Mezakar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEZACAR® (MEZACAR®)

Composition:

Active ingredient: carbamazepine;

1 tablet contains 200 mg of carbamazepine;

Excipients: microcrystalline cellulose, hypromellose E5, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white, round tablets with a beveled break line on one side and an embossing “K” on the other.

Pharmacotherapeutic group.

Antiepileptic agents. ATC code N03A F01.

Pharmacological Properties

Pharmacodynamics

As an anticonvulsant agent, the antiepileptic drug Mезacar® is effective in partial seizures (simple and complex), both with and without secondary generalization, 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 (particularly in children and adolescents), a psychotropic effect of the drug was observed, partially manifested as a positive impact on symptoms of anxiety and depression, as well as reduced irritability and aggressiveness.

As a neuropathic agent, carbamazepine is effective in certain neurological disorders. For example, it prevents painful attacks in idiopathic and secondary trigeminal neuralgia. Additionally, carbamazepine is used to alleviate neuropathic pain under 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 as a psychotropic agent, carbamazepine is effective in affective disorders, specifically: for the treatment of acute manic states, and for maintenance therapy of bipolar affective (manic-depressive) disorders (both as monotherapy and 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 the conventional tablet, 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.

When doses up to 300 mg of carbamazepine are administered, approximately 75% of the ingested dose reaches 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 extent of absorption 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 inter-individual 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 those of carbamazepine.

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 concomitantly administered drugs), as well as the patient's condition, drug dosage, and duration of treatment.

Distribution. Protein binding of carbamazepine to plasma proteins is 70–80%. The concentration of unchanged carbamazepine in cerebrospinal fluid and saliva is proportional to the unbound fraction of the active substance (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 ranges from 0.8 to 1.9 L/kg.

Metabolism. Carbamazepine is primarily metabolized in the liver via the epoxide pathway, resulting in the formation of main metabolites – the 10,11-trans-diol derivative and its glucuronic acid conjugate. 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 the pharmacologically active carbamazepine-10,11-epoxide, which is almost completely transformed into the 10,11-trans-diol 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 of carbamazepine lead to the formation of various monohydroxylated derivatives, as well as the N-glucuronide of carbamazepine, formed via uridine diphosphate-glucuronosyltransferase (UGT2B7).

Carbamazepine induces its own metabolism.

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

The average 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, approximately 1% as the pharmacologically active metabolite 10,11-epoxide, and approximately 30% as carbamazepine-10,11-trans-diol and other inactive metabolites.

Pharmacokinetic characteristics in specific patient populations

Elderly patients. There are no data indicating that the pharmacokinetics of carbamazepine change in elderly patients (compared to younger adults).

Patients with impaired renal or hepatic function. There are no pharmacokinetic data available for carbamazepine in patients with impaired renal or hepatic function.

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 seizure types.
  • Mesacar® can be used both as monotherapy and in combination therapy.
  • Carbamazepine 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.

Mesacar® is contraindicated:

• in patients with known hypersensitivity to carbamazepine or oxcarbazepine, or to structurally related medicinal products (such as tricyclic antidepressants), or to any other component of the drug;
• in atrioventricular block;
• in patients with a history of bone marrow depression;
• in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria);
• in combination with monoamine oxidase inhibitors (MAO inhibitors).

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 use of CYP3A4 inhibitors or epoxide hydrolase inhibitors with carbamazepine may lead to increased plasma concentrations of carbamazepine, which in turn may result in adverse reactions. Therefore, the dose of Mesacar® should be adjusted and plasma levels monitored. Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, potentially reducing plasma concentrations of carbamazepine and diminishing its therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, leading to increased plasma levels of carbamazepine. Therefore, dose adjustment of Mesacar® 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 converting carbamazepine-10,11-epoxide into 10,11-trans-diol derivatives. 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 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), the dosage of Mesacar® should be adjusted and/or plasma levels monitored 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 drugs: 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.

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.

Since elevated plasma levels of the active metabolite carbamazepine-10,11-epoxide may cause adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), dosage of Mesacar® should be adjusted and/or plasma levels monitored when Mesacar® is used concomitantly with the following medicinal products: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, valpromide, brivaracetam.

Medicinal products that may decrease carbamazepine plasma levels.

Dosage adjustment of Mesacar® may be necessary when used concomitantly with the following medicinal products.

Antiepileptic drugs: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic carbamazepine levels, it is recommended to adjust plasma phenytoin concentration 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 preparations containing St. John's wort (Hypericum perforatum).

Mefloquine may exhibit antagonistic properties against the antiepileptic effect of carbamazepine. Therefore, the dose of Mesacar® 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 Mesacar® on plasma levels of concomitantly administered medicinal products.

Carbamazepine may reduce plasma levels of certain medicinal products 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 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, rivaroxaban, dabigatran, apixaban, edoxaban).

Antidepressants: bupropion (carbamazepine may reduce plasma levels of bupropion and increase levels of its metabolite hydroxybupropion, thereby reducing the clinical efficacy and safety of bupropion), citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline, clomipramine). Concomitant use of Mesacar® with monoamine oxidase inhibitors (MAO inhibitors) is contraindicated. MAO inhibitors should be discontinued at least 2 weeks prior to initiation of Mesacar® (or earlier if clinically feasible).

Antiemetics: aprepitant.

Antiepileptic drugs: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Both increases and decreases in plasma phenytoin levels have been reported with carbamazepine. Isolated cases of increased plasma levels of mephenytoin have also been reported. To avoid phenytoin intoxication and subtherapeutic carbamazepine levels, recommended plasma phenytoin concentration should not exceed 13 µg/mL before starting carbamazepine therapy. There are isolated reports of increased plasma mephenytoin concentrations with carbamazepine use, which in rare cases may lead to confusion and even coma.

Antifungal agents: itraconazole, voriconazole, ketoconazole. Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.

Anthelmintics: praziquantel, albendazole.

Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.

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

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

Anxiolytics: alprazolam, midazolam.

Bronchodilators or antiasthmatic agents: theophylline.

Hormonal contraceptives (CYP3A4 substrates):

Carbamazepine is a strong inducer of CYP3A4. Carbamazepine may increase the metabolism of certain hormonal contraceptives (via CYP3A4 induction), such as oral and subdermal implanted contraceptives, resulting in significantly lower plasma hormone concentrations. This may lead to contraceptive failure or breakthrough bleeding. Alternative methods to oral and subdermal implanted contraceptives that are significantly affected by CYP3A4 induction should be considered; or alternative antiepileptic agents to carbamazepine [see sections "Special precautions for use" and "Use in specific populations"].

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, tacrolimus, sirolimus.

Thyroid agents: levothyroxine. It is expected that carbamazepine enhances the elimination of thyroid hormones and increases the requirement for thyroid hormones in patients with hypothyroidism. Therefore, thyroid function should be monitored in patients receiving replacement therapy both at the beginning and end of treatment with Mesacar®.

If necessary, the dose of thyroid hormones should be adjusted. Thyroid function may change, particularly when carbamazepine is used concomitantly with other anticonvulsant drugs (e.g., phenobarbital).

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

Combinations of medicinal products 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 or metoclopramide, as well as carbamazepine with neuroleptics (haloperidol, thioridazine), may increase adverse neurological effects (in the case of the latter combination, even at therapeutic plasma levels). Therefore, careful monitoring of clinical symptoms is required. At least 8 weeks should elapse after discontinuation of previous neuroleptic treatment. Concomitant treatment should also be avoided. Patients should be monitored for the development of neurotoxic symptoms: unsteady gait, ataxia, horizontal nystagmus, increased proprioceptive muscle reflexes, muscle spasms (fasciculations).

According to published data, adding carbamazepine to ongoing neuroleptic therapy may increase the risk of neuroleptic malignant syndrome or Stevens-Johnson syndrome.

Combination therapy with Mesacar® 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 medicinal products, may reduce tolerance to alcohol; therefore, patients are advised to abstain from alcohol consumption.

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 of thrombosis.

Contraindicated interaction.

Since carbamazepine is structurally similar to tricyclic antidepressants, Mesacar® is contraindicated for concomitant use with monoamine oxidase inhibitors (MAO inhibitors); prior to starting Mesacar®, MAO inhibitor therapy must be discontinued (at least 2 weeks or earlier if clinically feasible).

Effect on serological tests.

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

Carbamazepine and 10,11-epoxide may yield false-positive results in fluorescence polarization immunoassays for tricyclic antidepressants.

Special precautions for use.

General.

Mesacar® should be used only under medical supervision, only after assessment of the benefit/risk ratio and with careful monitoring of patients with cardiac, hepatic or renal disorders, history of hematological adverse reactions to other drugs, disorders of sodium metabolism, and patients with interrupted courses of therapy with Mesacar®.

It is recommended to perform urinalysis and blood urea nitrogen determination at the beginning and periodically during therapy.

Mesacar® exhibits mild anticholinergic activity; therefore, patients with elevated intraocular pressure should be warned and advised about possible risk factors.

One should remember about the possible activation of latent psychoses, and in elderly patients – about the possible activation of confusion and anxious agitation.

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

Hematological effects.

The use of the drug 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 significant risk associated with taking Mesacar®. The overall risk in untreated patients is 4.7 cases/1,000,000 per year for agranulocytosis and 2 cases/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 such reactions as fever, sore throat, groin infection, skin rashes, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura occur, they should immediately consult a physician.

If the number of leukocytes or platelets significantly decreases during therapy, the patient's condition should be carefully monitored, and regular complete blood counts should be performed. Treatment with Mesacar® should be discontinued if the patient develops leukopenia that is serious, progressive, or accompanied by clinical manifestations such as fever or sore throat. Mesacar® should be discontinued if signs of bone marrow suppression occur.

A temporary or persistent decrease in the number of platelets or white blood cells is occasionally or frequently observed with Mesacar®. However, most of these cases have been confirmed as temporary and do not indicate the development of aplastic anemia or agranulocytosis. Blood tests, including platelet count (and possibly reticulocyte count, hemoglobin level, and serum iron level), should be performed before the start of 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 Mesacar®. 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 Mesacar®. 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, Mesacar® should be discontinued immediately and alternative therapy initiated.

Pharmacogenomics.

Increasing evidence indicates the influence of various HLA alleles on a patient's susceptibility to immune system-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 in the population. The carrier frequency of this allele exceeds 15% in the populations of the Philippines and 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 defined populations carrying the respective allele. Thus, the percentage of patients carrying at least one copy of the allele on one 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.

In patients considered genetically at risk, testing for the presence of the (HLA)-B*1502 allele should be performed before initiating treatment with Mesacar®. If the patient's test for the (HLA)-B*1502 allele is positive, treatment with Mesacar® 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 have a negative result for (HLA)-B*1502 have a low risk of developing SJS, although such reactions are very rare.

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 associated with SJS/TEN should be avoided in patients carrying the (HLA)-B*1502 allele if alternative therapy is available. Genetic screening of patients from nationalities with a low frequency of the (HLA)-B*1502 allele is generally not recommended. Screening of patients already receiving Mesacar® is generally not recommended, 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 and patient management, 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 Mesacar®. 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 doses, 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 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 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 Mesacar® should be avoided.

Data from retrospective analyses in Japanese and Northern European patients 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 the use of carbamazepine.

The prevalence of this allele may vary among different ethnic groups: approximately 2–5% in the European population, about 10% in Japanese. The 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. Exceptions range from 5% to 12%. A prevalence of over 15% has been established in certain South American ethnic groups (Argentina and Brazil), Native North Americans (Navajo and Sioux tribes, Seri in Mexico), and South India (Tamil Nadu).

The allele prevalence stated in this document represents the percentage of chromosomes in defined populations carrying the respective allele. Thus, the percentage of patients carrying at least one copy of the allele on one 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.

Before initiating treatment with Mesacar®, screening is recommended for potential carriers of the HLA-A*3101 allele (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 possible risk. Screening for the HLA-A*3101 allele is generally not required in patients who have already been receiving Mesacar® for a prolonged period, as SJS/TEN, AGEP, DRESS, and maculopapular rash are typically observed only within the first few months of therapy.

Limits of genetic screening

Genetic screening results should not replace appropriate clinical monitoring and patient management. Other possible factors, such as dosage of the antiepileptic drug, adherence to therapy, and concomitant therapy, play a role in the development of these severe skin adverse reactions. The influence of other diseases and the level of skin disorder monitoring have not been studied.

Other dermatological reactions.

Transient and non-threatening mild dermatological reactions, such as isolated macular or maculopapular exanthema, may also occur. Usually, they resolve within a few days or weeks, both with continued dosing and after dose reduction. Since early signs of more serious dermatological reactions may be very difficult to distinguish from mild transient reactions, the patient should be under close observation to immediately discontinue the drug if the reaction worsens with continued use.

The presence of the HLA-A*3101 allele in a patient is associated with less serious adverse skin reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or minor rashes (maculopapular rashes). However, the presence of (HLA)-B*1502 has not been established as an indicator of risk for the aforementioned skin reactions.

Hypersensitivity. Mesacar® may provoke hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), multiple delayed-type 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 a patient is associated with less serious adverse skin reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or minor rashes (maculopapular rashes).

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).

In general, if symptoms indicating hypersensitivity occur, Mesacar® should be discontinued immediately.

Seizures. Since carbamazepine may induce or exacerbate absence seizures, Mesacar® should be used with caution in patients with mixed seizure types including absences (typical or atypical). Under these circumstances, the drug may provoke seizures. If seizures are provoked, Mesacar® should be discontinued immediately.

An increase in seizure frequency is possible during the transition from oral formulations of the drug 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 if there is an exacerbation of liver function disorders or during the active phase of liver disease.

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

Hyponatremia. Cases of hyponatremia are known 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, sodium levels should be measured every 2 weeks, then monthly for the first three months of treatment or according to clinical need. This particularly applies to elderly patients. Water intake should be limited in such cases.

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

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

Psychiatric effects. One should remember about the possible 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. A meta-analysis of data from placebo-controlled trials of antiepileptic drugs 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, if necessary, appropriate treatment should be prescribed. Patients (and caregivers) should be advised to consult a physician if signs of suicidal thoughts and behavior appear.

Pregnancy. Congenital malformations may occur with carbamazepine use during pregnancy. Carbamazepine should be used during pregnancy for epilepsy treatment only if the potential benefit outweighs the potential risks. 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 regarding 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.

Women of childbearing potential

Carbamazepine may harm the fetus when used by a pregnant woman. Pregnancy registries and epidemiological data indicate a potential association between prenatal exposure to carbamazepine and the risk of serious congenital malformations and other adverse developmental outcomes, including neural tube defects and malformations of other organ systems [e.g., craniofacial defects and cardiovascular system malformations] (see section "Pregnancy or lactation"). Animal studies with clinically relevant doses of carbamazepine during pregnancy have resulted in fetal developmental toxicity, including increased incidence of fetal malformations.

Unless, after careful consideration of alternative treatment options, the benefit is deemed to outweigh the risks, carbamazepine should not be used in women of childbearing potential.

Women of childbearing potential should be fully informed about the potential risk to the fetus if they take carbamazepine during pregnancy.

Before starting carbamazepine treatment, a pregnancy test should be considered in women of childbearing potential.

Women of childbearing potential 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 potential should consult about the use of other effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Pregnancy or lactation").

Women of childbearing potential should consult their physician as soon as they plan pregnancy to discuss switching to alternative treatment before conception and discontinuation of contraception (see section "Pregnancy or lactation").

Women of childbearing potential should be advised to immediately consult a physician if they become pregnant or think they may be pregnant while taking carbamazepine.

Endocrine effects. Due to hepatic enzyme induction, Mesacar® 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 Mesacar® 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 Mesacar® treatment.

Plasma drug level monitoring. Although the correlation between dosing and plasma carbamazepine levels, as well as between plasma carbamazepine levels and clinical efficacy and tolerability, is unreliable, monitoring plasma drug levels may be useful in the following cases: sudden increase in seizure frequency, checking patient compliance, during pregnancy, in children and adolescents; suspicion of impaired absorption, suspected toxicity, and when using multiple drugs.

Dosage reduction and drug discontinuation. Abrupt discontinuation of Mesacar® may provoke seizures. If abrupt discontinuation of therapy 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 tapered 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. Treatment with Mesacar® 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. For patients with diseases, conditions, or taking medications that exacerbate these conditions, a full risk assessment for falls should be regularly performed during long-term treatment with Mesacar®.

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

Use in children.

The safety and efficacy of carbamazepine for the treatment of bipolar disorder and trigeminal neuralgia pain have not been established in pediatric patients.

The safety and efficacy of carbamazepine in pediatric patients for the treatment of partial seizures, generalized tonic-clonic seizures, and mixed seizure types have been established (see sections "Indications" and "Dosage and administration").

Use during pregnancy or lactation.

Pregnancy

General risk associated with the use of antiepileptic medicinal products (AEDs)

All women of childbearing potential receiving antiepileptic therapy, and especially women planning pregnancy and pregnant women, should receive medical advice regarding the potential risk to the fetus from both seizures and antiepileptic treatment.

Abrupt discontinuation of AED treatment 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 epilepsy treatment during pregnancy, as therapy with multiple AEDs 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 risks of congenital malformations and other adverse developmental outcomes. Exposure to 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%. Malformations reported include neural tube defects in the fetus, craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, finger hypoplasia, and other anomalies affecting various organ systems of the fetus in mothers who used carbamazepine during pregnancy. Specialized antenatal 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 AEDs 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, after careful consideration of alternative treatment options, the benefit is deemed to outweigh the risks, carbamazepine should not be used in women during pregnancy. The woman should be fully informed and understand the risks of taking carbamazepine during pregnancy.

Data indicate that the risk of malformations with carbamazepine use may depend on the dose. If, based on a careful benefit/risk assessment, no suitable alternative treatment is available and carbamazepine treatment continues, monotherapy and the lowest effective dose of carbamazepine should be used, and plasma level monitoring is recommended. Plasma concentrations can be maintained in the lower part of the therapeutic range of 4–12 µg/mL, provided seizure control is maintained.

It has been reported that some AEDs, such as carbamazepine, reduce serum folate levels. This deficiency may contribute to an increased frequency of fetal malformations in mothers with epilepsy. Folic acid is recommended before and during pregnancy. Vitamin K1 is also recommended for the mother during the last weeks of pregnancy and for newborns to prevent coagulation disorders in the child.

If a woman plans to become pregnant, all efforts should be made before conception and discontinuation of contraception to switch 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 potential

Carbamazepine should not be used in women of childbearing potential, except when the potential benefit/risk outweighs alternative treatment options. The woman should be fully informed and understand the potential risk to the fetus when taking carbamazepine during pregnancy, so it is important to plan pregnancy in advance. Before starting carbamazepine treatment, the possibility of performing a pregnancy test should be considered in women of childbearing potential.

Women of childbearing potential should use effective contraception during and after discontinuation of treatment for two weeks. 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 potential should consult about the use of other effective contraceptive methods. At least one effective contraceptive method (e.g., intrauterine) or two additional forms of contraception, including a barrier method, should be used. Individual circumstances should be evaluated when choosing a contraceptive method, involving the patient in the discussion.

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 reported cases 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.

Lactation. In studies on rats, adverse effects were observed in offspring of females administered carbamazepine. 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. The benefits of breastfeeding generally outweigh the risk of adverse effects. Breastfeeding should be discontinued if the infant is not gaining weight properly, is excessively sleepy, or develops allergic skin reactions. Cases of cholestatic hepatitis have been described in children exposed to carbamazepine antenatally or through breast milk, so monitoring for adverse effects in the hepatobiliary system should be conducted in such children. Mothers receiving Mesacar® may breastfeed provided 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. However, a causal relationship between these disorders and carbamazepine has not yet been established.

Ability to affect reaction speed when driving vehicles or operating machinery.

The ability of a patient taking Mesacar® to react quickly (especially at the beginning of therapy or during dose adjustment) may be reduced both due to seizures caused by the disease and due to adverse effects resulting from carbamazepine use, such as dizziness, somnolence, ataxia, diplopia, accommodation disorders, and visual disturbances. Therefore, patients should exercise caution when driving vehicles or operating machinery.

Dosage and Administration

Mезakar® should be administered orally; the usual daily dose of the medicinal product should be divided into two or three doses. The medicinal product can be taken during, after meals or between meals, together with a small amount of liquid, for example, a glass of water.

Before starting treatment, patients who are potentially carriers of the HLA-A*3101 allele by ancestry should, if possible, be tested for the presence of this allele, as its presence may provoke the development of severe adverse reactions, such as skin reactions.

Epilepsy

Treatment should be initiated with a low daily dose, gradually increasing the dose of the medicinal product, which should be adjusted according to the individual needs of each patient.

Determining the plasma concentration of carbamazepine may be helpful in selecting the optimal dose of the medicinal product.

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

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

Adults: the recommended initial dose of the medicinal product is 100–200 mg once or twice daily. The dose should then be gradually increased until the optimal effect is achieved; the daily dose often reaches 400 mg twice or three times daily (corresponding to 800–1200 mg). Some patients may require a dose of Mезakar® up to 1600 mg or even 2000 mg per day, although such high doses should be avoided due to the higher frequency of adverse effects.

Elderly patients: in elderly patients, due to the possibility of drug interactions, the dose of Mезakar® should be carefully selected. The recommended initial dose is 100 mg twice daily.

Children: treatment can be initiated with a dose of 100 mg/day; the dose should be gradually increased by 100 mg each week.

The usual dose of the drug is 10–20 mg/kg body weight per day (taken in several divided 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, Mezakar® should be administered as monotherapy; however, when used concomitantly with other medicinal products, a gradual dose escalation of carbamazepine similar to that recommended for monotherapy is advised.

When initiating Mezakar® in addition to ongoing antiepileptic therapy, the dose of carbamazepine should be gradually increased without altering the dose of the currently used antiepileptic drug(s), or with dose adjustments as necessary.

Acute manic states and maintenance therapy in bipolar affective disorders

Dosage range – approximately 400 to 1600 mg daily; usually 400 to 600 mg daily, divided into 2–3 doses. In acute manic states, a relatively rapid dose escalation is recommended, whereas for optimal tolerability during maintenance therapy in bipolar disorders, a gradual increase in small doses is recommended.

Alcohol withdrawal syndrome

Average dose – 200 mg 3–4 times daily. In severe cases, during the first few days the dose may be increased (e.g., up to 400 mg 3 times daily (1200 mg/day)). Subsequently, the dose should be gradually reduced and therapy tapered off. In severe alcohol withdrawal, treatment should be initiated with a combination of Mezakar® and sedative-hypnotic agents (e.g., clomethiazole, chlordiazepoxide), following the dosage recommendations outlined above. After completion of the acute phase, treatment with Mezakar® may continue as monotherapy.

Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical). Idiopathic glossopharyngeal neuralgia

Initial dose of Mezakar® is 200–400 mg daily (100 mg twice daily for elderly patients). The dose should be slowly increased until pain relief is achieved (usually up to a dose of 200 mg 3–4 times daily). For most patients, a carbamazepine dose of 200 mg 3 or 4 times daily is sufficient to maintain a pain-free state. In some cases, a daily carbamazepine dose of up to 1600 mg may be required. After pain relief is achieved, the dose should be gradually reduced to the minimum effective maintenance dose. The maximum recommended dose is 1200 mg/day. Thereafter, the dose should be gradually reduced and therapy tapered off.

Children.

Due to a more rapid elimination of carbamazepine, children may require higher doses of the medicinal product (on a mg/kg basis) compared to adults. Mezakar® tablets may be administered to children aged 6 years and older.

Overdose.

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

Central nervous system: CNS depression; disorientation, depressed 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 leading to 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 an 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 extent of overdose.

Gastric evacuation, gastric lavage, and administration of activated charcoal should be performed. Late gastric evacuation may result in 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 restriction and slow, cautious intravenous infusion of 0.9% sodium chloride solution. These measures may help prevent cerebral edema.

Hemosorption using charcoal sorbents is recommended. Hemodialysis is an effective treatment method in carbamazepine overdose. 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 drug absorption.

Adverse reactions.

At the beginning of treatment with the medicinal product Mezakar® or when using too high an initial dose of carbamazepine, or when treating elderly patients, certain types of adverse reactions occur frequently or uncommonly, for example, from the central nervous system (dizziness, headache, ataxia, somnolence, general weakness, diplopia), from the gastrointestinal tract (nausea, vomiting), or allergic skin reactions.

Dose-dependent adverse reactions usually resolve within a few days either spontaneously or after temporary reduction of the carbamazepine dose. The development of adverse reactions from the CNS may be due to relative overdosing of the medicinal product or significant fluctuations in the plasma concentration of the active substance. In such cases, monitoring of the active substance level in plasma is recommended, and the daily dose of the medicinal product should be divided into smaller doses (e.g., 3–4) administered separately.

Adverse reactions occurred with the following frequency: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000), including isolated cases.

Blood and lymphatic system disorders: very common – leukopenia (11%), persistent in 2% of cases; common – thrombocytopenia, eosinophilia; rare – lymphadenopathy, folic acid deficiency; very rare – leukocytosis, agranulocytosis, aplastic anemia, pancytopenia, erythroblastopenia, anemia, megaloblastic anemia, acute intermittent porphyria, mixed porphyria, late cutaneous porphyria, reticulocytosis, hemolytic anemia.

Immune system disorders: rare – multiorgan hypersensitivity of delayed type with fever, skin rashes, vasculitis, lymphadenopathy; symptoms resembling lymphoma; arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, and altered liver function tests, and vanishing bile duct syndrome (destruction and disappearance of intrahepatic bile ducts), occurring in various combinations. Other organ involvement may occur (e.g., liver, lungs, kidneys, pancreas, myocardium, colon); very rare – aseptic meningitis with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioneurotic edema, hypogammaglobulinemia.

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 disorders, seizures, disorientation, impaired cognition, visual disturbances or encephalopathy (syndrome of inappropriate antidiuretic hormone secretion, SIADH); very rare – increased blood prolactin levels, with or without manifestations such as galactorrhea, gynecomastia, disturbances in bone metabolism (decreased calcium and 25-hydroxycholecalciferol levels in plasma), leading to osteomalacia/osteoporosis; in isolated cases – increased cholesterol concentration, including high-density lipoprotein cholesterol and triglycerides.

Metabolism and nutrition disorders: rare – folate deficiency, decreased appetite; very rare – acute porphyria (acute intermittent porphyria and mixed porphyria), non-acute porphyria (late cutaneous porphyria); unknown – 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, tic), nystagmus; rare – orofacial dyskinesia, eye movement disorders, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness and paresis; very rare – taste disturbances, malignant neuroleptic syndrome (NMS), aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

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, impaired perception of sound pitch.

Cardiac and vascular 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 – hypersensitivity reactions from the lungs characterized by fever, dyspnea, pneumonitis or pneumonia.

Gastrointestinal disorders: very common – nausea, vomiting (both 8%); common – dry mouth; uncommon – diarrhea or constipation; rare – abdominal pain; very rare – glossitis, stomatitis, pancreatitis.

Hepatobiliary disorders: very common – increased gamma-glutamyltransferase levels (due to induction of liver enzymes), which is usually not clinically significant; common – increased alkaline phosphatase levels in blood; 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 in severe form; uncommon – exfoliative dermatitis, erythroderma; rare – systemic lupus erythematosus, pruritus; very rare – Stevens-Johnson syndrome (in some Asian countries this adverse event has also been reported with an incidence classified as "rare"), toxic epidermal necrolysis, photosensitivity, multiform and nodular erythema, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism.

Musculoskeletal, connective tissue and bone disorders: rare – muscle weakness; very rare – arthralgia, myalgia, muscle spasms, bone metabolism disorders (decreased calcium and 25-hydroxycholecalciferol levels in plasma, which may lead to osteomalacia or osteoporosis).

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

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

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

General disorders: very common – general weakness.

Laboratory and instrumental findings: very common – increased gamma-glutamyltransferase levels (caused by induction of liver enzymes), which is usually not clinically significant; common – increased blood alkaline phosphatase levels; uncommon – increased transaminase levels; very rare – increased intraocular pressure, increased blood cholesterol levels (including increased high-density lipoprotein and triglyceride levels), increased blood triglyceride levels, changes in thyroid function tests: decreased L-thyroxine levels (free thyroxine (FT4), thyroxine (T4), triiodothyronine (T3)) and increased thyroid-stimulating hormone (TSH) levels, which usually do not have clinical manifestations; increased blood prolactin levels, hypogammaglobulinemia.

Adverse reactions based on spontaneous reports (frequency unknown).

Information about the adverse reactions listed below was obtained from post-marketing use of the drug from spontaneous reports and publications. Since the reports are spontaneous, it is impossible to accurately determine the number of patients and reliably assess the frequency of adverse reactions; therefore, their frequency is classified as "unknown."

Infections and parasitic diseases: reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: bone marrow insufficiency.

Nervous system disorders: lethargy, 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 (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal, connective tissue and bone disorders: fractures.

Laboratory and instrumental findings: decreased bone mineral density.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 5 blisters in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's location and address of its business activity.

54 Skryabina St., Sumy, Sumy region, 40020, Ukraine.

INSTRUCTION

for medical use of the medicinal product

MEZACAR®

(MEZACAR®)

Composition:

Active ingredient: carbamazepine;

1 tablet contains 200 mg of carbamazepine;

Inactive ingredients: microcrystalline cellulose, hypromellose E5, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white, round tablets with a bevelled break line on one side and embossing "K" on the other.

Pharmacotherapeutic group.

Antiepileptic drugs. ATC code N03AF01.

Pharmacological Properties

Pharmacodynamics

As an anticonvulsant agent, the antiepileptic drug Mезacar® 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.

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 partially manifested as a positive impact on symptoms of anxiety and depression, as well as reduced irritability and aggressiveness.

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

It has been confirmed that as a psychotropic agent, carbamazepine is effective in affective disorders, namely: for the treatment of acute manic states and for maintenance therapy of bipolar affective (manic-depressive) disorders (both as monotherapy and 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 the conventional tablet, 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.

When up to 300 mg of carbamazepine is administered, approximately 75% of the administered dose 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 extent of absorption of the active substance have been observed after administration of different oral formulations 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 inter-individual 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 concomitantly 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%. The concentration of unchanged carbamazepine in cerebrospinal fluid and saliva is proportional to the fraction of unbound active substance (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 ranges from 0.8 to 1.9 L/kg.

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 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 the pharmacologically active carbamazepine-10,11-epoxide, which is almost completely transformed into the 10,11-trans-diol 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 of carbamazepine lead to the formation of various monohydroxylated derivatives and the N-glucuronide of carbamazepine, formed via uridine diphosphate-glucuronosyltransferase (UGT2B7).

Carbamazepine induces its own metabolism.

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

The average 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, approximately 1% as the pharmacologically active metabolite 10,11-epoxide, and approximately 30% as carbamazepine-10,11-trans-diol and other inactive metabolites.

Pharmacokinetic characteristics in specific patient populations

Elderly patients. There are no data indicating that the pharmacokinetics of carbamazepine changes in elderly patients (compared to younger adults).

Patients with impaired renal or hepatic function. There are no data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function.

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 seizure types.
  • Mesacar® may be used both as monotherapy and in combination therapy.
  • Carbamazepine is generally not effective in absence seizures (a mild form of epileptic seizure) or 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 exacerbation.
• Alcohol withdrawal syndrome.
• Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical forms).
• Idiopathic glossopharyngeal neuralgia.

Contraindications.

Mesacar® is contraindicated:

• In patients with known hypersensitivity to carbamazepine, oxcarbazepine, or to structurally related medicinal products (such as tricyclic antidepressants), or to any other component of the preparation;
• In atrioventricular block;
• In patients with a history of bone marrow depression;
• In patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria);
• In combination with monoamine oxidase inhibitors (MAO inhibitors).

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, which in turn may lead to adverse reactions. Therefore, the dose of Mesacar® should be adjusted and plasma levels monitored. Concomitant use of CYP3A4 inducers may enhance the metabolism of carbamazepine, leading to potentially reduced plasma concentrations of carbamazepine and diminished therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, resulting in increased plasma levels of carbamazepine. Therefore, dose adjustment of Mesacar® 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 that are primarily metabolized by CYP3A4 through induction of their metabolism.

Human microsomal epoxide hydrolase is the enzyme responsible for the formation of 10,11-trans-dihydrodiol 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 thereby increase the risk of thrombosis. Therefore, if concomitant use is necessary, patients should be closely monitored for signs of thrombosis.

Medicinal products that may increase carbamazepine plasma levels.

Since elevated plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), the dosage of Mesacar® should be adjusted accordingly and/or plasma levels monitored when administered 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.

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.

Since elevated plasma levels of the active metabolite carbamazepine-10,11-epoxide may cause adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), dosage of Mesacar® should be adjusted and/or plasma levels of carbamazepine monitored when administered concomitantly with the following medicinal products: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, valpromide, brivaracetam.

Medicinal products that may decrease carbamazepine plasma levels.

Dose adjustment of Mesacar® may be required when administered concomitantly with the following medicinal products:

Antiepileptic agents: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin toxicity and subtherapeutic carbamazepine concentrations, it is recommended to adjust plasma phenytoin concentration to 13 µg/mL before 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 preparations containing St. John’s wort (Hypericum perforatum).

Mefloquine may exhibit antagonistic properties against the antiepileptic effect of carbamazepine. Therefore, the dose of Mesacar® 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 Mesacar® on plasma levels of concomitantly administered medicinal products.

Carbamazepine may reduce plasma levels of certain medicinal products 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, rivaroxaban, dabigatran, apixaban, edoxaban).

Antidepressants: bupropion (carbamazepine may reduce plasma levels of bupropion and increase levels of its metabolite hydroxybupropion, thereby reducing clinical efficacy and safety of bupropion), citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline, clomipramine). Concomitant use of Mesacar® with monoamine oxidase inhibitors (MAO inhibitors) is contraindicated. MAO inhibitors should be discontinued at least 2 weeks prior to initiation of Mesacar® (or earlier if clinically feasible).

Antiemetics: aprepitant.

Antiepileptic agents: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Both increases and decreases in plasma phenytoin levels have been reported with carbamazepine, as well as 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 before starting carbamazepine therapy. There are isolated reports of increased plasma concentrations of mephenytoin with carbamazepine, which in rare cases may cause confusion and even coma.

Antifungal agents: itraconazole, voriconazole, ketoconazole. Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.

Anthelmintics: praziquantel, albendazole.

Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.

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

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

Anxiolytics: alprazolam, midazolam.

Bronchodilators or antiasthmatic agents: theophylline.

Hormonal contraceptives (CYP3A4 substrates):

Carbamazepine is a strong inducer of CYP3A4. Carbamazepine may increase the metabolism of certain hormonal contraceptives (via induction of CYP3A4), such as oral and subdermal implanted contraceptives, leading to significantly lower hormone plasma concentrations. This may result in contraceptive failure or breakthrough bleeding. Alternative methods to oral and subdermal implanted contraceptives that are significantly affected by CYP3A4 induction should be considered; or alternative antiepileptic agents to carbamazepine should be considered [see sections "Special precautions for use" and "Use in specific populations"].

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, tacrolimus, sirolimus.

Thyroid agents: levothyroxine. Carbamazepine is expected to enhance 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 Mesacar®.

If necessary, the dose of thyroid hormones should be adjusted. Thyroid function may change, particularly when carbamazepine is used concomitantly with other anticonvulsants (e.g., phenobarbital).

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

Combinations of medicinal products requiring special consideration.

Concomitant use of carbamazepine and levetiracetam may increase carbamazepine toxicity.

Concomitant use of carbamazepine and isoniazid may increase the hepatotoxicity of isoniazid.

Concomitant use of carbamazepine with lithium or metoclopramide, as well as with neuroleptics (haloperidol, thioridazine), may increase neurological side effects (even at therapeutic plasma levels in the latter combination). Therefore, careful clinical monitoring is required. At least 8 weeks should elapse after discontinuation of previous neuroleptic therapy. Concomitant treatment 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 indicate that adding carbamazepine to ongoing neuroleptic therapy may increase the risk of neuroleptic malignant syndrome or Stevens-Johnson syndrome.

Combined therapy with Mesacar® 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.

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

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

Contraindicated interaction.

Since carbamazepine is structurally similar to tricyclic antidepressants, Mesacar® is contraindicated for concomitant use with monoamine oxidase inhibitors (MAO inhibitors); treatment with an MAO inhibitor must be discontinued at least two weeks (or earlier, if clinically feasible) before starting Mesacar®.

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 fluorescence polarization immunoassays for tricyclic antidepressants.

Special precautions.

General.

Mesacar® should be used only under medical supervision, only after benefit/risk assessment, and with careful monitoring of patients with cardiac, hepatic, or renal disorders, history of hematological adverse reactions to other drugs, sodium metabolism disorders, and patients with interrupted courses of Mesacar® therapy.

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

Mesacar® exhibits mild anticholinergic activity; therefore, patients with elevated intraocular pressure should be warned and advised about possible risk factors.

One should keep 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) and myoclonic seizures. Individual cases suggest that seizure exacerbation may occur in patients with atypical absences.

Hematological effects.

Use of the drug 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 significant risk associated with taking Mesacar®. 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, angina, groin infection, 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 carefully monitored, and regular complete blood counts should be performed. Mesacar® therapy should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical symptoms such as fever or sore throat. Mesacar® should be discontinued if signs of bone marrow suppression occur.

Temporary or persistent reduction in platelet or white blood cell counts has been observed periodically or frequently with Mesacar® use. However, most of these cases have been confirmed as temporary and do not indicate the development of aplastic anemia or agranulocytosis. Blood tests, 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 Mesacar® 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 Mesacar® treatment. It is estimated that these dermatological reactions occur in 1–6 out of 10,000 new patients in countries with predominantly Caucasian populations. However, the risk may be approximately 10 times higher in patients from certain Asian countries. If symptoms indicating serious dermatological reactions (e.g., SJS, Lyell’s syndrome/TEN) develop, Mesacar® 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 system-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. The prevalence of this HLA-B*1502 allele varies from 2% to 12% in Han Chinese patients and is approximately 8% in patients from Thailand. 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 rate of this allele in the Asian population exceeds 15% in the Philippines and in certain Malaysian populations. Prevalence of up to 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 respective 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 potentially at risk is nearly twice the allele prevalence.

In patients considered genetically at risk, testing for the presence of the (HLA)-B*1502 allele should be performed before initiating Mesacar® therapy. If the patient's test for (HLA)-B*1502 is positive, treatment with Mesacar® 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 of patients from nationalities with a low coefficient of the (HLA)-B*1502 allele is generally not recommended. Screening is generally not recommended for patients already receiving Mesacar®, 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 and management of patients, as many HLA-B*1502 carriers do not develop SJS/TEN, while others without genetic risk factors may develop SJS/TEN for other reasons. The situation is similar for carriers of the HLA-A*3101 allele receiving Mesacar®. 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 doses, 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, use of Mesacar® should be avoided.

Retrospective analysis data in Japanese and Northern European patients 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 prevalence of the allele is less than 5% in populations of Australia, Asia, Africa, and North America. In Western Europe, 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 ethnic groups in South America (Argentina and Brazil), Native North Americans (Navajo and Sioux tribes, Seri in Mexico), and South India (Tamil Nadu).

The allele prevalence stated in this document represents the percentage of chromosomes in specified populations carrying the respective 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 potentially at risk is nearly twice the allele prevalence.

Before initiating Mesacar® therapy, screening is recommended for potential carriers of the HLA-A*3101 allele (e.g., Japanese, Caucasians, Native Americans, Latin Americans, South Indians, and Arabs) (see section "Dosage and administration"). The drug should be used in carriers of this allele only when the benefit outweighs the potential risk. Screening for the HLA-A*3101 allele is generally not required in patients who have already been receiving Mesacar® 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 treatment of patients. Other possible factors, such as antiepileptic drug dosage, adherence to therapy, and concomitant therapy, play a role in the development of these severe skin adverse reactions. The impact of other diseases and the level of skin disorder monitoring have not been studied.

Other dermatological reactions.

Transient and non-life-threatening mild dermatological reactions, such as isolated macular or maculopapular exanthema, may also occur. They usually resolve within a few days or weeks, both with continued dosing and after dose reduction. Since early signs of more serious dermatological reactions may be very difficult to distinguish from mild transient reactions, the patient should be under close observation to immediately discontinue the drug if the reaction worsens with continued use.

The presence of the HLA-A*3101 allele in patients is associated with less serious adverse skin reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or minor 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. Mesacar® may provoke hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), multiple delayed-type 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 serious adverse skin reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or minor 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.

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

In general, if symptoms indicating hypersensitivity occur, Mesacar® should be immediately discontinued.

Seizures. Since carbamazepine may cause or exacerbate absence seizures, Mesacar® should be used with caution in patients with mixed seizures including absences (typical or atypical). Under such circumstances, the drug may provoke seizures. If seizures are provoked, Mesacar® 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 periodically during therapy, especially in patients with a history of liver disease and in elderly patients. The drug should be immediately discontinued if liver function disorders worsen or during the active phase of liver disease.

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

Hyponatremia. Cases of hyponatremia development have been reported with carbamazepine use. In patients with pre-existing renal dysfunction associated with low sodium levels, or in patients receiving concomitant therapy with drugs that reduce 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 during the first 3 months of treatment or as clinically necessary. This particularly applies to elderly patients. In such cases, water intake should be limited.

Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations; therefore, an increase in thyroid hormone replacement therapy dosage may be necessary for patients with hypothyroidism. Thus, monitoring of thyroid function is recommended to determine the appropriate dosage of replacement hormone therapy.

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

Psychiatric effects. One should keep 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. A meta-analysis of data from placebo-controlled trials of antiepileptic drugs 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 monitored for suicidal thoughts and behavior, and appropriate treatment should be initiated if necessary. Patients (and caregivers) should be advised to consult a physician if signs of suicidal thoughts or behavior occur.

Pregnancy. Congenital malformations may occur with carbamazepine use during pregnancy. For epilepsy treatment during pregnancy, carbamazepine should be used only if the potential benefit justifies the potential risks. 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 regarding the potential teratogenic risk to unborn children.

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

Women of childbearing potential

Carbamazepine may harm the fetus when used by a pregnant woman. Pregnancy registries and epidemiological data indicate a potential association between prenatal exposure to carbamazepine and the risk of serious congenital malformations and other adverse developmental outcomes, including neural tube defects and malformations of other organ systems [e.g., craniofacial defects and cardiovascular system malformations] (see section "Pregnancy or breastfeeding"). Animal studies have shown that carbamazepine use at clinically relevant doses during pregnancy resulted in fetal developmental toxicity, including increased incidence of fetal malformations.

Unless a careful evaluation of alternative treatment options concludes that benefits outweigh risks, carbamazepine should not be used in women of childbearing potential.

Women of childbearing potential should be fully informed about the potential risk to the fetus if they take carbamazepine during pregnancy.

Before initiating carbamazepine therapy, a pregnancy test should be considered in women of childbearing potential.

Women of childbearing potential should use effective contraception during treatment and for two weeks after discontinuation of treatment.

Due to enzyme induction, carbamazepine may interfere with the therapeutic effect of hormonal contraceptives;

therefore, women of childbearing potential should consult their physician about using other effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Pregnancy or breastfeeding").

Women of childbearing potential should consult their physician as soon as they plan pregnancy to discuss switching to alternative treatment before conception and discontinuation of contraception (see section "Pregnancy or breastfeeding").

Women of childbearing potential should be advised to immediately consult a physician if they become pregnant or suspect they may be pregnant while taking carbamazepine.

Endocrine effects. Due to hepatic enzyme induction, Mesacar® may cause reduced therapeutic effect of estrogen and/or progesterone-containing drugs. This may lead to reduced contraceptive efficacy, symptom recurrence, or breakthrough bleeding or spotting. Female patients taking Mesacar® who require hormonal contraception should receive a preparation containing at least 50 mcg of estrogen, or alternative effective and reliable non-hormonal contraceptive methods should be considered during Mesacar® treatment.

Plasma level monitoring. Although the correlation between dosage and carbamazepine plasma levels, as well as between carbamazepine plasma levels and clinical efficacy and tolerability, is unreliable, monitoring plasma levels may be useful in the following cases: sudden increase in seizure frequency, checking patient compliance, during pregnancy, in pediatric and adolescent patients; suspected absorption impairment, suspected toxicity, and when using multiple drugs.

Dose reduction and drug discontinuation. Abrupt discontinuation of Mesacar® may provoke seizures. If abrupt discontinuation is necessary, patients with epilepsy should be switched to a new antiepileptic drug while continuing appropriate medication therapy.

Dose reduction and withdrawal syndrome. Abrupt discontinuation of the drug may provoke seizures; therefore, carbamazepine should be gradually withdrawn 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, rectal diazepam, or intravenous phenytoin).

Falls. Mesacar® 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. For patients with conditions, diseases, or taking medications that exacerbate these conditions, a full risk assessment for falls should be regularly performed during long-term Mesacar® treatment.

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

Use in children.

The safety and efficacy of carbamazepine for the treatment of bipolar disorder and trigeminal neuralgia pain have not been established in pediatric patients.

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 types (see sections "Indications" and "Dosage and administration").

Use during pregnancy or breastfeeding.

Pregnancy

General risk associated with antiepileptic medicinal products (AEDs)

All women of childbearing potential receiving antiepileptic therapy, and especially women planning pregnancy and pregnant women, should receive medical advice regarding the potential risk to the fetus from both seizures and antiepileptic treatment.

Abrupt discontinuation of AED therapy should be avoided, as it may lead to seizures, which may have serious consequences for the woman and the unborn child.

If possible, monotherapy is preferred for epilepsy treatment during pregnancy, as therapy with multiple AEDs 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. Exposure to 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%. Malformations reported include neural tube defects in the fetus, craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, finger hypoplasia, and other anomalies affecting various fetal organ systems in mothers who used carbamazepine during pregnancy. Specialized antenatal 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 AEDs 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 in women 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 depend on the dose. If, based on a careful benefit/risk assessment, no suitable alternative treatment is available and carbamazepine therapy is continued, monotherapy and the lowest effective dose of carbamazepine should be used, and plasma level monitoring is recommended. Plasma concentrations can be maintained in the lower part of the therapeutic range of 4–12 mcg/mL, provided seizure control is maintained.

It has been reported that some AEDs, such as carbamazepine, reduce serum folate levels. This deficiency may contribute to an increased frequency of fetal malformations in mothers with epilepsy. Folic acid intake is recommended before and during pregnancy. Vitamin K1 is also recommended for the mother during the last weeks of pregnancy and for newborns to prevent coagulation disorders in the child.

If a woman plans to become pregnant, all efforts should be made before conception and before discontinuing contraception to switch 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 potential

Carbamazepine should not be used in women of childbearing potential, except when the potential benefit/risk outweighs alternative treatment options. The woman should be fully informed and understand the potential risk to the fetus if carbamazepine is taken during pregnancy; therefore, it is important to plan pregnancy in advance. Before initiating carbamazepine therapy, a pregnancy test should be considered in women of childbearing potential.

Women of childbearing potential should use effective contraception during and for two weeks after discontinuation of treatment. Due to enzyme induction, carbamazepine may interfere with the therapeutic effect of hormonal contraceptives (see section "Interaction with other medicinal products and other forms of interaction"); therefore, women of childbearing potential 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. When choosing a contraceptive method, individual circumstances should be evaluated, involving the patient in the discussion.

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 when dams were administered carbamazepine. 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. The benefits of breastfeeding generally outweigh the risk of adverse effects. Breastfeeding should be discontinued if the infant fails to gain weight adequately, is excessively sleepy, or develops allergic skin reactions. Cases of cholestatic hepatitis have been reported in children exposed to carbamazepine prenatally or through breast milk; therefore, monitoring of such children for adverse effects on the hepatobiliary system is recommended. Mothers receiving Mesacar® may breastfeed provided the infant is monitored for possible adverse reactions (e.g., excessive somnolence, allergic skin reactions).

Fertility.

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

Ability to influence reaction speed when driving or operating machinery.

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

Dosage and Administration

Mezakar® should be administered orally; the daily dose is usually divided into two or three doses. The medication may be taken during, after meals, or between meals, together with a small amount of liquid, for example, a glass of water.

Before initiating treatment, patients who are potentially of ancestry associated with the HLA-A*3101 allele should, if possible, be tested for the presence of this allele, as its presence may provoke severe adverse reactions, such as skin reactions.

Epilepsy

Treatment should be initiated with a low daily dose, gradually increasing the dose of the medication, which must be individually adjusted according to each patient's needs.

Determining plasma carbamazepine levels may be helpful in establishing the optimal dose of the drug.

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

Experience has shown that therapeutic carbamazepine levels range between 4–12 mcg/mL.

Adults: the recommended initial dose is 100–200 mg once or twice daily. The dose should then be gradually increased until the optimal effect is achieved; often, the daily dose is 400 mg twice or three times daily (corresponding to 800–1200 mg). Some patients may require a dose of Mezakar® up to 1600 mg or even 2000 mg daily, although such high doses should be avoided due to the increased frequency of adverse events.

Elderly patients: due to potential drug interactions, the dose of Mezakar® should be carefully titrated in elderly patients. 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.

The usual dosage is 10–20 mg/kg body weight per day (administered in 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, Mezakar® should be prescribed as monotherapy; however, when used concomitantly with other medicinal products, a similar gradual increase in carbamazepine dosage is recommended.

When Mezakar® is prescribed in addition to ongoing antiepileptic therapy, the carbamazepine dose should be gradually increased without changing the dose of the currently used antiepileptic drug(s), or adjusting it 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 escalation is recommended, whereas for optimal tolerability during maintenance therapy in bipolar disorders, a gradual increase in small increments is advised.

Alcohol withdrawal syndrome

Average dose – 200 mg 3–4 times daily. In severe cases, during the first few days the dose may be increased (e.g., up to 400 mg 3 times daily (1200 mg/day)). Subsequently, the dose should be gradually reduced and therapy tapered off. In severe alcohol withdrawal, treatment should be initiated with a combination of Mezakar® and sedative-hypnotic agents (e.g., with clomethiazole, chlordiazepoxide), following the above dosage recommendations. After completion of the acute phase, treatment with Mezakar® may continue as monotherapy.

Idiopathic trigeminal neuralgia and trigeminal neuralgia in multiple sclerosis (typical and atypical). Idiopathic glossopharyngeal neuralgia

Initial dose of Mezakar® is 200–400 mg daily (100 mg twice daily for elderly patients). The dose should be slowly increased until pain subsides (usually up to 200 mg 3–4 times daily). For most patients, a carbamazepine dose of 200 mg 3 or 4 times daily is sufficient to maintain a pain-free state. In some cases, a daily carbamazepine dose of 1600 mg may be required. After pain subsides, the dose should be gradually reduced to the minimum maintenance level. The maximum recommended dose is 1200 mg/day. Subsequently, the dose should be gradually reduced and therapy tapered off.

Children.

Due to a faster elimination of carbamazepine in children, higher doses of the medicinal product (on a mg/kg basis) may be required compared to adults. Mezakar® tablets may be administered to children aged 6 years and older.

Overdose.

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

Central nervous system: CNS depression; disorientation, depressed 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 toxic effects of carbamazepine have been reported.

Urinary system: Urinary retention, oliguria or anuria; fluid retention; hyperhydration due to carbamazepine’s antidiuretic hormone-like effect.

Laboratory findings: 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 extent of overdose.

Gastric evacuation, gastric lavage, and administration of activated charcoal are 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 disturbances.

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 restriction and slow, cautious intravenous infusion of 0.9% sodium chloride solution. These measures may help prevent cerebral edema.

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

Recurrence of overdose symptoms on the 2nd and 3rd day after the initial overdose should be anticipated due to delayed drug absorption.

Adverse Reactions

At the beginning of treatment with Mezakar® or when using too high an initial dose of carbamazepine, or during treatment of elderly patients, certain types of adverse reactions may frequently or infrequently occur, for example, from the central nervous system (dizziness, headache, ataxia, somnolence, general weakness, diplopia), from the gastrointestinal tract (nausea, vomiting), or allergic skin reactions.

Dose-dependent adverse reactions usually resolve within a few days either spontaneously or after temporary reduction of the carbamazepine dose. Development of adverse reactions from the CNS may result from relative overdose of the drug or significant fluctuations in plasma concentration of the active substance. In such cases, monitoring of the active substance level in plasma is recommended, and the daily dose of the drug should be divided into smaller doses (e.g., 3–4 doses).

Adverse reactions occurred with the following frequency: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000), including isolated cases.

Blood and lymphatic system disorders: very common – leukopenia (11%), persistent in 2% of cases; common – thrombocytopenia, eosinophilia; rare – lymphadenopathy, folic acid deficiency; very rare – leukocytosis, agranulocytosis, aplastic anemia, pancytopenia, erythroblastopenia, anemia, megaloblastic anemia, acute intermittent porphyria, mixed porphyria, late cutaneous porphyria, reticulocytosis, hemolytic anemia.

Immune system disorders: rare – multiorgan hypersensitivity of delayed type with fever, skin rash, vasculitis, lymphadenopathy; symptoms resembling lymphoma; arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, altered liver function tests, and vanishing bile duct syndrome (destruction and disappearance of intrahepatic bile ducts), occurring in various combinations. Other organs may also be affected (e.g., liver, lungs, kidneys, pancreas, myocardium, colon); very rare – aseptic meningitis with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioneurotic edema, hypogammaglobulinemia.

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 water intoxication 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 manifestations such as galactorrhea, gynecomastia, bone metabolism disorders (decreased levels of calcium and 25-hydroxycholecalciferol in plasma), leading to osteomalacia/osteoporosis; in isolated cases – increased cholesterol concentration, including high-density lipoprotein cholesterol and triglycerides.

Metabolism and nutrition disorders: rare – folate deficiency, decreased appetite; very rare – acute porphyria (acute intermittent porphyria and mixed porphyria), non-acute porphyria (late cutaneous porphyria); unknown – 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 disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness and paresis; very rare – taste disturbances, malignant neuroleptic syndrome (NMS), aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

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, impaired perception of sound pitch.

Cardiac and vascular disorders: rare – disturbances in cardiac 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 – hypersensitivity reactions affecting the lungs, characterized by fever, dyspnea, pneumonitis or pneumonia.

Gastrointestinal disorders: very common – nausea, vomiting (both 8%); common – dry mouth; uncommon – diarrhea or constipation; rare – abdominal pain; very rare – glossitis, stomatitis, pancreatitis.

Hepatobiliary disorders: very common – increased gamma-glutamyl transferase levels (due to induction of liver enzymes), usually without clinical significance; common – increased alkaline phosphatase levels in blood; 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 in severe form; uncommon – exfoliative dermatitis, erythroderma; rare – systemic lupus erythematosus, pruritus; very rare – Stevens-Johnson syndrome (in some Asian countries this adverse reaction has also been reported with a frequency of "rare"), toxic epidermal necrolysis, photosensitivity, erythema multiforme and nodosum, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism.

Musculoskeletal and connective tissue disorders: rare – muscle weakness; very rare – arthralgia, myalgia, muscle spasms, bone metabolism disorders (decreased calcium and 25-hydroxycholecalciferol levels in plasma, which may lead to osteomalacia or osteoporosis).

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

Reproductive system disorders: very rare – sexual dysfunction/impotence/erectile dysfunction, impaired spermatogenesis (with reduced number/motility of spermatozoa).

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

General disorders: very common – general weakness.

Laboratory and instrumental test abnormalities: very common – increased gamma-glutamyl transferase levels (due to induction of liver enzymes), usually without clinical significance; common – increased blood alkaline phosphatase levels; uncommon – increased transaminase levels; very rare – increased intraocular pressure, increased blood cholesterol levels (including high-density lipoprotein cholesterol and triglycerides), increased blood triglyceride levels, 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), which usually do not have clinical manifestations; increased blood prolactin levels, hypogammaglobulinemia.

Adverse reactions based on spontaneous reports (frequency unknown).

Information about the adverse reactions listed below was obtained from post-marketing use of the drug from spontaneous reports and publications. Since the reports are spontaneous, it is not possible to determine the exact number of patients or reliably estimate the frequency of adverse reactions; therefore, their frequency is classified as "unknown".

Infections and parasitic diseases: reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: bone marrow failure.

Nervous system disorders: lethargy, 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 (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal and connective tissue disorders: fractures.

Laboratory and instrumental test abnormalities: decreased bone mineral density.

Reporting of adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It allows ongoing monitoring of the benefit-risk balance of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 5 blisters in a cardboard package.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of business operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.

INSTRUCTION

for medical use of the medicinal product

MEZACAR®

(MEZACAR®)

Composition:

Active substance: carbamazepine;

One tablet contains 200 mg of carbamazepine;

Excipients: microcrystalline cellulose, hypromellose E5, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white, round tablets with a bevelled break line on one side and an embossing "K" on the other.

Pharmacotherapeutic group.

Antiepileptic agents. ATC code N03A F01.

Pharmacological Properties

Pharmacodynamics

As an anticonvulsant agent, the antiepileptic drug Mesacar® is effective in partial seizures (simple and complex), with or without secondary generalization, generalized tonic-clonic seizures, as well as in cases involving a combination of these seizure types.

In clinical studies, carbamazepine used as monotherapy in patients with epilepsy (particularly in children and adolescents) demonstrated psychotropic effects, including a beneficial impact on symptoms of anxiety and depression, as well as reduced irritability and aggressiveness.

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

It has been confirmed that as a psychotropic agent, carbamazepine is effective in affective disorders, specifically: for the treatment of acute manic states and for maintenance therapy of bipolar affective (manic-depressive) disorders (both as monotherapy and 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 conventional tablets, maximum plasma concentration (C_max) is reached after approximately 12 hours.

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

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

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

Plasma Concentrations
Clinically significant differences in the absorption of the active substance following administration of different oral formulations of the drug have not been observed. After a single 400 mg oral dose of carbamazepine, the mean C_max 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 those of carbamazepine.

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 concomitantly administered drugs), as well as the patient's condition, dosage, and duration of treatment.

Distribution
Protein binding of carbamazepine to plasma proteins is 70–80%. Concentrations of unchanged carbamazepine in cerebrospinal fluid and saliva are proportional to the unbound fraction of the active substance (20–30%). Carbamazepine concentrations in breast milk amount to 25–60% of its plasma levels. Carbamazepine crosses the placental barrier. Assuming complete absorption, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg.

Metabolism
Carbamazepine is primarily metabolized in the liver via the epoxide pathway, resulting in the formation of major metabolites—the 10,11-trans-diol derivative and its glucuronic acid conjugate. 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 the pharmacologically active carbamazepine-10,11-epoxide, which is almost entirely converted into the 10,11-trans-diol 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 via uridine diphosphate-glucuronosyltransferase (UGT2B7).

Carbamazepine induces its own metabolism.

Elimination
After a single oral dose, the elimination half-life of unchanged carbamazepine averages 36 hours; after repeated administration, it averages 16–24 hours (due to autoinduction of hepatic mono-oxygenase systems), depending on the duration of treatment. In patients concurrently receiving other drugs that induce the same hepatic enzyme system (e.g., phenytoin, phenobarbital), the elimination half-life of carbamazepine averages 9–10 hours.

The average elimination half-life of the 10,11-epoxide metabolite from plasma is approximately 6 hours after a single oral dose of the epoxide.

Following 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, about 1% as the pharmacologically active metabolite 10,11-epoxide, and approximately 30% as carbamazepine-10,11-trans-diol 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 impaired renal or hepatic function
There are no pharmacokinetic data available for carbamazepine in patients with impaired renal or hepatic function.

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.
  • Mesacar® can be used both as monotherapy and in combination therapy.
  • Carbamazepine 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.

Mesacar® is contraindicated:

• in patients with known hypersensitivity to carbamazepine or oxcarbazepine, or to structurally related medicinal products (such as tricyclic antidepressants), or to any other component of the drug;
• in atrioventricular block;
• in patients with a history of bone marrow depression;
• in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria);
• in combination with monoamine oxidase inhibitors (MAO inhibitors).

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 use of CYP3A4 inhibitors or epoxide hydrolase inhibitors with carbamazepine may increase plasma concentrations of carbamazepine, which in turn may lead to adverse reactions. Therefore, the dose of Mesacar® should be adjusted and plasma levels monitored. Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, potentially reducing plasma concentrations of carbamazepine and diminishing therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, leading to increased plasma levels of carbamazepine. Therefore, dose adjustment of Mesacar® may be necessary.

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II hepatic enzyme systems, and thus 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 converting carbamazepine-10,11-epoxide into 10,11-trans-diol derivatives. 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 of thrombosis.

Medicinal products that may increase plasma levels of carbamazepine.

Since elevated plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), the dosage of Mesacar® should be adjusted accordingly and/or plasma levels monitored when used concomitantly with the following medicinal products.

Analgesics, anti-inflammatory drugs: dextropropoxyphene, ibuprofen.

Androgens: danazol.

Antibiotics: macrolide antibiotics (e.g., erythromycin, troleandomycin, josamycin, clarithromycin, ciprofloxacin).

Antidepressants: desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.

Antiepileptic drugs: stiripentol, vigabatrin.

Antifungal drugs: azoles (e.g., itraconazole, ketoconazole, fluconazole, voriconazole). Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.

Antihistamines: loratadine, terfenadine.

Antipsychotics: olanzapine, loxapine, quetiapine.

Antituberculosis drugs: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular drugs: diltiazem, verapamil.

Drugs 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 of carbamazepine—10,11-epoxide.

Since elevated plasma levels of the active metabolite carbamazepine-10,11-epoxide may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), the dosage of Mesacar® should be adjusted and/or plasma levels of carbamazepine monitored when used concomitantly with the following medicinal products: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, valpromide, brivaracetam.

Medicinal products that may decrease plasma levels of carbamazepine.

Dosage adjustment of Mesacar® may be necessary when used concomitantly with the following medicinal products.

Antiepileptic drugs: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic carbamazepine concentrations, it is recommended to adjust plasma phenytoin concentration to 13 µg/mL before initiating carbamazepine therapy), fosphenytoin, primidone, and clonazepam (although data are conflicting).

Antineoplastic drugs: cisplatin or doxorubicin.

Antituberculosis drugs: rifampicin.

Bronchodilators or antiasthmatic drugs: theophylline, aminophylline.

Dermatological drugs: isotretinoin.

Interaction with other substances: herbal preparations containing St. John’s wort (Hypericum perforatum).

Mefloquine may exhibit antagonistic properties against the antiepileptic effect of carbamazepine. Therefore, the dose of Mesacar® 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 Mesacar® on plasma levels of concomitantly administered drugs.

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

Analgesics, anti-inflammatory drugs: 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, rivaroxaban, dabigatran, apixaban, edoxaban).

Antidepressants: bupropion (carbamazepine may reduce plasma levels of bupropion and increase levels of its metabolite hydroxybupropion, thereby reducing the clinical efficacy and safety of bupropion), citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline, clomipramine). Concomitant use of Mesacar® with monoamine oxidase inhibitors (MAO inhibitors) is contraindicated. Treatment with MAO inhibitors should be discontinued at least 2 weeks before initiating Mesacar® (or earlier if clinically feasible).

Antiemetics: aprepitant.

Antiepileptic drugs: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Both increases and decreases in plasma phenytoin levels have been reported with carbamazepine. Isolated cases of increased plasma levels of mephenytoin have also been reported. To avoid phenytoin intoxication and subtherapeutic carbamazepine concentrations, plasma phenytoin concentration should not exceed 13 µg/mL before starting carbamazepine therapy. There are isolated reports of increased plasma concentrations of mephenytoin with carbamazepine use, which in rare cases may lead to confusion and even coma.

Antifungal drugs: itraconazole, voriconazole, ketoconazole. Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.

Antihelminthic drugs: praziquantel, albendazole.

Antineoplastic drugs: imatinib, cyclophosphamide, lapatinib, temsirolimus.

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

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

Anxiolytics: alprazolam, midazolam.

Bronchodilators or antiasthmatic drugs: theophylline.

Hormonal contraceptives (CYP3A4 substrates):

Carbamazepine is a strong inducer of CYP3A4. Carbamazepine may increase the metabolism of certain hormonal contraceptives (via induction of CYP3A4), such as oral and subdermal implanted contraceptives, leading to significantly lower plasma hormone concentrations. This may result in contraceptive failure or breakthrough bleeding. Alternatives to oral and subdermal implanted contraceptives that are significantly affected by CYP3A4 induction should be considered; or alternatives to carbamazepine should be considered [see sections "Special precautions for use" and "Use in specific populations"].

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

Corticosteroids, including prednisolone, dexamethasone.

Drugs used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid drugs: levothyroxine. Carbamazepine is expected to enhance 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 Mesacar®.

If necessary, the dose of thyroid hormones should be adjusted. Thyroid function may change, particularly when carbamazepine is used concomitantly with other anticonvulsant drugs (e.g., phenobarbital).

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

Combinations of medicinal products requiring special consideration.

Concomitant use of carbamazepine and levetiracetam may increase carbamazepine toxicity.

Concomitant use of carbamazepine and isoniazid may enhance the hepatotoxicity of isoniazid.

Concomitant use of carbamazepine with lithium or metoclopramide, as well as with neuroleptics (haloperidol, thioridazine), may enhance neurological side effects (even at therapeutic plasma levels in the case of the latter combination). Therefore, careful monitoring of clinical symptoms is required. At least 8 weeks should elapse after discontinuation of previous neuroleptic therapy. Concomitant treatment 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).

According to published data, adding carbamazepine to ongoing neuroleptic therapy may increase the risk of neuroleptic malignant syndrome or Stevens-Johnson syndrome.

Combination therapy with Mesacar® 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 drugs may be required, and patients need careful monitoring due to the possibility of faster-than-expected termination of neuromuscular blockade.

Carbamazepine, like other psychotropic drugs, may reduce tolerance to alcohol; therefore, patients are advised to abstain from alcohol consumption.

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 of thrombosis.

Contraindicated interactions.

Since carbamazepine is structurally similar to tricyclic antidepressants, Mesacar® is contraindicated for concomitant use with monoamine oxidase inhibitors (MAO inhibitors); treatment with an MAO inhibitor must be discontinued at least two weeks (or earlier, if clinically feasible) before starting Mesacar®.

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.

General.

Mезakar® should be used only under medical supervision, only after assessment of the benefit/risk ratio and with careful monitoring of patients with cardiac, hepatic or renal disorders, history of adverse hematological reactions to other drugs, sodium metabolism disorders, and patients with interrupted courses of therapy with Mезakar®.

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

Mезakar® exhibits mild anticholinergic activity; therefore, patients with elevated intraocular pressure should be warned and advised regarding possible risk factors.

One should keep in mind the possibility of activation of latent psychosis, and in elderly patients — the possibility of developing confusion or anxious agitation.

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

Hematological effects.

The use of the drug 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 significant risk of taking Mезakar®. 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, angina, groin infection, 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 carefully monitored, and regular complete blood counts should be performed. Treatment with Mезakar® should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical manifestations such as fever or sore throat. Mезakar® should be discontinued if signs of bone marrow suppression occur.

Temporary or persistent reduction in platelet or white blood cell counts may occasionally or frequently occur with Mезakar® use. However, most of these cases have been confirmed as transient and do not indicate the development of aplastic anemia or agranulocytosis. Blood tests, 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 the use of Mезakar®. Patients with serious dermatological reactions may require hospitalization, as these conditions can be life-threatening and potentially fatal. Most cases of SJS/TEN occur within the first few months of Mезakar® treatment. It is estimated that these dermatological reactions occur in 1–6 of 10,000 new patients in countries with predominantly Caucasian populations. However, the risk may be approximately 10 times higher in patients from certain Asian countries. If symptoms indicating serious dermatological reactions (e.g., SJS, Lyell’s syndrome/TEN) develop, Mезakar® should be discontinued immediately and alternative therapy initiated.

Pharmacogenomics.

Increasing evidence suggests the influence of various 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. The prevalence of this HLA-B*1502 allele ranges from 2% to 12% in Han Chinese patients and is approximately 8% in patients from Thailand. 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 in the population. The carrier rate of this allele among the Asian population exceeds 15% in the Philippines and 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 Caucasian, African, Native American, and Latin American populations (<1%).

The allele prevalence stated in this document represents the percentage of chromosomes in specific 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 potentially at risk is nearly twice the allele prevalence.

In patients considered genetically at risk, testing for the presence of the (HLA)-B*1502 allele should be performed before initiating Mезakar® therapy. If the patient's test for (HLA)-B*1502 is positive, treatment with Mезakar® 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 have a negative result for (HLA)-B*1502 have a low risk of developing SJS, although such reactions are very rare.

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 of patients from ethnic groups with a low coefficient of the (HLA)-B*1502 allele is generally not recommended. Screening of patients already receiving Mезakar® is generally not recommended, 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 and patient management, 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 Mезakar®. 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 to determine how other factors (such as doses, adherence, concomitant drugs, 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 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 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 Mезakar® should be avoided.

Retrospective analysis data in Japanese patients and Northern European residents have demonstrated an association between severe skin lesions (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 prevalence of the allele is less than 5% in the populations of Australia, Asia, Africa, and North America. In Western Europe, the prevalence of the HLA-A*3101 allele is estimated at approximately 6.7%, depending on the geographical region. Exceptions range from 5% to 12%. A prevalence of over 15% has been established in certain ethnic groups in South America (Argentina and Brazil), Native Americans (Navajo and Sioux tribes, in Mexico — Seri), and South India (Tamil Nadu).

The allele prevalence stated in this document represents the percentage of chromosomes in specific 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 potentially at risk is nearly twice the allele prevalence.

Before initiating Mезakar® therapy, screening for the HLA-A*3101 allele is recommended in potential carriers (e.g., Japanese patients, 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 outweighs the potential risk. Screening for the HLA-A*3101 allele is generally not required in patients who have already been receiving Mезakar® 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, play a role in the development of these severe skin adverse reactions. The impact of other diseases and the level of skin disorder monitoring have not been studied.

Other dermatological reactions.

Transient and non-health-threatening mild dermatological reactions, such as isolated macular or maculopapular exanthema, may also occur. They usually resolve within a few days or weeks, both with continued dosing and after dose reduction. Since early signs of more serious dermatological reactions may be very difficult to distinguish from mild transient reactions, the patient should be under close supervision to discontinue the drug immediately 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 minor 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. Mезakar® may provoke hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), multiple delayed-type 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 adverse skin reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or minor 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.

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

In general, if symptoms indicating hypersensitivity occur, the use of Mезakar® should be discontinued immediately.

Seizures. Since carbamazepine may cause or exacerbate absence seizures, Mезakar® should be used with caution in patients with mixed seizures including absence seizures (typical or atypical). Under these circumstances, the drug may provoke seizures. If seizures are provoked, Mезakar® should be discontinued immediately.

An increase in seizure frequency may occur when switching from oral forms of the drug 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 if liver function disorders worsen or if the active phase of liver disease occurs.

Kidney function. Kidney function assessment and blood urea nitrogen determination are recommended at the beginning and periodically during the course of 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 treatment with drugs that reduce sodium levels (such as diuretics, drugs associated with inadequate antidiuretic hormone secretion), serum sodium levels should be measured before treatment. Subsequently, measurements should be taken every 2 weeks, then at monthly intervals during the first three months of treatment or as clinically necessary. This is particularly important for elderly patients. Water intake should be limited in such cases.

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

Anticholinergic effects. Mезakar® exhibits moderate anticholinergic activity. Therefore, patients with elevated intraocular pressure and urinary retention should be under close supervision 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 trials of antiepileptic drugs 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 prescribed if necessary. Patients (and caregivers) should be advised to consult a physician if signs of suicidal thoughts or behavior occur.

Pregnancy. Congenital malformations 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 risks. 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 regarding the potential teratogenic risk to unborn children.

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

Women of childbearing potential

Carbamazepine may harm the fetus when used by a pregnant woman. Pregnancy registries and epidemiological data indicate a potential association between prenatal exposure to carbamazepine and the risk of serious congenital malformations and other adverse developmental outcomes, including neural tube defects and malformations of other organ systems [e.g., craniofacial defects and cardiovascular malformations] (see section "Use in pregnancy or breastfeeding"). Animal studies have shown that carbamazepine use at clinically relevant doses during pregnancy leads to fetal developmental toxicity, including increased incidence of fetal malformations.

If, after careful consideration of alternative treatment options, the benefit does not outweigh the risks, carbamazepine should not be used in women of childbearing potential.

Women of childbearing potential should be fully informed about the potential risk to the fetus if they take carbamazepine during pregnancy.

Before initiating carbamazepine therapy, a pregnancy test should be considered in women of childbearing potential.

Women of childbearing potential should use effective contraception during treatment and for two weeks after discontinuation of treatment.

Due to enzyme induction, carbamazepine may interfere with the therapeutic effect of hormonal contraceptives;

therefore, women of childbearing potential should consult their physician regarding the use of other effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Use in pregnancy or breastfeeding").

Women of childbearing potential should consult their physician as soon as they plan pregnancy to discuss switching to alternative treatment before conception and discontinuation of contraception (see section "Use in pregnancy or breastfeeding").

Women of childbearing potential should be advised to immediately consult a physician if they become pregnant or suspect they may be pregnant while taking carbamazepine.

Endocrine effects. Due to hepatic enzyme induction, Mезakar® may cause a reduction in the therapeutic effect of estrogen and/or progesterone preparations. This may lead to reduced contraceptive efficacy, symptom recurrence, or breakthrough bleeding or spotting. Women taking Mезakar® who require hormonal contraception should receive a preparation containing at least 50 mcg of estrogen, or alternative effective and reliable non-hormonal contraceptive methods should be considered for such patients during Mезakar® treatment.

Plasma level monitoring. Although the correlation between dosage and carbamazepine plasma levels, as well as between carbamazepine plasma levels and clinical efficacy and tolerability, is unreliable, monitoring plasma levels may be appropriate in the following cases: sudden increase in seizure frequency, patient compliance check, during pregnancy, in the treatment of children and adolescents; suspected absorption impairment, suspected toxicity, and when using multiple drugs.

Dose reduction and discontinuation. Abrupt discontinuation of Mезakar® may provoke seizures. If abrupt discontinuation of therapy is necessary, patients with epilepsy should be switched to a new antiepileptic drug while continuing appropriate medication therapy.

Dose 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, rectal diazepam, or intravenous phenytoin).

Falls. Treatment with Mезakar® is associated with ataxia, dizziness, somnolence, hypotension, confusion, or lethargy (see "Adverse reactions"), which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or taking medications that exacerbate these conditions, a comprehensive risk assessment for falls should be regularly performed during long-term Mезakar® treatment.

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

Use in children.

The safety and efficacy of carbamazepine for the treatment of bipolar disorder and pain in trigeminal neuralgia have not been established in pediatric patients.

The safety and efficacy of carbamazepine in pediatric patients for the treatment of partial seizure attacks, generalized tonic-clonic seizures, and mixed seizure attacks have been established (see sections "Indications" and "Dosage and administration").

Use in pregnancy or breastfeeding.

Pregnancy

General risk associated with the use of antiepileptic medicinal products (AEDs)

All women of childbearing potential receiving antiepileptic therapy, and particularly women planning pregnancy and pregnant women, should receive medical advice regarding the potential risk to the fetus from both seizures and antiepileptic treatment.

Abrupt discontinuation of AED treatment should be avoided, as it may lead to seizures, which can have serious consequences for the woman and the unborn child.

If possible, monotherapy is preferred for epilepsy treatment during pregnancy, as treatment with multiple AEDs 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. Exposure to 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%. Malformations reported include neural tube defects in the fetus, craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, finger hypoplasia, and other anomalies affecting various fetal organ systems in mothers who used carbamazepine during pregnancy. Specialized antenatal 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 AEDs during pregnancy. Studies on the risk of neurodevelopmental disorders in children exposed to carbamazepine during pregnancy are conflicting, and the risk cannot be excluded.

If, after careful consideration of alternative treatment options, the benefit does not outweigh the risks, carbamazepine should not be used in women 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 depend on the dose. If, based on a careful benefit/risk assessment, no alternative treatment option is suitable and carbamazepine treatment continues, monotherapy and the lowest effective dose of carbamazepine should be used, and plasma levels should be monitored. Plasma concentrations can be maintained in the lower part of the therapeutic range of 4 to 12 mcg/mL, provided seizure control is maintained.

It has been reported that some AEDs, such as carbamazepine, reduce serum folate levels. This deficiency may contribute to an increased frequency of fetal malformations in mothers with epilepsy. Folic acid is recommended before and during pregnancy. Vitamin K1 is also recommended for the mother during the last weeks of pregnancy and for newborns to prevent coagulation disorders in the child.

If a woman plans to become pregnant, all efforts should be made before conception and discontinuation of contraception to switch 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 potential

Carbamazepine should not be used in women of childbearing potential, except when the potential benefit/risk outweighs alternative treatment options. The woman should be fully informed and understand the potential risk to the fetus when taking carbamazepine during pregnancy; therefore, it is important to plan pregnancy in advance. Before initiating carbamazepine therapy, the possibility of performing a pregnancy test should be considered in women of childbearing potential.

Women of childbearing potential should use effective contraception during and after discontinuation of treatment for two weeks. Due to enzyme induction, carbamazepine may interfere with the therapeutic effect of hormonal contraceptives (see section "Interaction with other medicinal products and other forms of interaction"); therefore, women of childbearing potential should consult their physician regarding the use of 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, involving the patient in the discussion.

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 cases of seizures and/or respiratory depression in newborns, several cases of vomiting, diarrhea, and/or poor appetite in newborns associated with the use of carbamazepine and other anticonvulsant drugs.

Breastfeeding. Adverse effects in offspring have been observed in rat studies where females were administered carbamazepine. Carbamazepine passes into breast milk (25–60% of plasma concentration). The benefits of breastfeeding with the remote possibility 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 skin allergic reactions. Cases of cholestatic hepatitis have been described in children exposed to carbamazepine prenatally or through breast milk, necessitating monitoring of such children for adverse effects on the hepatobiliary system. Mothers receiving Mезakar® may breastfeed provided the infant is monitored for possible adverse reactions (e.g., excessive sleepiness, allergic skin reactions).

Fertility.

Rare cases of impaired fertility in men and/or abnormalities in spermatogenesis parameters have been reported. However, a causal relationship of these disorders with 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 adjustment) while taking Mезakar® may be reduced due to both seizures caused by the disease and adverse effects resulting from carbamazepine use, such as dizziness, somnolence, ataxia, diplopia, accommodation disorders, and visual disturbances. Therefore, patients should exercise caution when driving or operating machinery.

Dosage and Administration

Mезакар® should be administered orally; the daily dose is usually divided into two or three doses. The medication may be taken during, after meals, or between meals, with a small amount of liquid, for example, a glass of water.

Before initiating treatment, patients who are potentially carriers of the HLA-A*3101 allele based on ancestry should, if possible, be tested for the presence of this allele, as its presence may provoke severe adverse reactions, such as skin reactions.

Epilepsy

Treatment should be initiated with a low daily dose, gradually increasing the dose, which must be individually adjusted according to each patient's needs.

Therapeutic drug monitoring by measuring carbamazepine plasma levels may be helpful in determining the optimal dosage.

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

Experience has shown that therapeutic carbamazepine levels range between 4–12 µg/mL.

Adults: the recommended initial dose is 100–200 mg once or twice daily. The dose should then be gradually increased until the optimal effect is achieved; a common daily dose is 400 mg twice or three times daily (corresponding to 800–1200 mg). Some patients may require a dose of Mезакар® up to 1600 mg or even 2000 mg daily, although such high doses should be avoided due to the higher frequency of adverse effects.

Elderly patients: due to the potential for drug interactions, dosage of Mезакар® in elderly patients should be carefully selected. The recommended initial dose is 100 mg twice daily.

Children: treatment may be initiated with 100 mg/day; the dose should be gradually increased by 100 mg each week.

The usual dosage is 10–20 mg/kg body weight per day (administered in several divided 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, Mesacar® should be prescribed as monotherapy; however, when used concomitantly with other medicinal products, a similar gradual increase in carbamazepine dosage is recommended.

When Mesacar® is prescribed in addition to ongoing antiepileptic therapy, the carbamazepine dose should be gradually increased without changing the dose of the currently used 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 escalation is recommended, whereas for optimal tolerance during maintenance therapy in bipolar disorders, gradual dose escalation in small increments is advised.

Alcohol withdrawal syndrome

Average dose – 200 mg three to four times daily. In severe cases, during the first few days the dose may be increased (e.g., up to 400 mg three times daily (1200 mg/day)). Subsequently, the dose should be gradually reduced and therapy tapered off. In severe alcohol withdrawal, treatment should be initiated with a combination of Mesacar® and sedative-hypnotic agents (e.g., with clomethiazole or chlordiazepoxide), following the dosage recommendations outlined above. After completion of the acute phase, treatment with Mesacar® may continue as monotherapy.

Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical). Idiopathic glossopharyngeal neuralgia

Initial dose of Mesacar® is 200–400 mg per day (100 mg twice daily for elderly patients). The dose should be slowly increased until pain subsides (usually to a dose of 200 mg three to four times daily). For most patients, a carbamazepine dose of 200 mg three or four times daily is sufficient to maintain a pain-free state. In some cases, a daily carbamazepine dose of up to 1600 mg may be required. After pain has subsided, the dose should be gradually reduced to the minimum effective maintenance dose. The maximum recommended dose is 1200 mg/day. Subsequently, the dose should be slowly decreased and therapy gradually discontinued.

Children.

Due to a faster elimination of carbamazepine, children may require higher doses of the medicinal product (on a mg/kg body weight basis) compared to adults. Mesacar® tablets may be administered to children aged 6 years and older.

Overdose.

Symptoms. Symptoms and complaints occurring in overdose typically reflect involvement of the central nervous, cardiovascular, and respiratory systems, as well as adverse reactions listed in section "Adverse Reactions".

Central nervous system: CNS depression; disorientation, depressed 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 stasis, reduced colonic motility.

Musculoskeletal system: Isolated cases of rhabdomyolysis associated with toxic effects 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 findings: 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 and assess the extent of overdose.

Gastric evacuation, gastric lavage, and administration of activated charcoal are 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, is recommended; in case of hyponatremia (water intoxication), fluid restriction and slow, cautious intravenous infusion of 0.9% sodium chloride solution are indicated. These measures may help prevent cerebral edema.

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

Recurrence of overdose symptoms on the 2nd and 3rd day after onset should be anticipated due to delayed drug absorption.

Adverse Reactions

At the beginning of treatment with the medicinal product Mезacar® or when using too high an initial dose of carbamazepine, or during treatment of elderly patients, certain types of adverse reactions occur frequently or uncommonly, 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 spontaneously or after temporary reduction of the carbamazepine dose within a few days. The development of adverse reactions affecting the CNS may result from relative overdosage or significant fluctuations in plasma concentrations of the active substance. In such cases, monitoring of the active substance level in plasma is recommended, and the daily dose of the medicinal product should be divided into smaller doses (e.g., 3–4 doses).

Adverse reactions occurred with the following frequencies: very common (> 1/10), common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000), including isolated cases.

Blood and lymphatic system disorders: very common – leukopenia (11%), persistent in 2% of cases; common – thrombocytopenia, eosinophilia; rare – lymphadenopathy, folic acid deficiency; very rare – leukocytosis, agranulocytosis, aplastic anemia, pancytopenia, erythroid aplasia, anemia, megaloblastic anemia, acute intermittent porphyria, mixed porphyria, late cutaneous porphyria, reticulocytosis, hemolytic anemia.

Immune system disorders: rare – multiorgan hypersensitivity of delayed type with fever, skin rashes, vasculitis, lymphadenopathy; signs resembling lymphoma; arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, altered liver function tests, and vanishing bile duct syndrome (destruction and disappearance of intrahepatic bile ducts), occurring in various combinations. Other organs may also be affected (e.g., liver, lungs, kidneys, pancreas, myocardium, colon); very rare – aseptic meningitis with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioneurotic edema, hypogammaglobulinemia.

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 disorders, seizures, disorientation, impaired cognition, visual disturbances, or encephalopathy (syndrome of inappropriate antidiuretic hormone secretion, SIADH); very rare – increased blood prolactin levels, with or without manifestations such as galactorrhea, gynecomastia, disturbances in bone metabolism (decreased plasma calcium and 25-hydroxycholecalciferol levels), leading to osteomalacia/osteoporosis; in isolated cases – increased cholesterol concentration, including high-density lipoprotein cholesterol and triglycerides.

Metabolism and nutrition disorders: rare – folate deficiency, decreased appetite; very rare – acute porphyria (acute intermittent porphyria and mixed porphyria), non-acute porphyria (late cutaneous porphyria); frequency unknown – 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 disorders (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.

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, disturbances in pitch perception.

Cardiac and vascular 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 – hypersensitivity reactions affecting the lungs, characterized by fever, dyspnea, pneumonitis, or pneumonia.

Gastrointestinal disorders: very common – nausea, vomiting (both 8%); common – dry mouth; uncommon – diarrhea or constipation; rare – abdominal pain; very rare – glossitis, stomatitis, pancreatitis.

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

Skin and subcutaneous tissue disorders: very common – allergic dermatitis, pruritus, urticaria, sometimes in severe form; 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.

Musculoskeletal, connective tissue and bone disorders: rare – muscle weakness; very rare – arthralgia, myalgia, muscle spasms, disturbances in bone metabolism (decreased calcium and 25-hydroxycholecalciferol levels in plasma, which may lead to osteomalacia or osteoporosis).

Renal and urinary disorders: very rare – tubulointerstitial nephritis, renal failure, impaired kidney function (e.g., albuminuria, hematuria, oliguria, increased blood urea/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 have been recorded regarding male fertility impairment and/or impaired spermatogenesis.

General disorders: very common – general weakness.

Investigations – abnormal laboratory and instrumental findings: very common – increased gamma-glutamyltransferase levels (due to induction of liver enzymes), which is usually not clinically significant; common – increased blood alkaline phosphatase levels; uncommon – increased transaminase levels; very rare – increased intraocular pressure, increased blood cholesterol levels (including increased high-density lipoprotein cholesterol and triglycerides), increased blood triglyceride levels, changes in thyroid function tests: decreased L-thyroxine levels (free thyroxine (FT4), thyroxine (T4), triiodothyronine (T3)) and increased thyroid-stimulating hormone (TSH) levels, which usually do not have clinical manifestations; increased blood prolactin levels, hypogammaglobulinemia.

Adverse reactions based on spontaneous reports (frequency unknown).

Information on the adverse reactions listed below was obtained from post-marketing use of the drug through spontaneous reports and publications. Since these reports are spontaneous, it is impossible to determine the exact number of patients or reliably estimate the frequency of adverse reactions; therefore, their frequency is classified as "unknown."

Infections and parasitic diseases: reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: bone marrow insufficiency.

Nervous system disorders: lethargy, 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 (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal, connective tissue and bone disorders: fractures.

Investigations – abnormal laboratory and instrumental findings: decreased bone mineral density.

Reporting of Adverse Reactions

Reporting of adverse reactions after medicinal product registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients or their legal representatives should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 4 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets per blister; 5 blisters per cardboard package.

Prescription status.

By prescription only.

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's location and address of its business activity.

54 Davydovskoho Hryhorii Street, Sumy, Sumy Oblast, 40020, Ukraine.