maculopapular rash) in carriers of the HLA-A*3101 allele of the human leukocyte antigen (HLA) gene and carbamazepine use.

The prevalence of this allele may vary among different ethnic groups: approximately 2–5% in the European population, about 10% in Japanese. The allele prevalence is less than 5% in the populations of Australia, Asia, Africa, and North America. For Western European populations, the prevalence of the HLA-A*3101 allele is estimated at approximately 6.7%, depending on the geographical region, with exceptions ranging from 5% to 12%. Prevalence exceeding 15% has been established in certain South American ethnic groups (Argentina and Brazil), Native North American populations (Navajo and Sioux tribes, in Mexico – Seri), and South India (Tamil Nadu).

Before initiating Carbamazepine-FS therapy, screening for the HLA-A*3101 allele is recommended for potential carriers (e.g., Japanese, Caucasians, Native Americans, Latin Americans, South Indian, and Arab populations) (see section "Dosage and administration"). The drug should be used in carriers of this allele only when the benefit of therapy outweighs the potential risk. Screening for the HLA-A*3101 allele is generally not required in patients who have already been receiving Carbamazepine-FS for a prolonged period, as SJS/TEN, AGEP, DRESS, and maculopapular rash are typically observed only within the first few months of therapy.

Limitations of genetic screening

Genetic screening results should not replace appropriate clinical monitoring and patient management. Other potential factors, such as antiepileptic drug dosage, adherence to therapy, and concomitant therapy, may play a role in the development of these severe skin adverse reactions. The impact of other diseases and the level of skin disorder 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, the patient should be under close observation to allow immediate discontinuation of the drug if the reaction worsens with continued use.

The presence of the HLA-A*3101 allele in patients is associated with less severe adverse skin 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 an indicator of risk for the aforementioned skin reactions.

Hypersensitivity.

Type I (immediate-type) hypersensitivity reactions have occurred with carbamazepine use, including rash, pruritus, urticaria, angioedema (affecting the larynx, glottis, lips, and eyelids), and cases of fatal or life-threatening anaphylaxis. If such reactions occur during Carbamazepine-FS use, the drug should be discontinued and alternative therapy initiated.

Carbamazepine may provoke delayed-type IVb hypersensitivity reactions, including drug rash 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).

Patients with hypersensitivity reactions to carbamazepine should be informed that approximately 25–30% of such patients may also have hypersensitivity reactions to oxcarbazepine.

Cross-hypersensitivity may occur with the use of carbamazepine and aromatic antiepileptic drugs (e.g., phenytoin, primidone, and phenobarbital).

Generally, if symptoms indicating hypersensitivity occur, Carbamazepine-FS should be discontinued immediately.

Seizures. Since carbamazepine may cause or exacerbate absence seizures, Carbamazepine-FS should be used with caution in patients with mixed seizure types that include absence seizures (typical or atypical). Under such circumstances, the drug may provoke seizures. If seizures are provoked, Carbamazepine-FS should be discontinued immediately.

An increase in seizure frequency may occur when switching from oral formulations to suppositories.

Liver function. Liver function should be assessed at baseline and periodically during therapy, especially in patients with a history of liver disease and in elderly patients. The drug should be discontinued immediately in case of exacerbation of liver function disorders or during the active phase of liver disease.

Renal function. Renal function assessment and blood urea nitrogen level determination are recommended at the beginning and periodically during therapy.

Hyponatremia. Cases of hyponatremia have been reported with carbamazepine use. In patients with pre-existing renal dysfunction associated with low sodium levels or in patients receiving concomitant medications that lower sodium levels (such as diuretics, drugs associated with inadequate antidiuretic hormone secretion), serum sodium levels should be measured before treatment. Subsequently, levels should be measured every 2 weeks, then monthly for the first 3 months of treatment or as clinically necessary. These risk factors (diuretic use, drug-induced hyponatremia, cranial trauma, initially low sodium levels) should be particularly considered for elderly patients. If hyponatremia occurs, water restriction is an important countermeasure if clinically indicated.

Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations, necessitating an increase in thyroid hormone replacement therapy dosage for patients with hypothyroidism. Therefore, monitoring of thyroid function is recommended to determine the appropriate dose of replacement hormone therapy.

Anticholinergic effects. Carbamazepine exhibits moderate anticholinergic activity. Therefore, patients with elevated intraocular pressure and urinary retention should be under close monitoring during therapy.

Psychiatric effects. The possibility of activation of latent psychosis should be considered, 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. A meta-analysis of data from placebo-controlled antiepileptic drug trials also 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 use.

Therefore, patients should be screened 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.

Pregnancy. Congenital malformations and nervous system disorders may occur when carbamazepine is used during pregnancy. For epilepsy treatment during pregnancy, carbamazepine should be used only if the potential benefit justifies the potential risk. For psychiatric indications and neuropathic pain, carbamazepine should not be used; alternative treatments should be considered for such patients.

Pregnant women and women planning pregnancy should be adequately counseled about the potential teratogenic risk to the unborn child.

Women planning pregnancy should use reliable contraception during carbamazepine treatment and for 2 weeks after the last dose.

Hormonal contraceptives. Breakthrough bleeding has been reported in women using hormonal contraceptives. Carbamazepine may negatively affect the efficacy of hormonal contraceptives. Therefore, women of reproductive age should be advised to use alternative non-hormonal contraceptive methods during carbamazepine therapy.

Endocrine effects. Due to hepatic enzyme induction, carbamazepine may cause a reduction in the therapeutic effect of estrogen and/or progesterone-containing drugs. This may lead to reduced contraceptive efficacy, symptom recurrence, or breakthrough bleeding or spotting. Women taking carbamazepine for whom hormonal contraception is necessary should receive a preparation containing at least 50 mcg of estrogen, or alternative effective and reliable non-hormonal contraceptive methods should be considered during carbamazepine therapy.

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 unreliable, monitoring plasma drug levels may be appropriate in the following cases: sudden increase in seizure frequency, checking patient compliance, during pregnancy, in the treatment of children and adolescents; suspicion of impaired absorption, suspected toxicity, and when using multiple drugs.

Dosage reduction and discontinuation of the drug. Abrupt discontinuation of Carbamazepine-FS may provoke seizures. If abrupt discontinuation of the drug is necessary, patients with epilepsy should be switched to a new antiepileptic drug while continuing appropriate medication therapy.

Dosage reduction and withdrawal syndrome. Abrupt discontinuation of the drug may provoke seizures; therefore, carbamazepine should be discontinued gradually over 6 months. If immediate discontinuation is necessary, patients with epilepsy should be switched to a new antiepileptic drug while continuing appropriate medication therapy (e.g., intravenous or rectal diazepam, or intravenous phenytoin).

Falls. Carbamazepine treatment is associated with ataxia, dizziness, somnolence, orthostatic hypotension, confusion, or lethargy (see "Adverse reactions"), which may lead to falls and, consequently, fractures or other injuries. In patients experiencing these conditions or taking medications that exacerbate them, a full fall risk assessment should be regularly performed during long-term carbamazepine treatment.

Other

During carbamazepine treatment, patients should avoid exposure to strong sunlight due to the risk of photosensitization.

Use during pregnancy or breastfeeding.

In animals, oral administration of carbamazepine caused developmental defects.

Due to enzyme induction, carbamazepine may counteract the therapeutic effect of drugs containing estrogens and/or progestogens, potentially leading to contraceptive failure. Therefore, women planning pregnancy should use alternative effective and reliable contraceptive methods during carbamazepine treatment.

Pregnancy

There is clear evidence of risk to the human fetus. Therefore, carbamazepine should not be used during pregnancy unless absolutely necessary (see section "Special precautions for use, Pregnancy").

It should be noted that developmental disorders, including congenital malformations, are observed 2–3 times more frequently in children of women with epilepsy than in healthy individuals. The extent to which these effects may be related to carbamazepine or the underlying disease is not fully established.

According to the North American Pregnancy Registry, the prevalence of serious structural anomalies requiring surgical, medical, or cosmetic correction, diagnosed within 12 weeks after birth, was 3.0% (95% CI [confidence interval] 2.1–4.2%) among 1,033 pregnant women who took carbamazepine as monotherapy in the first trimester, and 1.1% (95% CI 0.37–2.6%) among pregnant women who did not take any antiepileptic drugs (relative risk 2.7; 95% CI 1.0–7.0%).

According to the European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), the prevalence of major congenital malformations was 5.5% (95% CI: 4.5–6.6) among 1,957 pregnancies where carbamazepine was used. Major congenital malformations were recorded within 12 months after birth. Compared to lamotrigine, levetiracetam, and oxcarbazepine, carbamazepine was associated with an increased risk of serious congenital malformations (lamotrigine — OR [odds ratio]: 2.68, 95% CI: 1.71–4.19; levetiracetam — OR: 2.41, 95% CI: 1.33–4.38; oxcarbazepine — OR: 2.37, 95% CI: 1.17–4.80). Nervous system disorders have been reported in children of women with epilepsy who received carbamazepine alone or in combination with other antiepileptic drugs during pregnancy. Study results regarding the risk of neurodevelopmental disorders (such as autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, psychomotor retardation, cognitive disorders, learning disabilities, schizophrenia, etc.) in children exposed to carbamazepine in utero are conflicting, and this risk cannot be excluded.

Children whose mothers suffer from epilepsy show a predisposition to intrauterine developmental disorders, including congenital malformations. There have been reports suggesting that carbamazepine, like most antiepileptic drugs, increases the frequency of these disorders, although convincing evidence from controlled monotherapy studies with carbamazepine is lacking. However, intrauterine developmental disorders and congenital malformations associated with carbamazepine use have been reported, including spina bifida and other congenital anomalies, such as craniofacial defects, cardiovascular malformations, hypospadias, and developmental anomalies of various organ systems.

In particular, the drug dose should be minimal between the 20th and 40th day of pregnancy. Developmental anomalies are likely due to peak plasma levels. Therefore, during this period, the total daily dose should be administered in several divided doses throughout the day. Monitoring of plasma levels is recommended. Plasma concentration can be maintained at the lower end of the therapeutic range (4–12 mcg/mL) provided seizure control is maintained. Data indicate that the risk of malformations with carbamazepine use is dose-dependent, i.e., the frequency of developmental anomalies was lower at doses <400 mg/day compared to higher carbamazepine doses.

Throughout pregnancy and after delivery, patients should remain under monitoring (monitoring of serum levels and EEG). Plasma concentration should be maintained at the lower end of the therapeutic range (3–7 mcg carbamazepine/mL). The risk of malformations increases with combination therapy; therefore, combination with other antiepileptic drugs or other medications should be avoided to further reduce risk.

Monotherapy is indicated. Data suggest that the risk of malformations with carbamazepine use in polytherapy may vary depending on concomitant drugs and may be higher with combinations including valproate.

Considering carbamazepine's enzyme-inducing properties, folic acid supplementation (prevention of neural tube defects) is recommended before and during pregnancy.

Monitoring and prevention. Folic acid deficiency may occur during pregnancy. Antiepileptic drugs may increase the risk of folic acid 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 carbamazepine and other anticonvulsant drugs.

Breastfeeding. Adverse effects in offspring have been observed in rat studies where dams were administered carbamazepine. Carbamazepine passes into breast milk (25–60% of plasma concentration). The benefits of breastfeeding versus the remote probability of adverse effects in the infant should be carefully weighed. The benefits of breastfeeding generally outweigh the risk of adverse effects. Breastfeeding should be discontinued if the infant fails to gain weight, is excessively sleepy, or develops allergic skin reactions. Cases of cholestatic hepatitis have been described in children exposed to carbamazepine prenatally or via breast milk; therefore, monitoring of these children for adverse effects on the hepatobiliary system is recommended. Mothers receiving carbamazepine may breastfeed provided the infant is monitored for possible adverse reactions (e.g., excessive sleepiness, allergic skin reactions).

Fertility.

Very rare cases of impaired fertility in men and/or abnormalities in spermatogenesis parameters have been reported. However, a causal relationship between these disorders and carbamazepine has not yet been established.

Ability to affect reaction speed when driving or operating machinery.

The patient's ability to react quickly, especially at the beginning of therapy or during dose titration, may be impaired due to seizures caused by the disease and adverse effects from carbamazepine use, such as dizziness, somnolence, ataxia, diplopia, accommodation disorders, and visual disturbances. Therefore, patients should exercise caution when driving or operating machinery.

Administration and Dosage

The medicinal product Carbamazepine-FS should be administered orally. The daily dose is usually divided into two or three doses. The product can be taken during meals, after meals, or between meals, swallowing with a small amount of liquid.

Before starting treatment, patients who are potentially carriers of the HLA-A*3101 allele due to their ancestry should, if possible, be tested for the presence of this allele, as in such cases severe adverse reactions, such as skin reactions, may be provoked.

Epilepsy.

Treatment should begin with a low daily dose, which should then be gradually increased (adjusted according to the individual needs of each patient) until the optimal effect is achieved.

To determine the optimal dosage, measurement of carbamazepine levels in blood plasma may be helpful.

Particularly in combination therapy, therapeutic doses should be determined based on plasma carbamazepine levels and treatment efficacy.

Experience has shown that therapeutic levels of carbamazepine range from 4 to 12 mcg/mL.

Adults.

The recommended initial dose is 100*-200 mg once or twice daily, then the dose should be gradually increased until the optimal effect is achieved. The usual daily dose is 400 mg two or three times daily (corresponding to 800–1200 mg/day). Some patients may require a dose of Carbamazepine-FS up to 1600 mg/day or even 2000 mg/day, although such high doses should be avoided due to the higher frequency of adverse effects.

Elderly Patients.

In elderly patients, due to the potential for drug interactions, the dose of Carbamazepine-FS should be carefully selected. The recommended initial dose is 100* mg twice daily.

Children.

Treatment may be initiated with a dose of 100* mg/day; the dose should be gradually increased by 100* mg each week.

Usually, treatment is conducted at a dose of 10–20 mg/kg body weight per day (divided into several doses).

Child's age	Daily dose
6–10 years	400–600 mg (in 2–3 doses)
11–15 years	600–1000 mg (in 3 doses)

For children aged 15 years and older, the dosage is the same as for adults.

If possible, carbamazepine should be administered as monotherapy; however, when used in combination with other medicinal products, a similar gradual dose escalation regimen is recommended.

When carbamazepine is prescribed in addition to ongoing antiepileptic therapy, the dose should be gradually increased without changing the dose of the currently used antiepileptic drug(s), or, if necessary, adjusted accordingly.

Acute manic states and maintenance treatment of affective (bipolar) disorders. The dosage range is 400 to 1600 mg/day. Generally, therapy should be conducted at a dose of 400–600 mg/day given in 2–3 divided doses.

When treating acute manic states, the dose of Carbamazepine-FS should be increased relatively quickly. In acute manic states, a sufficiently rapid dose escalation is recommended, whereas for optimal tolerance during maintenance therapy in bipolar disorders, gradual dose escalation in small increments is advised.

Alcohol withdrawal syndrome.

The average dose is 200 mg 3–4 times daily. In severe cases, during the first few days the dose may be increased (e.g., to 400 mg 3 times daily (1200 mg/day)). Subsequently, the dose should be gradually reduced and therapy tapered off. In severe alcohol withdrawal symptoms, treatment should be initiated with a combination of Carbamazepine-FS and sedative-hypnotic agents (e.g., with clomethiazole, chlordiazepoxide), following the above-mentioned dosage recommendations. After completion of the acute phase, treatment with Carbamazepine-FS 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-FS is 200–400 mg/day (100* mg twice daily for elderly patients). The dose should be slowly increased until pain relief is achieved (usually up to 200 mg 3–4 times daily). For most patients, a dose of 200 mg 3–4 times daily is sufficient to maintain a pain-free state. In some cases, a daily dose of up to 1600 mg may be required. After pain subsides, the dose should be gradually reduced to the lowest effective maintenance dose. The maximum recommended dose is 1200 mg/day. Thereafter, the dose should be slowly decreased and therapy gradually discontinued.

* Carbamazepine preparations should be used at appropriate dosages.

Children.

Due to a faster elimination of carbamazepine in children, higher doses (on a per-kilogram body weight basis) may be required compared to adults. The medicinal product Carbamazepine-FS may be used in children aged 6 years and older.

Overdose.

Symptoms.

Signs and symptoms occurring in overdose generally reflect impairment of the central nervous, cardiovascular, and respiratory systems, as well as adverse reactions listed in the section "Adverse Reactions."

Central nervous system (CNS): CNS depression; confusion, decreased level of consciousness, drowsiness, agitation, 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 retention, decreased 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; water intoxication due to an antidiuretic hormone-like effect of carbamazepine.

Laboratory test changes: Hyponatremia, possible metabolic acidosis, hyperglycemia, increased 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 with this agent and to assess the degree of overdose.

Gastric evacuation, gastric lavage, and administration of activated charcoal should be performed. 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, administration of benzodiazepines (e.g., diazepam) or other anticonvulsants, such as phenobarbital (with caution due to increased risk of respiratory depression) or paraldehyde; in case of hyponatremia (water intoxication), fluid intake should be restricted and cautious slow intravenous infusion of 0.9% sodium chloride solution should be administered. These measures may help prevent cerebral edema.

Hemosorption using charcoal sorbents is recommended. Hemodialysis is an effective treatment method in carbamazepine overdose. Forced diuresis, hemodialysis, and peritoneal dialysis have been reported as ineffective.

Recurrence of overdose symptoms on the second and third day after onset should be anticipated due to delayed absorption of the drug.

Adverse Reactions.

At the beginning of carbamazepine therapy, or when using too high an initial dose, or when treating elderly patients, certain types of adverse reactions occur frequently or occasionally, for example, those affecting the central nervous system (dizziness, headache, ataxia, somnolence, general weakness, diplopia), the 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 reactions affecting the CNS may result from relative overdosage 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 portions (e.g., 3–4 doses).

The adverse effects observed during clinical trials and those identified from spontaneous post-marketing reports are listed below.

Adverse reactions are categorized by frequency as follows: 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); not known (frequency cannot be estimated from available data).

Infections and parasitic diseases: not known – reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: very common – leukopenia (11%), persistent in 2% of cases; common – thrombocytopenia, eosinophilia; rare – lymphadenopathy, folate deficiency; very rare – leukocytosis, agranulocytosis, aplastic anemia, pancytopenia, erythroid aplasia, anemia, megaloblastic anemia, acute intermittent porphyria, mixed porphyria, late cutaneous porphyria, reticulocytosis, hemolytic anemia; not known – bone marrow failure.

Immune system disorders: rare – multi-organ hypersensitivity reaction of delayed type with fever, skin rash, vasculitis, lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests, and vanishing bile duct syndrome (destruction and disappearance of intrahepatic bile ducts), occurring in various combinations. Involvement of other organs (e.g., liver, lungs, kidneys, pancreas, myocardium, colon) may also occur; very rare – aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactic reaction, angioedema, hypogammaglobulinemia; not known – drug reaction with eosinophilia and systemic symptoms (DRESS).

Endocrine system disorders: common – edema, fluid retention, weight gain, hyponatremia, and decreased plasma osmolality due to an antidiuretic hormone-like effect, which in isolated cases may lead to hyperhydration accompanied by lethargy, vomiting, headache, confusion, neurological disturbances, seizures, disorientation, impaired cognition, visual disturbances, or encephalopathy ("syndrome of inappropriate antidiuretic hormone secretion", SIADH); very rare – increased blood prolactin levels, with or without clinical manifestations such as galactorrhea, gynecomastia; changes in thyroid function tests: decreased levels of L-thyroxine (free thyroxine (FT4), thyroxine (T4), triiodothyronine (T3)) and increased levels of thyroid-stimulating hormone (TSH), usually without clinical symptoms; disturbances in bone metabolism (decreased plasma calcium and 25-hydroxycholecalciferol levels), leading to osteomalacia/osteoporosis; in individual cases – increased cholesterol levels, including high-density lipoprotein cholesterol and triglycerides.

Metabolism and nutrition disorders: rare – folate deficiency, decreased appetite; very rare – increased blood cholesterol levels (including increased levels of high-density lipoproteins and triglycerides), increased blood triglyceride levels, acute porphyria (acute intermittent porphyria and mixed porphyria), non-acute porphyria (late cutaneous porphyria); not known – hyperammonemia.

Psychiatric disorders: rare – hallucinations (visual or auditory), depression, loss of appetite, restlessness, aggression, agitation, confusion; very rare – activation of psychosis.

Nervous system disorders: very common – dizziness (10–50%), ataxia (children 10.4%, adults 50%), somnolence, general weakness; common – headache, diplopia, visual accommodation disorders (e.g., blurred vision); uncommon – abnormal involuntary movements (e.g., tremor, "fluttering" tremor, dystonia, tics), nystagmus; rare – orofacial dyskinesia, eye movement disorders, speech disturbances (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness and paresis; very rare – taste disturbances, neuroleptic malignant syndrome (NMS), aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia; not known – lethargy, sedative effect, memory impairment.

Eye disorders: common – accommodation disorders (e.g., blurred vision); very rare – lens opacities, conjunctivitis, increased intraocular pressure.

Ear and labyrinth disorders: very rare – hearing disorders, e.g., tinnitus, increased auditory sensitivity, decreased hearing sensitivity, pitch perception disturbances.

Cardiac disorders: rare – disturbances in intracardiac conduction; arterial hypertension or arterial hypotension; very rare – bradycardia, arrhythmias, atrioventricular block with syncope, circulatory collapse, congestive heart failure, exacerbation of ischemic heart disease, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), vasculitis.

Respiratory, thoracic and mediastinal disorders: very rare – pulmonary hypersensitivity reactions characterized by fever, dyspnea, pneumonitis, or pneumonia.

Gastrointestinal disorders: very common – nausea, vomiting (each 8%); common – dry mouth; uncommon – diarrhea or constipation; rare – abdominal pain; very rare – glossitis, stomatitis, pancreatitis; not known – colitis.

Hepatobiliary disorders: very common – increased gamma-glutamyl transferase levels (due to hepatic enzyme induction), usually not clinically significant; common – increased blood alkaline phosphatase levels; uncommon – increased transaminase levels; rare – hepatitis of cholestatic, parenchymal (hepatocellular), or mixed type, vanishing bile duct syndrome, jaundice; very rare – granulomatous hepatitis, liver failure.

Skin and subcutaneous tissue disorders: very common – allergic dermatitis, pruritus, urticaria, sometimes severe; uncommon – exfoliative dermatitis, erythroderma; rare – systemic lupus erythematosus, pruritus; very rare – Stevens-Johnson syndrome (in some Asian countries, this adverse event has been reported with a frequency of "rare"), toxic epidermal necrolysis, photosensitivity, erythema multiforme, nodular erythema, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism; not known – acute generalized exanthematous pustulosis, lichenoid keratosis, onychomadesis.

Musculoskeletal and connective tissue disorders: rare – muscle weakness; very rare – arthralgia, muscle pain, muscle spasms, disturbances in bone metabolism (decreased plasma calcium and 25-hydroxycholecalciferol levels, potentially leading to osteomalacia or osteoporosis); not known – decreased bone mineral density, fractures.

Renal and urinary disorders: very rare – tubulointerstitial nephritis, renal failure, impaired kidney function (e.g., albuminuria, hematuria, oliguria, increased blood urea nitrogen/azotemia), frequent urination, urinary retention.

Reproductive system disorders: very rare – sexual dysfunction/impotence/erectile dysfunction, impaired spermatogenesis (with decreased sperm count/motility).

Very rare reports of impaired male fertility and/or impaired spermatogenesis have been documented.

General disorders: very common – general weakness.

Laboratory and diagnostic test abnormalities: very common – increased gamma-glutamyl transferase levels (due to hepatic enzyme induction), usually not clinically significant; common – increased blood alkaline phosphatase levels; uncommon – increased transaminase levels; very rare – increased intraocular pressure, hypogammaglobulinemia.

Adverse reactions based on spontaneous reports (frequency not known).

The information on the above-mentioned adverse reactions was obtained from post-marketing use of the medicinal product through spontaneous reports and publications. Since these reports are spontaneous, it is not possible to accurately determine the number of affected patients or reliably estimate the frequency of adverse reactions; therefore, their frequency is classified as "not known."

Shelf life.

3 years.

Storage conditions.

Store in the original packaging, out of reach of children, at a temperature not exceeding 25°C.

Packaging.

10 tablets in a blister; 1, 2, 5, or 10 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Pharma Start LLC, Ukraine.

Manufacturer's address and location of business activity.

8 Vatslava Havela Boulevard, Kyiv, 03124, Ukraine.

If adverse effects occur or if you have questions regarding the safety of using the medicinal product, please contact the Pharmacovigilance Department of ASINO UKRAINE LLC at the following address:

8 Vatslava Havela Boulevard, Kyiv, 03124, Tel/Fax: +38 044 281 2333.