Mezakar® sr

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MEZACAR®SR (MEZACAR®SR)

Composition:

Active substance: carbamazepine;

1 tablet contains carbamazepine 400 mg;

Excipients: microcrystalline cellulose, hypromellose, sodium lauryl sulfate, povidone (PVP K 30), colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Prolonged-release tablets.

Main physico-chemical properties: white or almost white, round tablets with bevels on both sides and embossing "C400" on one side and a cross-shaped groove on the other.

Pharmacotherapeutic group. Antiepileptic drugs. ATC code N03AF01.

Pharmacological Properties

Pharmacodynamics

As an antiepileptic agent, carbamazepine is effective against partial seizures (simple and complex), with or without secondary generalization, generalized tonic-clonic seizures, as well as combinations of these seizure types. The mechanism of action of carbamazepine, the active ingredient in the medicinal product Mезакар**®** SR, has been only partially elucidated.

Carbamazepine stabilizes the membranes of overexcited nerve fibers, inhibits the generation of repetitive neuronal discharges, and reduces synaptic transmission of excitatory impulses.

It has been established that the primary mechanism of action of the drug is prevention of repetitive formation of sodium-dependent action potentials in depolarized neurons by blocking sodium channels.

The anticonvulsant effect of the drug is mainly due to reduced release of glutamate and stabilization of neuronal membranes, whereas the antimanic effect may be attributed to inhibition of dopamine and norepinephrine metabolism.

Pharmacokinetics

Absorption

After oral administration, carbamazepine is almost completely absorbed, but the rate of absorption varies between different dosage forms and among individual patients.

After single-dose administration of the prolonged-release formulation, peak plasma concentration (Cmax) of the active substance is reached within 24 hours.

Prolonged-release tablets. When administered as a single dose or multiple doses, prolonged-release tablets result in plasma concentrations of the active substance that are approximately 25% lower than those achieved with conventional tablets.

Prolonged-release tablets provide a statistically significant reduction in the fluctuation index, but do not significantly reduce Cmin at steady state.

Plasma concentration fluctuations with a twice-daily dosing regimen are minimal. The bioavailability of prolonged-release tablets of Mезакар**®** SR is approximately 15% lower than that of other oral dosage forms.

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

Bioavailability may vary among different carbamazepine formulations. To prevent a reduction in therapeutic efficacy or the risk of epileptic seizures or pronounced adverse effects, switching between different carbamazepine formulations should be avoided.

Food intake does not significantly affect the rate or extent of carbamazepine absorption (regardless of the dosage form).

Steady-state plasma concentrations of carbamazepine are 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.

The steady-state plasma concentrations of carbamazepine considered as the "therapeutic range" vary considerably among individuals: for most patients, the range is 4 to 12 micrograms/mL, corresponding to 17 to 50 micromoles/L.

Concentrations of carbamazepine-10,11-epoxide (a pharmacologically active metabolite): approximately 30% of carbamazepine levels.

Distribution

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

Biotransformation/Metabolism

Carbamazepine is metabolized in the liver primarily via the epoxide pathway, resulting in the formation of major metabolites – the 10,11-trans-diol derivative and its glucuronic acid conjugate.

The main isoenzyme responsible for biotransformation of carbamazepine into carbamazepine-10,11-epoxide is cytochrome P450 3A4.

Human microsomal epoxide hydrolase has been identified as the enzyme responsible for converting carbamazepine-10,11-epoxide into the 10,11-trans-diol derivative. 9-Hydroxymethyl-10-carbamoylacridan is a minor metabolite associated with this pathway.

After single oral administration 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, as well as the N-glucuronide of carbamazepine, formed via uridine diphosphate glucuronosyltransferase (UGT2B7).

Elimination

After single oral administration, the 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 duration of treatment.

In patients concurrently receiving other drugs that induce the same hepatic enzyme system (e.g., phenytoin, phenobarbital), the half-life of carbamazepine averages 9–10 hours.

The average half-life of the 10,11-epoxide metabolite in plasma is approximately 6 hours after single oral administration of the epoxide.

After single oral administration of 400 mg carbamazepine, 72% of the administered dose is excreted in urine and 28% in feces. Nearly 2% of the administered dose is excreted unchanged in urine, and approximately 1% as the pharmacologically active metabolite 10,11-epoxide.

Pharmacokinetic characteristics in specific patient populations

Children

Due to faster elimination of carbamazepine in children, higher doses (mg/kg body weight) may be required compared to adults to maintain therapeutic concentrations.

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

Clinical characteristics.

Indications.

• As an anticonvulsant in the treatment of epilepsy (generalized tonic-clonic and partial types of seizures).
• Paroxysmal pain in trigeminal neuralgia.

Mesacar® SR may also be used to relieve deafferentation pain, such as in glossopharyngeal neuralgia, peripheral diabetic neuropathy, spinal spasticity, superior laryngeal neuralgia, postherpetic neuralgia, as well as stump pain and phantom limb pain.

• Treatment of symptoms of alcohol withdrawal.
• Treatment of mania and prophylaxis of bipolar affective disorders, particularly in patients who have not responded clinically to lithium therapy.

Contraindications.

• Known hypersensitivity to carbamazepine or to structurally related medicinal products (e.g., tricyclic antidepressants), or to any other component of the drug.
• Atrioventricular block.
• History of bone marrow depression.
• History of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria).
• Concomitant use with monoamine oxidase inhibitors (MAOIs) (see section "Interaction with other medicinal products and other forms of interaction").
• Concomitant use with herbal preparations containing St. John’s wort (Hypericum perforatum) due to the risk of reduced plasma concentrations of carbamazepine and, consequently, diminished clinical efficacy of the drug (see section "Interaction with other medicinal products and other forms of interaction").

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 with carbamazepine may lead to increased plasma concentrations of carbamazepine, which in turn may result in adverse reactions. Concomitant use of CYP3A4 inducers may enhance the metabolism of carbamazepine, leading to a potential decrease in serum concentrations and therapeutic effect of carbamazepine. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, resulting in increased plasma levels of carbamazepine.

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-diol derivatives of carbamazepine-10,11-epoxide.

Concomitant administration of inhibitors of human microsomal epoxide hydrolase may lead to increased plasma concentrations of carbamazepine-10,11-epoxide.

Interactions leading to contraindications

Concomitant use of Mesacar® SR with monoamine oxidase inhibitors (MAOIs) is contraindicated. Prior to initiating Mesacar® SR, MAO inhibitors should be discontinued for at least 2 weeks or longer, if clinically feasible (see section "Contraindications").

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), dosage adjustment of Mesacar® SR and/or monitoring of plasma levels are necessary when co-administered with the following medicinal products:

Analgesics, anti-inflammatory agents: dextropropoxyphene, ibuprofen.

Androgens: danazol.

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

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

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.

Antituberculosis agents: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular agents: diltiazem, verapamil.

Agents for gastrointestinal (GI) 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 carbamazepine-10,11-epoxide may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), the dose of Mesacar® SR should be adjusted accordingly and/or its plasma levels monitored when co-administered with the following substances:

loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, valpromide, brivaracetam.

Medicinal products that may reduce carbamazepine plasma levels.

Dosage adjustment of Mesacar® SR may be necessary when co-administered with the following medicinal products:

Antiepileptic agents: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin toxicity and subtherapeutic carbamazepine concentrations, plasma phenytoin concentration should be adjusted to 13 µg/mL prior to starting carbamazepine therapy), fosphenytoin, primidone, and clonazepam (although data are conflicting).

Antineoplastic agents: cisplatin or doxorubicin.

Antimalarial agents: mefloquine, which may antagonize the anticonvulsant effect of carbamazepine.

Antituberculosis agents: rifampicin.

Bronchodilators or antiasthmatic agents: theophylline, aminophylline.

Dermatological agents: isotretinoin.

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

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

Effect of carbamazepine on plasma levels of concomitantly administered drugs.

Plasma or whole blood concentrations of carbamazepine may be reduced when co-administered with herbal preparations containing St. John’s wort (Hypericum perforatum). This is due to enzyme induction by St. John’s wort involved in carbamazepine metabolism. Herbal preparations containing St. John’s wort are contraindicated during concomitant use with carbamazepine (see section "Contraindications"). The inducing effect of St. John’s wort preparations may persist for at least 2 weeks after discontinuation. If a patient is already receiving treatment with St. John’s wort preparations, they should be discontinued and carbamazepine plasma concentration determined. Carbamazepine levels may increase after discontinuation of St. John’s wort preparations. Dose adjustment of carbamazepine may be required.

Carbamazepine may reduce plasma levels or diminish or even abolish the effect of certain drugs. Dosage of such drugs may need to be adjusted 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, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline, clomipramine).

Antiemetics: aprepitant.

Antiepileptic agents: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin toxicity and subtherapeutic carbamazepine concentrations, recommended plasma phenytoin concentration should not exceed 13 µg/mL prior to initiation of carbamazepine therapy. There are isolated reports of increased plasma concentrations of mephenytoin during carbamazepine treatment.

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

Anthelmintic agents: praziquantel, albendazole.

Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.

Antipsychotic agents: 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, leading to significantly lower hormone plasma concentrations. This may result in contraceptive failure or breakthrough bleeding. Alternatives to oral and subdermal implanted contraceptives, which are significantly affected by CYP3A4 induction, should be considered; or alternative to carbamazepine [see sections "Special precautions for use" and "Use in specific populations"].

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

Corticosteroids: corticosteroids (e.g., prednisolone, dexamethasone).

Agents used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

Interaction with other agents: preparations containing estrogens and/or progestogens (gestrinone, trenbolone, toremifene).

Both increased and decreased plasma levels of phenytoin have been reported with carbamazepine, as well as isolated cases of increased plasma levels of mephenytoin.

Combinations requiring special consideration.

Concomitant use of carbamazepine and paracetamol (acetaminophen) may reduce the bioavailability of paracetamol.

Concomitant use of carbamazepine and levetiracetam may lead to increased carbamazepine toxicity.

Concomitant use of carbamazepine and isoniazid may lead to enhanced hepatotoxicity of isoniazid.

Concomitant use of carbamazepine with lithium preparations or metoclopramide, as well as with neuroleptics (haloperidol, thioridazine), may lead to increased neurological side effects (even at therapeutic plasma levels in the latter combination).

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

Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g., pancuronium).

Carbamazepine, like other psychotropic agents, 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 lead to reduced plasma concentrations of direct oral anticoagulants and, thus, increase the risk of thrombosis. Therefore, if concomitant use is necessary, patients should be closely monitored for signs and symptoms of thrombosis.

Effect on serological tests.

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

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

Special precautions for use.

Mezakar®SR should be used only under medical supervision. Mezakar®SR should be prescribed only after careful assessment of the benefit/risk ratio and with close monitoring of patients with cardiac, hepatic, or renal disorders, patients with previous hematological adverse reactions to other drugs, and patients with previous intermittent courses of carbamazepine therapy.

Hematological effects.

Carbamazepine has been associated with the development of agranulocytosis and aplastic anemia; however, due to the extremely low incidence of these conditions, it is difficult to assess the actual risk associated with Mezakar®SR use.

The overall risk in patients who have not previously received carbamazepine therapy is 4.7 cases per 1,000,000 patients per year for agranulocytosis and 2 cases per 1,000,000 patients per year for aplastic anemia.

Transient or persistent reduction in platelet or white blood cell counts may occasionally or frequently occur during carbamazepine treatment. Complete blood count, including platelet count, should be performed before initiating therapy and periodically during treatment (and possibly reticulocyte count and serum iron levels).

If leukocyte or platelet counts significantly decrease during therapy, the patient should be closely monitored and regular complete blood counts should be performed (see section "Adverse reactions"). Treatment with Mezakar®SR should be discontinued if the patient develops serious, progressive, or clinically symptomatic leukopenia (e.g., fever or sore throat). Mezakar®SR should be discontinued if signs of bone marrow suppression occur.

Patients and their relatives should be informed about early signs of toxicity and symptoms of possible hematological disorders, as well as dermatological and hepatic reactions.

Patients should be advised to seek immediate medical attention if any of the following reactions occur: fever, sore throat, skin rash, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura.

Dermatological reactions.

Serious, sometimes fatal, dermatological reactions, including toxic epidermal necrolysis (TEN) or Lyell's syndrome, and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine use. Patients should be advised to carefully monitor for signs and symptoms of skin reactions.

It is estimated that these dermatological reactions occur in 1–6 per 10,000 new patients in countries with predominantly Caucasian populations. However, in some Asian countries, the risk may be approximately 10 times higher.

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 carbamazepine treatment.

If signs or symptoms of SJS, Lyell's syndrome/TEN (e.g., progressive skin rash, often with blisters or mucosal involvement) develop, Mezakar®SR should be discontinued immediately and alternative therapy initiated.

The best outcomes in treating SJS/TEN are achieved with early diagnosis and immediate discontinuation of any suspected drug. Early withdrawal is associated with a better prognosis.

If a patient develops SJS/TEN during Mezakar®SR treatment, further carbamazepine therapy is contraindicated.

Pharmacogenomics.

Increasing evidence suggests that different HLA alleles influence a patient's susceptibility to immune-mediated adverse reactions (see section "Dosage and administration").

Association with HLA-B*1502

Retrospective studies in Han Chinese patients have demonstrated a strong correlation between carbamazepine-associated skin reactions (SJS/TEN) and the presence of the human leukocyte antigen (HLA) allele HLA-B*1502.

The prevalence of the HLA-B*1502 allele ranges from 2% to 12% in Han Chinese patients and is approximately 8% in Thailand. The 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 certain Malaysian populations). In Korea and India, the prevalence of this allele is up to 2% and 6%, respectively.

There is evidence suggesting an increased risk of serious carbamazepine-associated SJS/TEN in other Asian populations. Due to the high prevalence of this allele in other Asian populations (e.g., over 15% in the Philippines and Malaysia), genetic testing for HLA-B*1502 in at-risk groups may be considered.

The prevalence of the HLA-B*1502 allele is low among European, African, Native American, Latin American, and Japanese populations (<1%).

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

For patients considered genetically at risk, HLA-B*1502 allele testing should be performed before initiating carbamazepine therapy (see section "Dosage and administration").

If HLA-B*1502 allele testing is required, high-resolution "HLA-B*1502 genotyping" is recommended. The test is considered positive if one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.

Carbamazepine therapy should not be initiated in patients with a positive HLA-B*1502 test result, except when no other therapeutic options are available.

Patients who have tested negative for HLA-B*1502 have a low risk of developing SJS, although such reactions may still very rarely occur.

The HLA-B*1502 allele may be a risk factor for SJS/TEN in Han Chinese patients receiving other antiepileptic drugs that may be associated with SJS/TEN.

Therefore, other drugs potentially associated with SJS/TEN should be avoided in patients carrying the HLA-B*1502 allele, if alternative therapy is available.

Genetic screening is generally not recommended for patients from ethnic groups with a low prevalence of the HLA-B*1502 allele.

Screening is generally not recommended for patients already receiving carbamazepine, as the risk of SJS/TEN is largely confined to the first few months of treatment, regardless of the presence of the HLA-B*1502 allele.

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

Association with HLA-A*3101

There is evidence suggesting that the 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 in patients of European descent and Japanese patients (see section "Adverse reactions").

The prevalence of HLA-A*3101 varies among different ethnic groups: approximately 2–5% in European populations and about 10% in Japanese populations.

The prevalence of this allele is less than 5% in populations of Australia, Asia, Africa, and North America. Exceptions range from 5% to 12%.

Prevalence exceeding 15% has been reported in certain South American ethnic groups (Argentina and Brazil), Native North American populations (Navajo and Sioux tribes, Seri in Mexico), South India (Tamil Nadu), 10–15% in other indigenous ethnic groups in these regions, and approximately 10% in Japanese populations.

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

The presence of the HLA-A*3101 allele may increase the risk of carbamazepine-induced dermatological reactions (mostly less severe) from 5% (in the general population) to 26% (in individuals of European descent). Conversely, the absence of this allele may reduce the risk from 5.0% to 3.8%.

Before initiating Mezakar®SR therapy in potential carriers of the HLA-A*3101 allele (e.g., Japanese, Caucasian, Native American, Latin American, South Indian, and Arab patients), screening for this allele is recommended (see section "Dosage and administration").

If HLA-A*3101 allele testing is performed, high-resolution "HLA-A*3101 genotyping" is recommended. The test is positive if one or two HLA-A*3101 alleles are detected and negative if no HLA-A*3101 alleles are detected. Carbamazepine should be used in carriers of this allele only if the benefit of therapy outweighs the potential risk.

Screening for the HLA-A*3101 allele is generally not required in patients who have already been receiving carbamazepine for a prolonged period, as SJS/TEN, AGEP, DRESS, and maculopapular rash typically occur only within the first few months of therapy.

Limits of genetic screening

Genetic screening results should not replace appropriate clinical monitoring and management of patients. Many Asian patients with a positive HLA-B*1502 test result who take carbamazepine do not develop SJS/TEN. Conversely, SJS/TEN may occur in patients of any ethnicity with a negative HLA-B*1502 test result. Similarly, many patients with a positive HLA-A*3101 test result who take carbamazepine do not develop SJS/TEN, DRESS, AGEP, or maculopapular rash, while these serious skin adverse reactions may develop in patients of any ethnicity with a negative HLA-A*3101 test result. Other potential factors, such as antiepileptic drug dosage, adherence to therapy, and concomitant medications, may play a role in the development of these severe skin adverse reactions. The impact of other diseases and the level of skin disorder monitoring 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. These usually resolve within a few days or weeks, either with continued carbamazepine dosing or after dose reduction.

Since early signs of more serious dermatological reactions may be difficult to distinguish from mild transient reactions, patients should be closely monitored so that drug use can be discontinued immediately if the reaction worsens with continued treatment.

The presence of the HLA-A*3101 allele is associated with less serious adverse skin reactions during carbamazepine use, such as anticonvulsant hypersensitivity syndrome or mild rashes (maculopapular eruptions). However, the presence of HLA-B*1502 has not been shown to indicate a risk of the aforementioned skin reactions.

Hypersensitivity.

Carbamazepine may trigger hypersensitivity reactions, including 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 present in various combinations. Clinical manifestations in other organs (lungs, kidneys, pancreas, myocardium, colon) are also possible (see section "Adverse reactions").

The presence of the HLA-A*3101 allele in patients is associated with the development of hypersensitivity syndrome, including maculopapular rash.

Patients with hypersensitivity reactions to carbamazepine should be informed that hypersensitivity reactions to oxcarbazepine may occur in approximately 25–30% of such patients. Cross-hypersensitivity may occur with carbamazepine and aromatic antiepileptic drugs (e.g., phenytoin, primidone, and phenobarbital).

In general, Mezakar®SR should be discontinued immediately if signs and symptoms suggesting hypersensitivity occur.

Seizures.

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

An increase in seizure frequency may occur during the transition from oral carbamazepine formulations to suppositories.

Sudden discontinuation of Mezakar®SR may provoke seizures.

Liver function.

Liver function should be assessed at baseline and periodically during carbamazepine therapy, especially in patients with a history of liver disease and in elderly patients.

Mezakar®SR should be discontinued immediately in cases of acute liver function deterioration or in patients with active liver disease.

Some laboratory parameters used to assess liver function may be outside the normal range in patients taking carbamazepine, particularly gamma-glutamyl transferase (GGT). This is likely due to the induction of hepatic enzymes.

Enzyme induction may also lead to a moderate increase in alkaline phosphatase levels. Such increased functional activity of hepatic metabolism is not an indication for carbamazepine discontinuation.

Severe hepatic reactions due to carbamazepine use are very rare.

If signs or symptoms of hepatic dysfunction or active liver disease occur, the patient should be urgently evaluated, and Mezakar®SR therapy should be suspended until evaluation results are obtained.

Renal function. Renal function assessment and blood urea nitrogen levels should be performed at the beginning and periodically during carbamazepine therapy.

Hyponatremia.

Cases of hyponatremia have been reported with carbamazepine use. Sodium levels in blood should be measured before treatment in patients with pre-existing renal impairment associated with low sodium levels or in patients receiving concomitant therapy with drugs that reduce sodium levels (e.g., diuretics, drugs associated with inadequate antidiuretic hormone secretion). Subsequent measurements should be performed every 2 weeks, then monthly for the first 3 months of treatment or as clinically necessary. This is particularly important for elderly patients. Water intake should be limited if clinically necessary.

Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations due to enzyme induction. Therefore, an increase in thyroid hormone replacement dose may be necessary for patients with hypothyroidism. Monitoring of thyroid function is recommended to determine the appropriate replacement hormone dose.

Anticholinergic effects.

Carbamazepine exhibits moderate anticholinergic activity. Therefore, patients with elevated intraocular pressure or urinary retention should be warned about potential risks and closely monitored during therapy.

Psychiatric effects. The possibility of activation of latent psychosis and confusion or agitation in elderly patients, especially when high doses of Mezakar®SR are used, should be considered.

Suicidal thoughts and behavior. There have been several reports of suicidal thoughts and behavior in patients receiving antiepileptic drugs for various indications.

A meta-analysis of data from randomized 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.

Therefore, patients should be monitored for suicidal thoughts and behavior, and appropriate treatment should be initiated if necessary. Patients (and caregivers) should be advised to seek medical attention if signs of suicidal thoughts or behavior occur.

Women of childbearing potential.

Carbamazepine may harm the fetus when used during pregnancy. Pregnancy registries and epidemiological data suggest a potential association between prenatal exposure to carbamazepine and an increased risk of major 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 "Pregnancy and lactation"). Animal studies have shown developmental toxicity with clinically relevant doses of carbamazepine during pregnancy, including an increased incidence of fetal malformations.

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

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 age.

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

Due to enzyme induction, carbamazepine may interfere with the therapeutic effect of hormonal contraceptives; therefore, women of childbearing age 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 "Pregnancy and lactation").

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

Women of childbearing potential should be advised to seek immediate medical attention if they become pregnant or suspect they may be pregnant while taking carbamazepine.

Endocrine effects.

Due to hepatic enzyme induction, carbamazepine may reduce the activity of hormones in combined oral contraceptives. This may lead to breakthrough bleeding or spotting.

Breakthrough bleeding has been reported in women taking carbamazepine and hormonal contraceptives.

Since the reliability of hormonal contraceptives may be negatively affected by carbamazepine therapy, women of childbearing potential should be advised to use alternative contraceptive methods during Mezakar®SR treatment.

Plasma level monitoring.

Although the correlation between dosage and plasma carbamazepine levels, as well as between plasma carbamazepine levels and clinical efficacy and tolerability, is unreliable, plasma level monitoring may be useful in the following situations: sudden increase in seizure frequency, assessment of patient compliance, during pregnancy, in pediatric and adolescent patients, suspected malabsorption, suspected toxicity, and concomitant use of multiple drugs (see section "Interaction with other medicinal products and other forms of interaction").

Dose reduction and discontinuation.

Sudden discontinuation of carbamazepine may provoke seizures; therefore, the drug should be tapered gradually over 6 months. If necessary, in patients with epilepsy, abrupt discontinuation of Mezakar®SR should be followed by transition to another antiepileptic drug while continuing appropriate therapy.

Several cases of seizures and/or respiratory depression in newborns have been reported, associated with maternal use of carbamazepine and other concomitant anticonvulsant drugs. Several cases of vomiting, diarrhea, and/or decreased appetite in newborns have also been reported in association with maternal carbamazepine use. These reactions may indicate neonatal withdrawal syndrome.

Interaction.

Concomitant use of CYP3A4 inhibitors or epoxide hydrolase inhibitors with carbamazepine may cause adverse reactions (increased plasma concentrations of carbamazepine or carbamazepine-10,11 epoxide, respectively). Appropriate dose adjustment of carbamazepine and/or plasma level monitoring is recommended.

Concomitant use of CYP3A4 inducers with carbamazepine may reduce plasma carbamazepine concentrations and its therapeutic effect; conversely, discontinuation of CYP3A4 inducers may lead to increased plasma carbamazepine concentrations. Dose adjustment of carbamazepine may be required.

Carbamazepine is a potent inducer of the CYP3A4 isoenzyme and other hepatic phase I and phase II drug-metabolizing enzyme systems and, when used concomitantly with drugs metabolized by the CYP3A4 isoenzyme, may induce metabolism and reduce their plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").

Women of childbearing age should be warned that concomitant use of carbamazepine with hormonal contraceptives may negatively affect their effectiveness. When using Mezakar®SR, consideration should be given to using alternative non-hormonal contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Pregnancy and lactation").

Falls.

Carbamazepine therapy may be 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 concomitant medications that exacerbate these conditions, a full risk assessment for falls should be performed regularly during long-term carbamazepine therapy.

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").

Excipients.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially sodium-free.

Pregnancy and lactation.

Pregnancy

General risk associated with antiepileptic medicinal products (AEDs)

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

Sudden discontinuation of AEDs should be avoided, as this may lead to seizures, which can have serious consequences for the woman and the unborn child.

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. The impact of carbamazepine during pregnancy is associated with a 2–3 times higher frequency of serious congenital malformations compared to the general population (2–3%). Malformations reported include neural tube defects (spina bifida), 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.

Carbamazepine should not be used during pregnancy unless, after careful consideration of alternative treatment options, the benefit is deemed to outweigh the risks. The woman should be fully informed and understand the risks of taking carbamazepine during pregnancy.

Data suggest that the risk of malformations with carbamazepine use may be dose-dependent. If, after careful benefit/risk assessment, no suitable alternative treatment is available and carbamazepine therapy is continued, monotherapy with 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 (4–12 µg/mL), provided seizure control is maintained.

Some AEDs, including carbamazepine, have been reported to reduce serum folate levels. This deficiency may contribute to an increased frequency of fetal malformations in mothers with epilepsy. Folic acid supplementation 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 transition to appropriate alternative therapy. 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 outweighs the risks compared to alternative treatment options. The woman should be fully informed and understand the potential risk to the fetus if carbamazepine is taken during pregnancy; therefore, pregnancy planning should be done 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 therapy. 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 contraceptive method (e.g., intrauterine) or two additional contraceptive methods, including a barrier method, should be used. The choice of contraceptive method should consider individual circumstances, with patient involvement 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.

Several cases of seizures and/or respiratory depression in newborns have been reported, associated with maternal use of carbamazepine and other anticonvulsant drugs.

Several cases of vomiting, diarrhea, and/or decreased appetite in newborns have been reported in association with maternal carbamazepine use.

These reactions may indicate neonatal withdrawal syndrome.

Lactation. Although carbamazepine passes into breast milk at concentrations of 25–60% of the plasma level, it is considered that this does not pose a significant risk to the infant, who is likely to receive up to 10% of the corresponding therapeutic dose of carbamazepine appropriate for a child of its age with epilepsy. As with all other medicinal products, the benefits of breastfeeding should be carefully weighed against the remote possibility of adverse effects in the infant.

Mothers taking carbamazepine may breastfeed provided the infant is monitored for possible adverse reactions (e.g., excessive drowsiness, allergic skin reactions).

Cholestatic hepatitis has been reported in children exposed to carbamazepine prenatally or via breast milk; therefore, monitoring of these children for adverse effects on the hepatobiliary system is recommended.

Fertility. Very rare cases of impaired fertility and/or impaired spermatogenesis in men have been reported (see section "Adverse reactions").

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

Mesacar**®** SR is administered orally; the daily dose is usually divided into two to four administrations.

The total daily dose of Mesacar**®** SR is generally the same as the dose of immediate-release carbamazepine tablets.

In some patients, switching from other oral formulations of carbamazepine to Mesacar**®** SR extended-release tablets may require an increase in the total daily dose.

Final dose adjustment should always depend on the individual patient's clinical response.

The drug can be taken during meals, after meals, or between meals, with a glass of water. Mesacar**®** SR tablets should not be chewed.

Due to the slow and controlled release of the active substance from the prolonged-release tablets, they are usually taken twice daily.

Before initiating treatment, patients belonging to the Han Chinese ethnic group or of Thai origin should, whenever possible, be tested for the presence of HLA-B*1502, as this allele may trigger the development of severe carbamazepine-associated Stevens-Johnson syndrome (see section "Special Warnings and Precautions for Use").

Epilepsy

Treatment should begin with a low daily dose, which should then be gradually increased until optimal effect is achieved. The carbamazepine dose should be adjusted according to individual patient needs to achieve adequate seizure control.

Therapeutic drug monitoring of plasma levels of the active substance may be helpful in determining the optimal dose.

In epilepsy treatment, the carbamazepine dose is usually adjusted so that the plasma concentration ranges between 4–12 µg/mL (17–50 µmol/L) (see section "Special Warnings and Precautions for Use").

Whenever possible, Mesacar**®** SR should be used as monotherapy. However, when used in combination with other medicinal products, the same gradual dose escalation regimen is recommended (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adults

Mesacar**®** SR should be taken in divided doses.

Recommended initial dose: 100–200 mg once or twice daily, then gradually and slowly increased until optimal effect is achieved. The usual daily dose is 800–1200 mg, divided into two doses. Some patients may require a Mesacar**®** SR dose up to 1600 mg or even 2000 mg per day.

Elderly Patients

Due to potential drug interactions and differences in pharmacokinetics of antiepileptic drugs, Mesacar**®** SR doses in elderly patients should be selected with caution.

Children and Adolescents

Treatment is usually initiated at a dose of 10–20 mg/kg body weight per day (in divided doses).

Children under 1 year of age: 100–200 mg/day, divided into several doses.

Children aged 1 to 5 years: 200–400 mg/day, divided into several doses.

Children aged 5 to 10 years: 400–600 mg/day, divided into several doses.

Children aged 10 to 15 years: 600–1000 mg/day, divided into several doses.

Children aged 15 years and older: adult dosing (800–1200 mg/day, divided into two doses).

Maximum Recommended Doses:

Under 6 years: 35 mg/kg/day

6–15 years: 1000 mg/day

15 years: 1200 mg/day.

Mesacar**®** SR is not recommended for children under 5 years of age.

Trigeminal Neuralgia and Other Types of Deafferentation Pain

Individual dosage requirements may vary significantly depending on patient age and body weight. A low initial dose is recommended, although some patients may require a higher initial dose. The usual dose is 200 mg 3–4 times daily, but the dose may be gradually increased to achieve satisfactory clinical effect, which in some cases may require up to 1600 mg/day.

An initial dose of Mesacar**®** SR 200–400 mg/day should be slowly increased until pain relief is achieved (usually up to 200 mg 3–4 times daily).

The dose should then be gradually reduced to the minimum effective maintenance dose. The maximum recommended dose is 1200 mg/day. After pain subsides, therapy should be gradually discontinued until a new episode occurs.

Alcohol Withdrawal Symptoms

The dose should be individually adjusted for each patient. The usual dose is 600–800 mg/day, but in patients with delirium, a dose of 1200–1600 mg/day may be required, followed by gradual reduction.

Treatment of Mania and Prophylaxis of Bipolar Affective Disorders

Initial dose: 100–200 mg/day, divided into several doses, gradually increased until symptoms are controlled or until a total daily dose of 1600 mg is reached. The usual dose range is 400–1600 mg/day, divided into several doses.

Patients with Renal or Hepatic Impairment

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

Children

Mesacar**®** SR tablets may be administered to children aged 5 years and older.

Overdose

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

Central Nervous System: 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, changes in blood pressure (arterial hypotension, sometimes hypertension), cardiac arrhythmias, conduction disturbances with widening of the QRS complex; syncope associated with cardiac arrest.

Gastrointestinal Tract: Vomiting, gastric retention, decreased intestinal peristalsis.

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 carbamazepine's antidiuretic hormone-like effect.

Laboratory Findings: Hyponatremia, possible metabolic acidosis, hyperglycemia, elevated creatine phosphokinase muscle fraction.

Treatment. There is no specific antidote. Initial treatment should be based on the patient's clinical condition. Hospitalization may be necessary. Plasma carbamazepine concentration should be measured to confirm poisoning and assess the degree of overdose.

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

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

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

Adverse reactions.

Summary of safety profile.

At the beginning of carbamazepine treatment, or when using too high an initial dose, or when treating elderly patients, certain types of adverse reactions occur very commonly or commonly, such as those affecting the central nervous system (dizziness, headache, ataxia, somnolence, general weakness, diplopia), gastrointestinal tract (nausea, vomiting), or allergic skin reactions.

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

There have been reports of decreased bone mineral density, osteopenia, osteoporosis, and fractures in patients receiving long-term carbamazepine therapy. The mechanism by which carbamazepine affects bone metabolism has not been established.

Adverse reactions occurred with the following frequencies: 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; common – thrombocytopenia, eosinophilia; rare – lymphadenopathy, leukocytosis; very rare – agranulocytosis, aplastic anemia, pancytopenia, erythroblastopenia, anemia, megaloblastic anemia, reticulocytosis, hemolytic anemia.

Immune system disorders: rare – multiorgan hypersensitivity of delayed type (serum sickness-like) with fever, skin rash, 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 organs may also be involved (e.g., lungs, kidneys, pancreas, myocardium, colon). In case such hypersensitivity reactions occur, treatment must be discontinued immediately. very rare – anaphylactic reaction, angioedema, hypogammaglobulinemia.

Endocrine system disorders: common – edema, fluid retention, weight gain, hyponatremia and decreased plasma osmolarity due to an antidiuretic hormone-like effect, which in isolated cases may lead to overhydration accompanied by lethargy, vomiting, headache, confusion, and neurological disturbances; very rare – galactorrhea, gynecomastia.

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, aggression, agitation, restlessness, confusion; very rare – activation of psychosis.

Nervous system disorders: very common – ataxia, dizziness, somnolence; common – diplopia, headache; uncommon – abnormal involuntary movements (e.g., tremor, "fluttering" tremor, dystonia, tics), nystagmus; rare – dyskinesia, eye movement disorders, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, paresis; very rare – neuroleptic malignant syndrome (NMS), aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

Eye disorders: common – accommodation disorders (e.g., blurred vision); very rare – lens opacity, conjunctivitis.

Ear and labyrinth disorders: very rare – hearing disorders, e.g., tinnitus, hyperacusis, hypoacusis, disturbances in pitch perception.

Cardiac disorders: rare – disturbances in cardiac conduction; very rare – arrhythmia, atrioventricular block with syncope, bradycardia, congestive heart failure, exacerbation of ischemic heart disease.

Vascular disorders: rare – arterial hypertension or arterial hypotension; very rare – circulatory collapse, embolism (e.g., pulmonary embolism), thrombophlebitis.

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

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

Hepatobiliary disorders: rare – cholestatic, parenchymal (hepatocellular), or mixed type hepatitis, vanishing bile duct syndrome, jaundice; very rare – liver failure, granulomatous hepatitis.

Skin and subcutaneous tissue disorders: very common – urticaria, sometimes in severe form, allergic dermatitis; uncommon – exfoliative dermatitis; rare – systemic lupus erythematosus, pruritus; very rare – severe skin reactions, such as Stevens–Johnson syndrome (in some Asian countries this adverse event has also been reported with a frequency of "rare"), toxic epidermal necrolysis (see section "Special precautions for use"), photosensitivity reactions, erythema multiforme, nodular erythema, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism.

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

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

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

General disorders: very common – general weakness.

Investigations – laboratory and instrumental test abnormalities: very common – increased gamma-glutamyl transferase 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, increased high-density lipoprotein and triglyceride levels, 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.

Injury, poisoning and procedural complications: unknown – falls (associated with ataxia, dizziness, somnolence, hypotension, confusion, sedative effect during carbamazepine treatment) (see section "Special precautions for use").

Additional adverse reactions based on spontaneous reports (frequency unknown).

Information on the adverse reactions listed below was obtained during the post-marketing period from spontaneous reports and publications. Since these 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.

Immune system disorders: drug reaction with eosinophilia and systemic symptoms (DRESS).

Metabolism disorders: hyperammonemia.

Nervous system disorders: sedative effect, memory impairment.

Gastrointestinal disorders: colitis.

Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal and connective tissue and bone disorders: fractures.

Investigations – laboratory and instrumental test abnormalities: decreased bone mineral density.

Growing evidence supports an association between genetic markers and the occurrence of skin-related adverse reactions such as SJS/TEN, DRESS, AGEP, and maculopapular rash. It has been reported that in patients of European descent and Japanese patients, these reactions are associated with carbamazepine use and the presence of the HLA-A*3101 allele. Another marker, HLA-B*1502, has been shown to be strongly associated with SJS/TEN among Han Chinese, Thai, and some other Asian populations (see sections "Dosage and administration" and "Special precautions for use").

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. 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 through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 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.

LLC "GLEDPHARM LTD".

Manufacturer's location and address of business activity.

40020, Ukraine, Sumy region, Sumy city, Davydovskoho Hryhoriia St., 54.

INSTRUCTION

for medical use of the medicinal product

MEZACAR®SR

(MEZACAR®SR)

Composition:

Active ingredient: carbamazepine;

1 tablet contains 400 mg of carbamazepine;

Excipients: microcrystalline cellulose, hypromellose, sodium lauryl sulfate, povidone (PVP K 30), colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Extended-release tablets.

Main physicochemical characteristics: white or almost white, round tablets, bevelled on both sides, with "C400" embossed on one side and a cross-shaped score line on the other.

Pharmacotherapeutic group.
Antiepileptic drugs. ATC code N03A F01.

Pharmacological Properties

Pharmacodynamics

As an antiepileptic agent, carbamazepine is effective against partial seizures (simple and complex), with or without secondary generalization; generalized tonic-clonic seizures; as well as combinations of these seizure types. The mechanism of action of carbamazepine—the active ingredient in the medicinal product Mезакар**®** SR—is only partially understood.

Carbamazepine stabilizes membranes of overexcited nerve fibers, inhibits the generation of repetitive neuronal discharges, and reduces synaptic transmission of excitatory impulses.

The primary mechanism of action has been established to be prevention of repetitive formation of sodium-dependent action potentials in depolarized neurons by blocking sodium channels.

The anticonvulsant effect of the drug is primarily due to reduced glutamate release and stabilization of neuronal membranes, whereas the antimanic effect may be attributed to inhibition of dopamine and norepinephrine metabolism.

Pharmacokinetics

Absorption

After oral administration, carbamazepine is almost completely absorbed, but the rate of absorption varies and may differ between various dosage forms and among individual patients.

Following single-dose administration of the prolonged-release formulation, peak plasma concentration (C_max) of the active substance is reached after 24 hours.

Prolonged-release tablets. When administered as single or multiple doses, prolonged-release tablets result in approximately 25% lower peak plasma concentrations of the active substance compared to conventional tablets.

Prolonged-release tablets provide a statistically significant reduction in the fluctuation index, but no clinically significant reduction in steady-state C_min.

Plasma concentration fluctuations with a twice-daily dosing regimen are minimal. The bioavailability of prolonged-release tablets Мезакар**®** SR is approximately 15% lower than that of other oral dosage forms.

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

Bioavailability may vary among different carbamazepine formulations. To prevent a reduction in therapeutic efficacy or risk of epileptic seizures or pronounced adverse effects, switching between carbamazepine formulations should be avoided.

Food intake does not significantly affect the rate or extent of carbamazepine absorption (regardless of the dosage form).

Steady-state plasma concentrations of carbamazepine are 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.

The "therapeutic range" of steady-state plasma carbamazepine concentrations varies considerably among individuals: for most patients, it ranges from 4 to 12 µg/mL, corresponding to 17 to 50 µmol/L.

Concentrations of carbamazepine-10,11-epoxide (a pharmacologically active metabolite): approximately 30% of carbamazepine levels.

Distribution

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

Biological transformation / Metabolism

Carbamazepine is metabolized in the liver primarily via the epoxide pathway, resulting in the formation of main metabolites—10,11-trans-diol derivative and its glucuronic acid conjugate.

The primary isoenzyme responsible for the biotransformation of carbamazepine into carbamazepine-10,11-epoxide is cytochrome P450 3A4.

Human microsomal epoxide hydrolase has been identified as the enzyme responsible for converting carbamazepine-10,11-epoxide into the 10,11-trans-diol derivative. 9-Hydroxymethyl-10-carbamoylacridan is a minor metabolite associated with this pathway.

After single oral administration 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, as well as the N-glucuronide of carbamazepine, formed via uridine diphosphate glucuronosyltransferase (UGT2B7).

Elimination

After single oral administration, the 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 duration of treatment.

In patients concurrently taking other drugs that induce the same hepatic enzyme system (e.g., phenytoin, phenobarbital), the half-life of carbamazepine averages 9–10 hours.

The average half-life of the 10,11-epoxide metabolite in plasma is approximately 6 hours after single oral administration of the epoxide.

After single oral administration of 400 mg carbamazepine, 72% of the administered dose is excreted in urine and 28% in feces. Nearly 2% of the administered dose is excreted unchanged in urine, and approximately 1% as the pharmacologically active metabolite 10,11-epoxide.

Pharmacokinetic characteristics in specific patient populations

Children

Due to faster elimination of carbamazepine in children, higher doses (mg/kg body weight) may be required compared to adults to maintain therapeutic drug concentrations.

Elderly patients

There are no data indicating that the pharmacokinetics of carbamazepine are altered in elderly patients compared to younger adults.

Patients with impaired renal or hepatic function

Data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function are currently unavailable.

Clinical characteristics.

Indications.

• As an anticonvulsant in the treatment of epilepsy (generalized tonic-clonic and partial types of seizures).
• Paroxysmal pain in trigeminal neuralgia.

Mesacar® SR can also be used to relieve deafferentation pain, such as glossopharyngeal neuralgia, peripheral diabetic neuropathy, spinal spasticity, superior laryngeal neuralgia, postherpetic neuralgia, as well as stump pain and phantom limb pain.

• Treatment of symptoms of alcohol withdrawal.
• Treatment of mania and prevention of bipolar affective disorders, especially in patients who have not responded clinically to lithium therapy.

Contraindications.

• Known hypersensitivity to carbamazepine or to drugs chemically related to it (e.g., tricyclic antidepressants), or to any other component of the drug.
• Atrioventricular block.
• History of bone marrow depression.
• History of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria).
• Concomitant use with monoamine oxidase inhibitors (MAOIs) (see section "Interaction with other medicinal products and other types of interactions").
• Concomitant use with herbal preparations containing St. John’s wort (Hypericum perforatum) due to the risk of reduced plasma concentration of carbamazepine and, consequently, reduced clinical efficacy of the drug (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing the formation of the active metabolite of carbamazepine—10,11-epoxide. Concomitant use of CYP3A4 inhibitors with carbamazepine may lead to increased plasma concentrations of carbamazepine, which in turn may cause adverse reactions. Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, potentially leading to decreased serum concentrations of carbamazepine and reduced therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, resulting in increased plasma levels of carbamazepine.

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-transdiol derivatives from carbamazepine-10,11-epoxide.

Concomitant administration of inhibitors of human microsomal epoxide hydrolase may lead to increased plasma concentrations of carbamazepine-10,11-epoxide.

Interactions leading to contraindications

Concomitant use of Mesacar® SR with monoamine oxidase inhibitors (MAOIs) is contraindicated. Treatment with MAOIs should be discontinued at least 2 weeks prior to starting Mesacar® SR, or longer if clinically appropriate (see section "Contraindications").

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), dosage adjustment of Mesacar® SR and/or monitoring of plasma levels is necessary when used concomitantly with the following medicinal products:

Analgesics, anti-inflammatory agents: dextropropoxyphene, ibuprofen.

Androgens: danazol.

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

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

Antiepileptic agents: stiripentol, vigabatrin.

Antifungal agents: azoles (e.g., itraconazole, ketoconazole, fluconazole, voriconazole).

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

Antihistamines: loratadine, terfenadine.

Antipsychotics: olanzapine.

Antituberculosis agents: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular agents: diltiazem, verapamil.

Agents for gastrointestinal (GI) 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 carbamazepine-10,11-epoxide may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), the dose of Mesacar® SR should be adjusted accordingly and/or plasma levels monitored when used concomitantly with the following substances:

loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, valpromide, brivaracetam.

Medicinal products that may decrease plasma levels of carbamazepine.

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

Antiepileptic agents: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin toxicity and subtherapeutic carbamazepine concentrations, plasma phenytoin concentration should be adjusted to 13 µg/mL prior to initiating carbamazepine therapy), fosphenytoin, primidone, and clonazepam (although data are conflicting).

Antineoplastic agents: cisplatin or doxorubicin.

Antimalarial agents: mefloquine, which may antagonize the anticonvulsant effect of carbamazepine.

Antituberculosis agents: rifampicin.

Bronchodilators or antiasthmatic agents: theophylline, aminophylline.

Dermatological agents: isotretinoin.

It has been reported that isotretinoin may alter the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide. Carbamazepine plasma levels should be monitored.

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

Effect of carbamazepine on plasma levels of concomitantly administered drugs.

Plasma or whole blood concentrations of carbamazepine may be reduced when used concomitantly with herbal preparations containing St. John’s wort (Hypericum perforatum). This is due to enzyme induction by St. John’s wort involved in carbamazepine metabolism. Herbal preparations containing St. John’s wort are contraindicated for concomitant use with carbamazepine (see section "Contraindications"). The inducing effect of St. John’s wort preparations may persist for at least 2 weeks after discontinuation. If a patient is already receiving treatment with St. John’s wort preparations, they should be discontinued and carbamazepine plasma concentration should be measured. Carbamazepine levels may increase after discontinuation of St. John’s wort preparations. Dose adjustment of carbamazepine may be required.

Carbamazepine may reduce plasma levels or weaken or even abolish the effect of certain drugs. Dosage of such drugs may need to be adjusted 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, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline, clomipramine).

Antiemetics: aprepitant.

Antiepileptic agents: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin toxicity and subtherapeutic carbamazepine concentrations, the recommended plasma concentration of phenytoin should not exceed 13 µg/mL prior to initiating carbamazepine therapy. There are isolated reports of increased plasma concentrations of methyphenytoin with carbamazepine use.

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

Anthelmintic agents: praziquantel, albendazole.

Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.

Antipsychotic agents: 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 plasma concentrations of hormones. This may result in contraceptive failure or breakthrough bleeding. Alternative methods to oral and subdermal implanted contraceptives, which are significantly affected by CYP3A4 induction, should be considered; or alternative antiepileptic drugs to carbamazepine should be considered [see sections "Special precautions for use" and "Use in specific population groups"].

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

Corticosteroids: corticosteroids (e.g., prednisolone, dexamethasone).

Agents used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

Interaction with other agents: preparations containing estrogens and/or progestogens (gestrinone, trenbolone, toremifene).

Both increased and decreased plasma levels of phenytoin due to carbamazepine have been reported, as well as isolated cases of increased plasma levels of methyphenytoin.

Combinations requiring special consideration.

Concomitant use of carbamazepine and paracetamol (acetaminophen) may reduce the bioavailability of paracetamol.

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 preparations or metoclopramide, as well as with neuroleptics (haloperidol, thioridazine), may enhance neurological adverse effects (in the latter combination, even at therapeutic plasma levels).

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

Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g., pancuronium).

Like other psychotropic drugs, carbamazepine may reduce tolerance to alcohol; therefore, patients are advised to avoid alcohol consumption.

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

Effect on serological tests.

Carbamazepine may give a false-positive result in HPLC (high-performance liquid chromatography) analysis for perphenazine concentration.

Carbamazepine and 10,11-epoxide may give a false-positive result in immunoassay methods using fluorescence polarization for the determination of tricyclic antidepressant concentrations.

Special precautions for use.

Mezakar®SR should be used only under medical supervision. Mezakar®SR should be prescribed only after evaluation of the benefit/risk ratio and with careful monitoring of patients with cardiac, hepatic or renal disorders, previous hematological adverse reactions to other drugs, and patients with interrupted courses of carbamazepine therapy.

Hematological effects.

Carbamazepine has been associated with the development of agranulocytosis and aplastic anemia; however, due to the extremely low frequency of these conditions, it is difficult to assess the significant risk associated with Mezakar®SR use.

The overall risk for patients who have not previously received carbamazepine therapy is 4.7 cases per 1,000,000 patients per year for agranulocytosis and 2 cases per 1,000,000 patients per year for aplastic anemia.

Transient or persistent reduction in platelet or white blood cell counts may occur occasionally or frequently with carbamazepine use. Complete blood count, including platelet count (and possibly reticulocyte count and serum iron levels), should be performed before initiating therapy and periodically during treatment.

If leukocyte or platelet counts significantly decrease during therapy, the patient should be closely monitored and regular complete blood counts should be performed (see section "Adverse reactions"). Treatment with Mezakar®SR should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical symptoms such as fever or sore throat. Mezakar®SR should be discontinued if signs of bone marrow suppression occur.

Patients and their relatives 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 reactions such as fever, sore throat, skin rash, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura occur, they should seek medical attention immediately.

Dermatological reactions.

Serious, sometimes fatal, dermatological reactions, including toxic epidermal necrolysis (TEN) or Lyell's syndrome, and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine use. Patients should be advised to closely monitor for signs and symptoms of skin reactions.

It is estimated that these dermatological reactions occur in 1–6 per 10,000 new patients in countries with predominantly Caucasian populations. However, in some Asian countries, the risk may be approximately 10 times higher.

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 carbamazepine treatment.

If signs or symptoms of SJS, Lyell’s syndrome/TEN (e.g., progressive skin rash, often with blisters or mucosal involvement) develop, Mezakar®SR should be discontinued immediately and alternative therapy initiated.

The best outcomes in treating SJS/TEN are achieved with early diagnosis and immediate discontinuation of any suspected drug. Early discontinuation is associated with a better prognosis.

If SJS/TEN develops in a patient during Mezakar®SR treatment, further carbamazepine therapy is contraindicated.

Pharmacogenomics.

Increasing evidence indicates the influence of different HLA alleles on a patient's susceptibility to immune-related adverse reactions (see section "Dosage and administration").

Association with HLA-B*1502

Retrospective studies in Han Chinese patients have demonstrated a strong correlation between carbamazepine-associated skin reactions (SJS/TEN) and the presence of the human leukocyte antigen (HLA) allele HLA-B*1502.

The prevalence of the HLA-B*1502 allele varies from 2% to 12% in Han Chinese patients and is approximately 8% in 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 among the Asian population exceeds 15% (in the Philippines and some Malaysian populations). In Korea and India, the prevalence of this allele is up to 2% and 6%, respectively.

There is evidence indicating an increased risk of serious carbamazepine-associated SJS/TEN in other Asian populations. Due to the prevalence of this allele in other Asian populations (e.g., over 15% in the Philippines and Malaysia), genetic testing for HLA-B*1502 in at-risk groups may be considered.

The prevalence of the HLA-B*1502 allele is low among European, African, Native American, Latin American, and Japanese populations (<1%).

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

For patients considered genetically at risk, testing for the presence of the HLA-B*1502 allele should be performed before initiating carbamazepine therapy (see section "Dosage and administration").

If HLA-B*1502 allele testing is required, high-resolution "HLA-B*1502 genotyping" is recommended. The test is positive if one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are found.

If a patient tests positive for the HLA-B*1502 allele, carbamazepine therapy should not be initiated, except when no other therapeutic options are available.

Patients who have tested negative for HLA-B*1502 have a low risk of developing SJS, although such reactions may still very rarely occur.

The HLA-B*1502 allele may be a risk factor for SJS/TEN in Chinese patients receiving other antiepileptic drugs that may be associated with SJS/TEN.

Therefore, other drugs potentially associated with SJS/TEN should be avoided in patients carrying the HLA-B*1502 allele if alternative therapy is available.

Genetic screening is generally not recommended for patients from ethnic groups with a low prevalence of the HLA-B*1502 allele.

Screening is generally not recommended for patients already receiving carbamazepine, 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.

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

Association with HLA-A*3101

There is evidence suggesting that the human leukocyte antigen may be a risk factor for skin adverse reactions such as SJS, TEN, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and maculopapular rash in patients of European descent and Japanese (see section "Adverse reactions").

The prevalence of HLA-A*3101 may vary among different ethnic groups: approximately 2–5% in European populations, about 10% in Japanese.

The prevalence of this allele is less than 5% in populations of Australia, Asia, Africa, and North America. Exceptions range from 5% to 12%.

A prevalence greater than 15% has been established in certain ethnic groups in South America (Argentina and Brazil), Native North Americans (Navajo and Sioux tribes, in Mexico - Seri), South India (Tamil Nadu), 10–15% in other indigenous ethnic groups in these regions, and about 10% among Japanese.

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

The presence of the HLA-A*3101 allele may increase the risk of carbamazepine-induced dermatological reactions (mostly less severe) from 5% (in the general population) to 26% (among subjects of European descent). Conversely, the absence of this allele may reduce the risk from 5.0% to 3.8%.

Before initiating Mezakar®SR therapy in potential carriers of the HLA-A*3101 allele (e.g., patients of Japanese nationality, Caucasians, Native Americans, Latin Americans, South Indian and Arab populations), screening for this allele is recommended (see section "Dosage and administration").

If HLA-A*3101 allele testing is performed, high-resolution "HLA-A*3101 genotyping" is recommended. The test is positive if one or two HLA-A*3101 alleles are detected and negative if no HLA-A*3101 alleles are found. Carbamazepine should be used in carriers of this allele only if the benefit of therapy outweighs the potential risk.

Screening for the HLA-A*3101 allele is generally not required for patients who have already received carbamazepine 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 management of patients. Many Asian patients with a positive HLA-B*1502 test who take carbamazepine do not develop SJS/TEN. Conversely, SJS/TEN may occur in patients of any ethnicity with a negative HLA-B*1502 test. Similarly, many patients with a positive HLA-A*3101 test who take carbamazepine will not develop SJS/TEN, DRESS, AGEP, or maculopapular rash, while these serious skin adverse reactions may develop in patients of any ethnicity with a negative HLA-A*3101 test. Other potential factors contributing to these severe skin adverse reactions include antiepileptic drug dosage, adherence to therapy, and concomitant medications. The impact of other diseases and the level of skin disorder monitoring have not been studied.

Other dermatological reactions.

Transient, non-serious, mild dermatological reactions such as isolated macular or maculopapular exanthema may also occur. These usually resolve within days or weeks, either with continued carbamazepine dosing or after dose reduction.

Since early signs of more serious dermatological reactions may be difficult to distinguish from mild transient reactions, patients should be closely monitored to allow immediate discontinuation of the drug if the reaction worsens with continued use.

The presence of the HLA-A*3101 allele is associated with less severe skin adverse reactions during carbamazepine use, such as anticonvulsant hypersensitivity syndrome or mild rashes (maculopapular eruptions). However, the presence of HLA-B*1502 has not been established as an indicator of risk for the aforementioned skin reactions.

Hypersensitivity.

Carbamazepine may trigger hypersensitivity reactions, including 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. Clinical manifestations involving other organs may also occur (lungs, kidneys, pancreas, myocardium, colon; see section "Adverse reactions").

The presence of the HLA-A*3101 allele in a patient is associated with the development of hypersensitivity syndrome, including maculopapular rash.

Patients with hypersensitivity reactions to carbamazepine should be informed that hypersensitivity reactions may also occur in approximately 25–30% of such patients when using oxcarbazepine. Cross-hypersensitivity may occur with carbamazepine and aromatic antiepileptic drugs (e.g., phenytoin, primidone, and phenobarbital).

In general, Mezakar®SR should be discontinued immediately if signs and symptoms indicating hypersensitivity occur.

Seizures.

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

An increase in seizure frequency may occur during the transition from oral carbamazepine formulations to suppositories.

Sudden discontinuation of Mezakar®SR may provoke seizures.

Liver function.

Liver function should be assessed at baseline and periodically during carbamazepine therapy, especially in patients with a history of liver disease and in elderly patients.

Mezakar®SR should be discontinued immediately in cases of acute exacerbation of liver dysfunction or in patients with active liver disease.

Some laboratory parameters used to assess liver function may be outside the normal range in patients taking carbamazepine, particularly gamma-glutamyl transferase (GGT). This is likely due to induction of hepatic enzymes.

Enzyme induction may also lead to a moderate increase in alkaline phosphatase levels. Such increased functional activity of hepatic metabolism is not an indication for discontinuing carbamazepine.

Severe hepatic reactions due to carbamazepine use are very rare.

If signs or symptoms of hepatic dysfunction or active liver disease occur, the patient should be urgently evaluated, and Mezakar®SR therapy should be suspended until evaluation results are obtained.

Renal function. Renal function assessment and blood urea nitrogen levels should be evaluated at the beginning and periodically during carbamazepine therapy.

Hyponatremia.

Cases of hyponatremia have been reported with carbamazepine use. In patients with pre-existing renal impairment associated with low sodium levels or in patients receiving concomitant medications that reduce sodium levels (such as diuretics or drugs associated with inappropriate antidiuretic hormone secretion), serum sodium levels should be measured before treatment. Levels should then be measured every 2 weeks, followed by monthly intervals during the first 3 months of treatment or as clinically necessary. This is particularly important for elderly patients. Water intake should be limited in such cases if clinically necessary.

Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations due to enzyme induction. Therefore, an increase in thyroid hormone replacement therapy dosage may be necessary for patients with hypothyroidism. Monitoring of thyroid function is recommended to determine the appropriate dosage of replacement hormone therapy.

Anticholinergic effects.

Carbamazepine exhibits moderate anticholinergic activity. Therefore, patients with elevated intraocular pressure or urinary retention should be warned about potential risks and closely monitored during therapy.

Psychiatric effects. The possibility of activation of latent psychosis and confusion or agitation in elderly patients, especially when high doses of Mezakar®SR are used, should be considered.

Suicidal thoughts and behavior. There have been several reports of suicidal thoughts and behavior in patients receiving antiepileptic drugs for various indications.

A meta-analysis of data from randomized 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.

Therefore, patients should be monitored for suicidal thoughts and behavior, and appropriate treatment should be initiated if necessary. Patients (and caregivers) should be advised to seek medical attention if signs of suicidal thoughts or behavior occur.

Women of childbearing potential.

Carbamazepine may harm the fetus when used during pregnancy. 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 "Pregnancy and breastfeeding"). Animal studies have shown that carbamazepine use at clinically relevant doses during pregnancy leads to fetal developmental toxicity, including an 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 age.

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

Due to enzyme induction, carbamazepine may impair the therapeutic effect of hormonal contraceptives; therefore, women of childbearing age should consult regarding the use of other effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Pregnancy and breastfeeding").

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

Women of childbearing potential should be advised to seek medical attention immediately if they become pregnant or suspect they may be pregnant while taking carbamazepine.

Endocrine effects.

Due to hepatic enzyme induction, carbamazepine may reduce the activity of hormones in combined oral contraceptives. This may lead to breakthrough bleeding or spotting.

Breakthrough bleeding has been reported in women taking carbamazepine and hormonal contraceptives.

Since the effectiveness of hormonal contraceptives may be negatively affected by carbamazepine therapy, women of childbearing potential should be advised to use alternative contraceptive methods during Mezakar®SR treatment.

Plasma level monitoring.

Although the correlation between dosage and plasma carbamazepine levels, as well as between plasma carbamazepine levels and clinical efficacy and tolerability, is unreliable, monitoring plasma levels may be useful in the following cases: sudden increase in seizure frequency, assessment of patient compliance, during pregnancy, in pediatric and adolescent patients; suspected malabsorption, suspected toxicity, and when multiple drugs are used (see section "Interaction with other medicinal products and other forms of interaction").

Dose reduction and discontinuation.

Sudden discontinuation of carbamazepine may provoke seizures; therefore, the drug should be tapered gradually over 6 months. If necessary, in patients with epilepsy, abrupt discontinuation of Mezakar®SR therapy should be followed by transition to a new antiepileptic drug while continuing appropriate therapy.

Several cases of seizures and/or respiratory depression in newborns have been reported, associated with maternal use of carbamazepine and other concomitant anticonvulsant drugs. Several cases of vomiting, diarrhea, and/or decreased appetite in newborns have also been reported in association with maternal use of carbamazepine. These reactions may indicate neonatal withdrawal syndrome.

Interaction.

Concomitant use of CYP3A4 inhibitors or epoxide hydrolase inhibitors with carbamazepine may cause adverse reactions (increased plasma concentrations of carbamazepine or carbamazepine-10,11 epoxide, respectively). Appropriate dose adjustment of carbamazepine and/or plasma level monitoring is recommended.

Concomitant use of CYP3A4 inducers with carbamazepine may reduce plasma concentrations of carbamazepine and its therapeutic effect, while discontinuation of CYP3A4 inducers may lead to increased plasma concentrations of carbamazepine. Dose adjustment of carbamazepine may be required.

Carbamazepine is a potent inducer of the CYP3A4 isoenzyme and other hepatic enzyme systems of phase I and phase II drug metabolism, and when used concomitantly with drugs metabolized by the CYP3A4 isoenzyme, it may induce metabolism and reduce their plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").

Women of childbearing age should be warned that concomitant use of carbamazepine with hormonal contraceptives may negatively affect their effectiveness. When using Mezakar®SR, consideration should be given to using alternative non-hormonal contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Pregnancy and breastfeeding").

Falls.

Carbamazepine therapy may be 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 medications that exacerbate these conditions, a comprehensive risk assessment for falls should be regularly performed during long-term carbamazepine therapy.

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").

Excipients.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., practically sodium-free.

Pregnancy and breastfeeding.

Pregnancy

General risk associated with antiepileptic medicinal products (AEDs)

All women of childbearing age 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.

Sudden discontinuation of AEDs 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 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. The impact of carbamazepine during pregnancy is associated with a 2–3 times higher frequency of serious congenital malformations compared to the general population, where the frequency is 2–3%. Malformations such as fetal neural tube defects (spina bifida), craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, finger hypoplasia, and other anomalies affecting various fetal organ systems have been reported 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 during pregnancy. The woman should be fully informed and understand the risks of taking carbamazepine during pregnancy.

Data suggest that the risk of congenital malformations with carbamazepine use may depend on the dose. If, after careful benefit/risk assessment, no suitable alternative treatment is available and carbamazepine therapy is continued, monotherapy with 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 to 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 supplementation 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 pregnancy, all efforts should be made before conception and discontinuation of contraception to transition to appropriate alternative therapy. 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, pregnancy planning should be done in advance. Before initiating carbamazepine therapy, a pregnancy test should be considered in women of childbearing age.

Women of childbearing potential should use effective contraception during and for two weeks after discontinuation of therapy. 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"); therefore, women of childbearing potential should consult regarding 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. The choice of contraceptive method should consider individual circumstances, with the patient involved 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.

Several cases of seizures and/or respiratory depression in newborns have been reported, associated with maternal use of carbamazepine and other anticonvulsant drugs.

Several cases of vomiting, diarrhea, and/or decreased appetite in newborns have been reported in association with maternal use of carbamazepine.

These reactions may indicate neonatal withdrawal syndrome.

Breastfeeding. Although carbamazepine passes into breast milk at concentrations of 25–60% of plasma levels, it is considered that this does not pose a significant risk to the infant, who is likely to receive a maximum of 10% of the corresponding therapeutic dose of carbamazepine appropriate for a child of its age with epilepsy. As with all other medicinal products, the benefits of breastfeeding should be carefully weighed against the remote possibility of adverse effects in the infant.

Mothers taking carbamazepine may breastfeed provided the infant is monitored for possible adverse reactions (e.g., excessive drowsiness, allergic skin reactions).

Cholestatic hepatitis has been reported in children exposed to carbamazepine prenatally or via breast milk; therefore, monitoring of such children is recommended to diagnose adverse effects on the hepatobiliary system.

Fertility.

Very rare cases of impaired fertility in men and/or impaired spermatogenesis have been reported (see section "Adverse reactions").

Ability to influence reaction speed when driving or operating machinery.

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

Method of Administration and Dosage

Mезakar**®** SR is administered orally; the daily dose is usually divided into two to four doses.

The total daily dose of Mезakar**®** SR is generally the same as the dose of carbamazepine in immediate-release tablets.

In some patients, switching from other oral formulations of carbamazepine to prolonged-release Mезakar**®** SR tablets may require an increase in the total daily dose.

Final dose adjustment should always depend on the individual patient's clinical response.

The drug may be taken during meals, after meals, or between meals, swallowed with a glass of water. Mезakar**®** SR tablets should not be chewed.

Due to the slow and controlled release of the active substance from the prolonged-release tablets, they are usually taken twice daily.

Before initiating treatment, patients belonging to the Han Chinese ethnic group or those of Thai origin should, if possible, be tested for the presence of HLA-B*1502 allele, as this allele may trigger the development of severe carbamazepine-associated Stevens-Johnson syndrome (see section "Special Warnings and Precautions for Use").

Epilepsy

Treatment should be initiated with a low daily dose, which should then be gradually increased until the optimal effect is achieved. The carbamazepine dose should be adjusted according to the individual needs of the patient to achieve adequate seizure control.

Plasma level monitoring of the active substance may be helpful in determining the optimal dose.

In epilepsy treatment, the carbamazepine dose is usually adjusted so that the plasma concentration ranges between 4–12 µg/mL (17–50 µmol/L) (see section "Special Warnings and Precautions for Use").

Whenever possible, Mезakar**®** SR should be prescribed as monotherapy. However, when used concomitantly with other medicinal products, the same gradual dose escalation regimen is recommended (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adults

Mезakar**®** SR should be taken in divided doses.

The recommended initial dose is 100–200 mg once or twice daily, gradually increasing the dose until the optimal effect is achieved; the usual daily dose is 800–1200 mg, divided into two doses. Some patients may require a dose of Mезakar**®** SR up to 1600 mg or even 2000 mg/day.

Elderly Patients

Due to drug interactions and variable pharmacokinetics of antiepileptic agents, Mезakar**®** SR doses in elderly patients should be carefully titrated.

Children and Adolescents

Treatment is usually initiated at a dose of 10–20 mg/kg body weight per day (in divided doses).

Children under 1 year of age: 100–200 mg/day, divided into several doses.

Children aged 1 to 5 years: 200–400 mg/day, divided into several doses.

Children aged 5 to 10 years: 400–600 mg/day, divided into several doses.

Children aged 10 to 15 years: 600–1000 mg/day, divided into several doses.

Children aged 15 years and older: dosing as in adults (800–1200 mg/day, divided into two doses).

Maximum Recommended Doses:

Under 6 years: 35 mg/kg/day

6–15 years: 1000 mg/day

15 years: 1200 mg/day.

Mезakar**®** SR is not recommended for children under 5 years of age.

Trigeminal Neuralgia and Other Forms of Deafferentation Pain

Individual dosage requirements may vary significantly depending on the patient's age and body weight. A low initial dose is recommended, although some patients may require a higher initial dose. The usual dose is 200 mg 3–4 times daily, but the dose may be gradually increased until a satisfactory clinical effect is achieved, which in some cases may require up to 1600 mg/day.

The initial dose of Mезakar**®** SR (200–400 mg/day) should be gradually increased until pain relief is achieved (usually up to 200 mg 3–4 times daily).

The dose should then be gradually reduced to the minimum effective maintenance dose. The maximum recommended dose is 1200 mg/day. After pain subsides, therapy should be gradually discontinued until a new episode occurs.

Alcohol Withdrawal Symptoms

The dose should be individually adjusted for each patient. The usual dose is 600–800 mg/day, but in patients with delirium, a dose of 1200–1600 mg/day may be required, followed by gradual reduction.

Treatment of Mania and Prophylaxis of Bipolar Affective Disorders

The initial dose is 100–200 mg/day, divided into several doses, gradually increasing until symptoms are controlled or until a total daily dose of 1600 mg is reached. The usual dose range is 400–1600 mg/day, divided into several doses.

Patients with Renal or Hepatic Impairment

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

Children

Mезakar**®** SR tablets may be administered to children aged 5 years and older.

Overdose

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

Central Nervous System: 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, changes in blood pressure (arterial hypotension, occasionally arterial hypertension), cardiac arrhythmias, conduction disturbances with QRS complex widening; syncope associated with cardiac arrest.

Gastrointestinal Tract: Vomiting, gastric retention, decreased intestinal peristalsis.

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 carbamazepine's antidiuretic hormone-like effect.

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 may be necessary. Plasma carbamazepine concentration should be measured to confirm poisoning and assess the degree of overdose.

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

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

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

Adverse Reactions

Summary of safety profile

At the beginning of treatment with carbamazepine, or when using too high an initial dose, or when treating elderly patients, certain types of adverse reactions occur very commonly or commonly, such as those affecting the central nervous system (dizziness, headache, ataxia, somnolence, general weakness, diplopia), gastrointestinal tract (nausea, vomiting), or allergic skin reactions.

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

There have been reports of decreased bone mineral density, osteopenia, osteoporosis, and fractures in patients receiving long-term carbamazepine therapy. The mechanism by which carbamazepine affects bone metabolism has not been established.

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; common – thrombocytopenia, eosinophilia; rare – lymphadenopathy, leukocytosis; very rare – agranulocytosis, aplastic anemia, pancytopenia, erythroblastic aplasia, anemia, megaloblastic anemia, reticulocytosis, hemolytic anemia.

Immune system disorders: rare – multi-organ hypersensitivity reaction of delayed type (serum sickness-like syndrome) with fever, skin rash, vasculitis, lymphadenopathy, lymphoma-like symptoms, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests, and vanishing bile duct syndrome (destruction and disappearance of intrahepatic bile ducts), occurring in various combinations. Other organs may also be involved (e.g., lungs, kidneys, pancreas, myocardium, colon). In case such hypersensitivity reactions occur, treatment must be discontinued immediately. very rare – 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 associated with lethargy, vomiting, headache, confusion, and neurological disturbances; very rare – galactorrhea, gynecomastia.

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, aggression, agitation, restlessness, confusion; very rare – activation of psychosis.

Nervous system disorders: very common – ataxia, dizziness, somnolence; common – diplopia, headache; uncommon – abnormal involuntary movements (e.g., tremor, "fluttering" tremor, dystonia, tics), nystagmus; rare – dyskinesia, eye movement disorders, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, paresis; very rare – neuroleptic malignant syndrome (NMS), aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

Eye disorders: common – accommodation disorders (e.g., blurred vision); very rare – lens opacity, conjunctivitis.

Ear and labyrinth disorders: very rare – hearing disorders, e.g., tinnitus, hyperacusis, hypoacusis, disturbances in pitch perception.

Cardiac disorders: rare – disturbances in intracardiac conduction; very rare – arrhythmia, atrioventricular block with syncope, bradycardia, congestive heart failure, exacerbation of ischemic heart disease.

Vascular disorders: rare – arterial hypertension or arterial hypotension; very rare – circulatory collapse, embolism (e.g., pulmonary embolism), thrombophlebitis.

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

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

Hepatobiliary disorders: rare – cholestatic, parenchymal (hepatocellular), or mixed type hepatitis, vanishing bile duct syndrome, jaundice; very rare – liver failure, granulomatous hepatitis.

Skin and subcutaneous tissue disorders: very common – urticaria, sometimes in severe form, allergic dermatitis; uncommon – exfoliative dermatitis; rare – systemic lupus erythematosus, pruritus; very rare – severe skin reactions, e.g., Stevens-Johnson syndrome (in some Asian countries this adverse event has been reported with a frequency of "rare"), toxic epidermal necrolysis (see section "Special precautions for use"), photosensitivity reactions, erythema multiforme, nodular erythema, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism.

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

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

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

General disorders: very common – general weakness.

Investigations: very common – increased gamma-glutamyl transferase (GGT) 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, increased high-density lipoprotein and triglyceride levels, increased blood triglyceride levels, changes in thyroid function tests: decreased levels of L-thyroxine (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.

Injury, poisoning and procedural complications: unknown – falls (associated with ataxia, dizziness, somnolence, hypotension, confusion, sedative effect during carbamazepine treatment) (see section "Special precautions for use").

Additional adverse reactions based on spontaneous reports (frequency unknown).

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

Infections and infestations: reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: bone marrow failure.

Immune system disorders: drug reaction with eosinophilia and systemic symptoms (DRESS).

Metabolism and nutrition disorders: hyperammonemia.

Nervous system disorders: sedative effect, memory impairment.

Gastrointestinal disorders: colitis.

Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal and connective tissue disorders: fractures.

Investigations: decreased bone mineral density.

Growing evidence links genetic markers with the occurrence of skin-related adverse reactions such as SJS/TEN, DRESS, AGEP, and maculopapular rash. It has been reported that in patients of European descent and Japanese patients, these reactions are associated with carbamazepine use and the presence of the HLA-A*3101 allele. Another marker, HLA-B*1502, has been shown to be strongly associated with SJS/TEN among Han Chinese, Thai, and some other Asian populations (see sections "Dosage and administration" and "Special precautions for use").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued 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 via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

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

Prescription status.

Prescription-only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address.

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

INSTRUCTION

for medical use of the medicinal product

MEZACAR®SR

(MEZACAR®SR)

Composition:

Active ingredient: carbamazepine;

One tablet contains 400 mg of carbamazepine;

Excipients: microcrystalline cellulose, hypromellose, sodium lauryl sulfate, povidone (PVP K 30), colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Extended-release tablets.

Main physicochemical characteristics: white or almost white, round tablets with beveled edges, marked "C400" on one side and a cross-score on the other.

Pharmacotherapeutic group.
Antiepileptic drugs. ATC code N03A F01.

Pharmacological Properties

Pharmacodynamics

As an antiepileptic agent, carbamazepine is effective in partial seizures (simple and complex), with or without secondary generalization, generalized tonic-clonic seizures, as well as in combination of these seizure types. The mechanism of action of carbamazepine, the active substance of the medicinal product Mезакар**®** SR, has been only partially elucidated.

Carbamazepine stabilizes membranes of overexcited nerve fibers, inhibits the generation of repetitive neuronal discharges, and reduces synaptic transmission of excitatory impulses.

It has been established that the main mechanism of action of the drug is prevention of repeated formation of sodium-dependent action potentials in depolarized neurons by blocking sodium channels.

The anticonvulsant effect of the drug is primarily due to reduction in glutamate release and stabilization of neuronal membranes, whereas the antimanic effect may be attributed to inhibition of dopamine and norepinephrine metabolism.

Pharmacokinetics

Absorption

After oral administration, carbamazepine is almost completely absorbed, but the rate of absorption from tablets is slow and may vary between different dosage forms and among individual patients.

After single administration of the prolonged-release formulation, peak plasma concentration (Cmax) of the active substance is reached within 24 hours.

Prolonged-release tablets. When administered as single or multiple doses, prolonged-release tablets result in plasma peak concentrations of the active substance approximately 25% lower than those achieved with conventional tablets.

Prolonged-release tablets provide a statistically significant reduction in the fluctuation index, but no significant reduction in Cmin at steady state.

Plasma concentration fluctuations with a twice-daily dosing regimen are minimal. The bioavailability of prolonged-release tablets Мезакар**®** SR is approximately 15% lower than that of other oral dosage forms.

It has been shown that the bioavailability of various oral dosage forms of carbamazepine ranges between 85–100%.

Bioavailability of different carbamazepine formulations may vary. To prevent a reduction in therapeutic efficacy or the risk of epileptic seizures or pronounced adverse effects, switching between different carbamazepine formulations should be avoided.

Food intake does not significantly affect the rate or extent of carbamazepine absorption (regardless of the dosage form).

Steady-state plasma concentrations of carbamazepine are reached 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.

The steady-state plasma concentrations of carbamazepine considered as the "therapeutic range" vary considerably among individuals: for most patients, the range is 4–12 micrograms/mL, corresponding to 17–50 micromoles/L.

Concentrations of carbamazepine-10,11-epoxide (pharmacologically active metabolite): approximately 30% of carbamazepine levels.

Distribution

Plasma protein binding of carbamazepine 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 range from 25–60% of plasma levels. Carbamazepine crosses the placental barrier. Assuming complete absorption, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg.

Biotransformation/Metabolism

Carbamazepine is metabolized in the liver primarily via the epoxide pathway, resulting in the formation of major metabolites – 10,11-trans-diol derivative and its glucuronic acid conjugate.

The main isoenzyme responsible for biotransformation of carbamazepine into carbamazepine-10,11-epoxide is cytochrome P450 3A4.

Human microsomal epoxide hydrolase has been identified as the enzyme responsible for conversion of carbamazepine-10,11-epoxide into the 10,11-trans-diol derivative. 9-Hydroxymethyl-10-carbamoylacridan is a minor metabolite associated with this pathway.

After single oral administration of carbamazepine, approximately 30% of the active substance is excreted in urine as end products of epoxide metabolism.

Other important pathways of carbamazepine biotransformation lead to the formation of various monohydroxylated derivatives, as well as the N-glucuronide of carbamazepine, formed via uridine diphosphate glucuronosyltransferase (UGT2B7).

Elimination

After single oral administration, the half-life of unchanged carbamazepine averages 36 hours; after repeated administration, it averages 16–24 hours (due to autoinduction of hepatic mono-oxygenase system), depending on duration of treatment.

In patients concurrently receiving other drugs that induce the same hepatic enzyme system (e.g., phenytoin, phenobarbital), the half-life of carbamazepine averages 9–10 hours.

The average half-life of the 10,11-epoxide metabolite in plasma is approximately 6 hours after single oral administration of the epoxide.

After single oral administration of 400 mg carbamazepine, 72% of the administered dose is excreted in urine and 28% in feces. Nearly 2% of the administered dose is excreted unchanged in urine, and approximately 1% as the pharmacologically active metabolite 10,11-epoxide.

Pharmacokinetic characteristics in specific patient populations

Children

Due to faster elimination of carbamazepine, children may require higher doses of carbamazepine on a mg/kg body weight basis compared to adults to maintain therapeutic concentrations.

Elderly patients

There are no data indicating that the pharmacokinetics of carbamazepine are altered in elderly patients compared to younger adults.

Patients with impaired renal or hepatic function

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

Clinical characteristics.

Indications.

• As an anticonvulsant in the treatment of epilepsy (generalized tonic-clonic and partial types of seizures).
• Paroxysmal pain in trigeminal neuralgia.

Mazakar**®** SR can also be used to relieve deafferentation pain, for example, in glossopharyngeal neuralgia, peripheral diabetic neuropathy, spinal tabes, superior laryngeal nerve neuralgia, postherpetic neuralgia, as well as stump pain and phantom limb pain.

• Treatment of symptoms of alcohol withdrawal.
• Treatment of mania and prophylaxis of bipolar affective disorders, especially in patients who did not respond clinically to lithium therapy.

Contraindications.

• Known hypersensitivity to carbamazepine or to drugs chemically related to it (e.g., tricyclic antidepressants), or to any other component of the drug.
• Atrioventricular block.
• History of bone marrow depression.
• History of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria).
• Concomitant use with monoamine oxidase inhibitors (MAOIs) (see section "Interaction with other medicinal products and other forms of interactions").
• Concomitant use with herbal preparations containing St. John's wort (Hypericum perforatum) due to the risk of reduced plasma concentration of carbamazepine and, consequently, reduced clinical efficacy of the drug (see section "Interaction with other medicinal products and other forms of interactions").

Interaction with other medicinal products and other forms of interactions.

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing the formation of the active metabolite of carbamazepine—10,11-epoxide. Concomitant use of CYP3A4 inhibitors with carbamazepine may increase plasma concentrations of carbamazepine, which in turn may lead to the development of adverse reactions. Concomitant use of CYP3A4 inducers may enhance the metabolism of carbamazepine, leading to a potential decrease in serum carbamazepine concentration and therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, resulting in increased plasma levels of carbamazepine.

Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II hepatic enzyme systems; therefore, it may reduce plasma concentrations of other drugs that are primarily metabolized via CYP3A4 by inducing their metabolism.

Human microsomal epoxide hydrolase is the enzyme responsible for the formation of 10,11-trans-diol derivatives from carbamazepine-10,11-epoxide.

Concomitant administration of inhibitors of human microsomal epoxide hydrolase may lead to increased plasma concentrations of carbamazepine-10,11-epoxide.

Interactions leading to contraindications

Concomitant use of Mazakar**®** SR with monoamine oxidase inhibitors (MAOIs) is contraindicated. Administration of MAOIs should be discontinued at least 2 weeks prior to initiation of Mazakar**®** SR, or longer if clinically appropriate (see section "Contraindications").

Medicinal products that may increase plasma levels of carbamazepine.

Since increased plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), dosage adjustment of Mazakar**®** SR and/or monitoring of its plasma levels are necessary when used concomitantly with the following drugs:

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.

Antituberculosis agents: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular agents: diltiazem, verapamil.

Agents for gastrointestinal (GI) 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 increased plasma levels of carbamazepine-10,11-epoxide may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), the dose of Mazakar**®** SR should be adjusted accordingly and/or its plasma levels monitored when used concomitantly with the following substances:

loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, valpromide, brivaracetam.

Medicinal products that may decrease plasma levels of carbamazepine.

Dosage adjustment of Mazakar**®** SR may be necessary when used 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 starting carbamazepine therapy), fosphenytoin, primidone, and clonazepam (although data are conflicting).

Antineoplastic agents: cisplatin or doxorubicin.

Antimalarial agents: mefloquine, which may antagonize the anticonvulsant effect of carbamazepine.

Antituberculosis agents: rifampicin.

Bronchodilators or antiasthmatic agents: theophylline, aminophylline.

Dermatological agents: isotretinoin.

It has been reported that isotretinoin alters the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide. Carbamazepine levels should be monitored.

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

Effect of carbamazepine on plasma levels of concomitantly administered drugs.

Plasma or whole blood concentrations of carbamazepine may be reduced when used concomitantly with herbal preparations containing St. John's wort (Hypericum perforatum). This is due to enzyme induction by St. John's wort involved in carbamazepine metabolism. Herbal preparations containing St. John's wort are contraindicated for concomitant use with carbamazepine (see section "Contraindications"). The inducing effect of St. John's wort preparations may persist for at least 2 weeks after discontinuation. If a patient is already receiving St. John's wort therapy, its use should be discontinued and carbamazepine plasma concentration determined. Carbamazepine levels may increase after discontinuation of St. John's wort preparations. Dose adjustment of carbamazepine may be required.

Carbamazepine may reduce plasma levels or diminish or even abolish the effects of certain drugs. Dosage of such drugs may need to be adjusted according to clinical requirements:

Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (prolonged 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, citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline, clomipramine).

Antiemetics: aprepitant.

Antiepileptic agents: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. To avoid phenytoin toxicity and subtherapeutic carbamazepine concentrations, recommended plasma phenytoin concentration should not exceed 13 µg/mL before initiation of carbamazepine therapy. Isolated reports of increased plasma concentrations of mefenitoin during carbamazepine treatment have been reported.

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

Anthelmintics: praziquantel, albendazole.

Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.

Antipsychotic agents: 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 concentrations in plasma. This may result in contraceptive failure or breakthrough bleeding. Alternative methods to oral and subdermal implanted contraceptives significantly affected by CYP3A4 induction should be considered; or alternative to carbamazepine [see sections "Special precautions for use" and "Use in specific populations"].

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

Corticosteroids: corticosteroids (e.g., prednisolone, dexamethasone).

Agents used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

Interaction with other agents: preparations containing estrogens and/or progestogens (gestrinone, trenbolone, toremifene).

Both increased and decreased plasma levels of phenytoin due to carbamazepine have been reported, as well as isolated cases of increased plasma levels of mefenitoin.

Combinations requiring special consideration.

Concomitant use of carbamazepine and paracetamol (acetaminophen) may reduce the bioavailability of paracetamol.

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 with neuroleptics (haloperidol, thioridazine), may enhance neurological adverse effects (in the latter combination, even at therapeutic plasma levels).

Combined therapy with carbamazepine and certain diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.

Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g., pancuronium).

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 lead to reduced plasma concentrations of direct oral anticoagulants and, thus, increase the risk of thrombosis. Therefore, if concomitant use is necessary, patients should be closely monitored for signs and symptoms of thrombosis.

Effect on serological tests.

Carbamazepine may give a false-positive result in HPLC (high-performance liquid chromatography) analysis for determination of perphenazine concentration.

Carbamazepine and 10,11-epoxide may give a false-positive result in immunoassay using fluorescence polarization technique for determination of tricyclic antidepressant concentrations.

Special precautions for use.

Mezakar®SR should be used only under medical supervision. Mezakar®SR should be prescribed only after a benefit/risk assessment and with careful monitoring of patients with cardiac, hepatic or renal disorders, previous hematological adverse reactions to other drugs, and patients with interrupted courses of carbamazepine therapy.

Hematological effects.

Carbamazepine has been associated with the development of agranulocytosis and aplastic anemia; however, due to the extremely low incidence of these conditions, it is difficult to assess the significant risk associated with Mezakar®SR use.

The overall risk in patients who have not previously received carbamazepine therapy is 4.7 cases per 1,000,000 patients per year for agranulocytosis and 2 cases per 1,000,000 patients per year for aplastic anemia.

Transient or persistent reduction in platelet or white blood cell counts may occasionally or frequently occur during carbamazepine treatment. A complete blood count, including platelet count (and possibly reticulocyte count and serum iron levels), should be performed before initiating therapy and periodically during treatment.

If leukocyte or platelet counts significantly decrease during therapy, the patient's condition should be closely monitored and regular complete blood counts should be performed (see section "Adverse reactions"). Treatment with Mezakar®SR should be discontinued if the patient develops serious, progressive leukopenia or leukopenia accompanied by clinical symptoms such as fever or sore throat. Mezakar®SR should be discontinued if signs of bone marrow suppression occur.

Patients and their relatives 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 symptoms such as fever, sore throat, skin rash, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura occur, they should immediately consult a physician.

Dermatological reactions.

Serious, sometimes fatal, dermatological reactions, including toxic epidermal necrolysis (TEN) or Lyell's syndrome, and Stevens-Johnson syndrome (SJS), have been reported during carbamazepine therapy. Patients should be advised to carefully monitor for signs and symptoms of skin reactions.

It is estimated that these dermatological reactions occur in 1 to 6 per 10,000 new patients in countries with predominantly Caucasian populations. However, in some Asian countries, the risk may be approximately 10 times higher.

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 carbamazepine treatment.

If signs and symptoms of SJS, Lyell's syndrome/TEN (e.g., progressive skin rash, often with blisters or mucosal involvement) develop, Mezakar®SR should be discontinued immediately and alternative therapy initiated.

The best outcomes in treating SJS/TEN are achieved with early diagnosis and immediate discontinuation of any suspected drug. Early discontinuation is associated with a better prognosis.

If a patient develops SJS/TEN during treatment with Mezakar®SR, further carbamazepine therapy is contraindicated.

Pharmacogenomics.

Increasing evidence indicates the influence of different HLA alleles on patient susceptibility to immune system-related adverse reactions (see section "Dosage and administration").

Association with HLA-B*1502

Retrospective studies in Han Chinese patients have demonstrated a strong correlation between carbamazepine-associated skin reactions (SJS/TEN) and the presence of human leukocyte antigen (HLA) allele HLA-B*1502 in these patients.

The prevalence of the HLA-B*1502 allele varies from 2% to 12% in Han Chinese patients and is approximately 8% in Thailand. A higher frequency of SJS reports (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). In Korea and India, the prevalence of this allele in the population is up to 2% and 6%, respectively.

There is evidence indicating an increased risk of serious carbamazepine-associated SJS/TEN in other Asian populations. Due to the prevalence of this allele in other Asian populations (e.g., over 15% in the Philippines and Malaysia), genetic testing for HLA-B*1502 in at-risk groups may be considered.

The prevalence of the HLA-B*1502 allele is low among European and African populations, as well as among Native Americans, Latino populations, and Japanese (<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 carbamazepine therapy (see section "Dosage and administration").

If testing for the HLA-B*1502 allele is required, high-resolution "HLA-B*1502 genotyping" is recommended. The test is positive if one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.

Carbamazepine therapy should not be initiated in patients with a positive HLA-B*1502 test result, except when no other therapeutic options are available.

Patients who have been tested and have a negative result for HLA-B*1502 have a low risk of developing SJS, although very rare cases may still occur.

The HLA-B*1502 allele may be a risk factor for SJS/TEN in Chinese patients receiving other antiepileptic drugs that may be associated with SJS/TEN.

Therefore, other drugs potentially associated with SJS/TEN should be avoided in patients carrying the HLA-B*1502 allele, if alternative therapy is available.

Genetic screening is generally not recommended for patients of nationalities with a low HLA-B*1502 allele frequency.

Screening is generally not recommended for patients already receiving carbamazepine, as the risk of SJS/TEN is significantly limited to the first few months of treatment, regardless of the presence of the HLA-B*1502 allele.

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

Association with HLA-A*3101

There is evidence suggesting that the human leukocyte antigen may be a risk factor for skin adverse reactions such as SJS, TEN, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and maculopapular rash in patients of European descent and Japanese (see section "Adverse reactions").

The prevalence of HLA-A*3101 may vary among different ethnic groups: approximately 2–5% in the European population and about 10% in the Japanese population.

The prevalence of this allele is less than 5% in the populations of Australia, Asia, Africa, and North America. 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 North Americans (Navajo and Sioux tribes, in Mexico - Sonora Seri), South India (Tamil Nadu), 10%–15% in other indigenous ethnic groups in these regions, and about 10% in the Japanese population.

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.

The presence of the HLA-A*3101 allele may increase the risk of carbamazepine-induced dermatological reactions (mostly less severe) from 5% (in the general population) to 26% (among subjects of European descent). Conversely, the absence of this allele may reduce the risk from 5.0% to 3.8%.

Before initiating Mezakar®SR therapy in potential carriers of the HLA-A*3101 allele (e.g., patients of Japanese nationality, Caucasians, Native Americans, Latinos, South Indians, and Arabs), screening for this allele is recommended (see section "Dosage and administration").

If testing for the HLA-A*3101 allele is performed, high-resolution "HLA-A*3101 genotyping" is recommended. The test is positive if one or two HLA-A*3101 alleles are detected and negative if no HLA-A*3101 alleles are detected. Carbamazepine should be used in carriers of this allele only if the benefit of therapy outweighs the potential risk.

Screening for the HLA-A*3101 allele is generally not required in patients who have already received carbamazepine for a prolonged period, as SJS/TEN, AGEP, DRESS, and maculopapular rash are typically observed only during the first few months of therapy.

Limitations of genetic screening

Genetic screening results should not replace appropriate clinical monitoring and management of patients. Many Asian patients with a positive HLA-B*1502 test result who take carbamazepine do not develop SJS/TEN. Conversely, SJS/TEN may occur in patients of any ethnic origin with a negative HLA-B*1502 test result. Similarly, many patients with a positive HLA-A*3101 test result who take carbamazepine do not develop SJS/TEN, DRESS, AGEP, or maculopapular rash, while these serious skin adverse reactions may develop in patients of any ethnic origin with a negative HLA-A*3101 test result. Other potential factors, such as antiepileptic drug dosage, adherence to therapy, and concomitant therapy, may play a role in the development of these severe skin adverse reactions. The impact of other diseases and the level of skin disorder monitoring 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. These usually resolve within a few days or weeks, either with continued carbamazepine dosing or after dose reduction.

Since early signs of more serious dermatological reactions may be difficult to distinguish from mild transient reactions, the patient should be closely monitored to allow immediate discontinuation of the drug if the reaction worsens with continued use.

The presence of the HLA-A*3101 allele is associated with less severe skin adverse reactions during carbamazepine use, 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.

Carbamazepine may provoke hypersensitivity reactions, including DRESS, multiple slow-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. Clinical manifestations in other organs (lungs, kidneys, pancreas, myocardium, colon) are also possible (see section "Adverse reactions").

The presence of the HLA-A*3101 allele in patients is associated with the development of hypersensitivity syndrome, including maculopapular rash.

Patients with hypersensitivity reactions to carbamazepine should be informed that approximately 25–30% of such patients may also experience hypersensitivity reactions to oxcarbazepine. Cross-hypersensitivity may occur with carbamazepine and aromatic antiepileptic drugs (e.g., phenytoin, primidone, and phenobarbital).

In general, Mezakar®SR should be discontinued immediately if signs and symptoms indicating hypersensitivity occur.

Seizures.

Since carbamazepine may cause or exacerbate absence seizures, Mezakar®SR 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, Mezakar®SR therapy should be discontinued immediately.

An increase in seizure frequency may occur during the transition from oral carbamazepine formulations to suppositories.

Sudden discontinuation of Mezakar®SR may provoke seizures.

Liver function.

Liver function should be assessed at baseline and periodically during carbamazepine therapy, especially in patients with a history of liver disease and in elderly patients.

Mezakar®SR should be discontinued immediately in cases of acute liver function deterioration or in patients with active liver disease.

Some laboratory parameters used to assess liver function may be outside the normal range in patients taking carbamazepine, particularly gamma-glutamyl transferase (GGT). This is likely due to the induction of hepatic enzymes.

Enzyme induction may also lead to a moderate increase in alkaline phosphatase levels. Such increased functional activity of hepatic metabolism is not an indication for carbamazepine discontinuation.

Severe hepatic reactions due to carbamazepine are very rare.

If signs or symptoms of hepatic dysfunction or active liver disease occur, the patient should be urgently evaluated, and Mezakar®SR therapy should be suspended until test results are obtained.

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

Hyponatremia.

Cases of hyponatremia have been reported with carbamazepine use. In patients with pre-existing renal impairment associated with low sodium levels, or in patients receiving concomitant therapy with drugs that reduce sodium levels (such as diuretics, drugs associated with inappropriate antidiuretic hormone secretion), serum sodium levels should be measured before treatment. Subsequently, levels should be measured every 2 weeks, then monthly for the first 3 months of treatment or as clinically necessary. This is particularly important for elderly patients. Water intake should be limited in these cases if clinically necessary.

Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations due to enzyme induction. Therefore, an increased dose of thyroid hormone replacement therapy may be required for patients with hypothyroidism. Monitoring of thyroid function is recommended to determine the dose of replacement hormone therapy.

Anticholinergic effects.

Carbamazepine exhibits moderate anticholinergic activity. Therefore, patients with elevated intraocular pressure or urinary retention should be warned about potential risks and closely monitored during therapy.

Psychiatric effects. The possibility of activation of latent psychosis and confusion or agitation in elderly patients, especially with high doses of Mezakar®SR, should be considered.

Suicidal thoughts and behavior. There have been several reports of suicidal thoughts and behavior in patients receiving antiepileptic drugs for various indications.

A meta-analysis of data from randomized 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.

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.

Women of childbearing potential.

Carbamazepine may harm the fetus when administered to 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 and breastfeeding").

Animal studies have shown that carbamazepine administration at clinically relevant doses during pregnancy resulted in developmental toxicity, including an increased incidence of fetal malformations.

Carbamazepine should not be used in women of childbearing potential unless, after careful consideration of alternative treatment options, the benefit outweighs the risks.

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 age.

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

Due to enzyme induction, carbamazepine may interfere with the therapeutic effect of hormonal contraceptives; therefore, women of childbearing age should consult their physician about using other effective methods of contraception (see sections "Interaction with other medicinal products and other forms of interaction" and "Pregnancy and breastfeeding").

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

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

Endocrine effects.

Due to enzyme induction, carbamazepine may reduce the activity of hormones in combined oral contraceptives. This may lead to breakthrough bleeding or spotting.

Breakthrough bleeding has been reported in women taking carbamazepine and hormonal contraceptives.

Since the efficacy of hormonal contraceptives may be negatively affected by carbamazepine therapy, women of childbearing potential should be advised to use alternative contraceptive methods during Mezakar®SR therapy.

Monitoring of plasma drug levels.

Although the correlation between dosage and plasma carbamazepine levels, as well as between plasma carbamazepine levels and clinical efficacy and tolerability, is unreliable, monitoring plasma drug levels may be useful in the following cases: a sudden increase in seizure frequency, assessment of patient compliance, during pregnancy, in pediatric and adolescent patients; in suspected malabsorption, suspected toxicity, and with concomitant use of multiple drugs (see section "Interaction with other medicinal products and other forms of interaction").

Dose reduction and discontinuation.

Sudden discontinuation of carbamazepine may provoke seizures; therefore, the drug should be tapered gradually over 6 months. In cases where abrupt discontinuation of Mezakar®SR is necessary in patients with epilepsy, transition to a new antiepileptic drug should be performed while continuing appropriate therapy.

Several cases of seizures and/or respiratory depression in newborns have been reported, associated with maternal use of carbamazepine and other concomitant anticonvulsant drugs. Several cases of vomiting, diarrhea, and/or decreased appetite in newborns have also been reported in association with maternal carbamazepine use. These reactions may indicate neonatal withdrawal syndrome.

Interaction.

Concomitant use of CYP3A4 inhibitors or epoxide hydrolase inhibitors with carbamazepine may cause adverse reactions (increased plasma concentrations of carbamazepine or carbamazepine-10,11 epoxide, respectively). Appropriate dose adjustment of carbamazepine and/or monitoring of plasma drug levels is recommended.

Concomitant use of CYP3A4 inducers with carbamazepine may reduce plasma carbamazepine concentrations and its therapeutic effect, while discontinuation of CYP3A4 inducers may lead to increased plasma carbamazepine concentrations. Dose adjustment of carbamazepine may be required.

Carbamazepine is a potent inducer of the CYP3A4 isoenzyme and other hepatic enzyme systems of phase I and phase II drug metabolism and, when used concomitantly with drugs metabolized by the CYP3A4 isoenzyme, may induce metabolism and reduce their plasma concentrations (see section "Interaction with other medicinal products and other forms of interaction").

Women of childbearing age should be warned that concomitant use of carbamazepine with hormonal contraceptives may negatively affect their efficacy. When using Mezakar®SR, the possibility of using alternative non-hormonal contraceptive methods should be considered (see sections "Interaction with other medicinal products and other forms of interaction" and "Pregnancy and breastfeeding").

Falls.

Carbamazepine therapy may be 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 carbamazepine therapy.

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").

Excipients

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., practically sodium-free.

Pregnancy and 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.

Sudden 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 the treatment of epilepsy 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. The impact of carbamazepine during pregnancy is associated with a 2–3 times higher frequency of serious malformations compared to the general population, where the frequency is 2–3%. Malformations such as fetal neural tube defects (spina bifida), craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, finger hypoplasia, and other anomalies affecting various fetal organ systems have been reported 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.

Carbamazepine should not be used during pregnancy in women unless, after careful consideration of alternative treatment options, the benefit outweighs the risks. The woman should be fully informed and understand the risks of taking carbamazepine during pregnancy.

Data suggest that the risk of malformations with carbamazepine use may be dose-dependent. If, after careful benefit/risk assessment, no suitable alternative treatment option is available and carbamazepine therapy is continued, 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 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 women with epilepsy. Folic acid supplementation 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 pregnancy, all efforts should be made before conception and discontinuation of contraception to switch to appropriate alternative therapy. 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 she takes carbamazepine during pregnancy; therefore, pregnancy planning should be done 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 for two weeks after discontinuation of therapy. 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 methods of contraception.

At least one effective method of contraception (e.g., intrauterine) or two additional forms of contraception, including a barrier method, should be used. The choice of contraceptive method should consider individual circumstances, with the patient involved 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.

Several cases of seizures and/or respiratory depression in newborns have been reported, associated with maternal use of carbamazepine and other anticonvulsant drugs.

Several cases of vomiting, diarrhea, and/or decreased appetite in newborns have been reported in association with maternal carbamazepine use.

These reactions may indicate neonatal withdrawal syndrome.

Breastfeeding. Although carbamazepine passes into breast milk at concentrations of 25–60% of plasma levels, it is considered that this does not pose a significant risk to the infant, who is likely to receive a maximum of 10% of the corresponding therapeutic dose of carbamazepine appropriate for a child of that age with epilepsy. As with all other medicinal products, the benefits of breastfeeding should be carefully weighed against the remote probability of adverse effects in the infant.

Mothers taking carbamazepine may breastfeed, provided the infant is monitored for possible adverse reactions (e.g., excessive drowsiness, allergic skin reactions).

Cholestatic hepatitis has been reported in children exposed to carbamazepine prenatally or through breast milk, necessitating monitoring of these children for adverse effects on the hepatobiliary system.

Fertility.

Very rare cases of impaired fertility in men and/or impaired spermatogenesis have been reported (see section "Adverse reactions").

Ability to influence reaction speed when driving or operating machinery.

The patient's ability to react quickly (especially at the beginning of therapy or during dose titration) may be reduced due to seizures caused by the disease and due to adverse effects associated with Mezakar®SR 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

Mesacar® SR is administered orally; the daily dose is usually divided into two to four administrations.

The total daily dose of Mesacar® SR is generally the same as the dose of immediate-release carbamazepine tablets.

In some patients, switching from other oral formulations of carbamazepine to prolonged-release Mesacar® SR tablets may require an increase in the total daily dose.

Final dose adjustment should always depend on the individual patient's clinical response.

The drug may be taken during meals, after meals, or between meals, with a glass of water. Mesacar® SR tablets must not be chewed.

Due to the slow and controlled release of the active substance from the prolonged-release tablets, they are usually taken twice daily.

Before initiating treatment, patients of Han Chinese ethnicity or those of Thai origin should, whenever possible, be tested for the presence of HLA-B*1502, as this allele may predispose to the development of severe carbamazepine-associated Stevens-Johnson syndrome (see section "Special Warnings and Precautions for Use").

Epilepsy

Treatment should be initiated with a low daily dose, which should then be gradually increased until the optimal effect is achieved. The carbamazepine dose should be adjusted according to individual patient needs to achieve adequate seizure control.

Plasma level monitoring of the active substance may be helpful in determining the optimal dose.

In epilepsy treatment, the carbamazepine dose is usually adjusted to maintain plasma concentrations between 4–12 µg/mL (17–50 µmol/L) (see section "Special Warnings and Precautions for Use").

Whenever possible, Mesacar® SR should be used as monotherapy. However, when used in combination with other medicinal products, a similar gradual dose escalation regimen is recommended (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Adults

Mesacar® SR should be taken in divided doses.

Recommended initial dose: 100–200 mg once or twice daily, gradually and slowly increasing the dose until optimal effect is achieved. The usual daily dose is 800–1200 mg, divided into two doses. Some patients may require a Mesacar® SR dose up to 1600 mg or even 2000 mg per day.

Elderly Patients

Due to potential drug interactions and altered pharmacokinetics of antiepileptic drugs, Mesacar® SR doses in elderly patients should be selected cautiously.

Children and Adolescents

Treatment is usually initiated at a dose of 10–20 mg/kg body weight per day (in divided doses).

Children under 1 year: 100–200 mg/day, divided into several doses.

Children aged 1 to 5 years: 200–400 mg/day, divided into several doses.

Children aged 5 to 10 years: 400–600 mg/day, divided into several doses.

Children aged 10 to 15 years: 600–1000 mg/day, divided into several doses.

Children aged 15 years and older: adult dosing (800–1200 mg/day, divided into two doses).

Maximum Recommended Doses:

Under 6 years: 35 mg/kg/day

6–15 years: 1000 mg/day

15 years: 1200 mg/day.

Mesacar® SR is not recommended for children under 5 years of age.

Trigeminal Neuralgia and Other Forms of Deafferentation Pain

Individual dosage requirements may vary significantly depending on age and body weight. A low initial dose is recommended, although some patients may require a higher initial dose. The usual dose is 200 mg 3–4 times daily, but the dose may be gradually increased until a satisfactory clinical effect is achieved, which in some cases may require up to 1600 mg/day.

The initial dose of Mesacar® SR (200–400 mg/day) should be slowly increased until pain subsides (usually up to a dose of 200 mg 3–4 times daily).

The dose should then be gradually reduced to the minimum effective maintenance dose. The maximum recommended dose is 1200 mg/day. After pain has subsided, therapy should be gradually discontinued until a new episode occurs.

Alcohol Withdrawal Symptoms

The dose should be individually adjusted for each patient. The usual dose ranges from 600 to 800 mg/day, but in patients with delirium, doses of 1200 to 1600 mg/day may be required, followed by gradual reduction.

Treatment of Mania and Prophylaxis of Bipolar Affective Disorders

Initial dose: 100–200 mg/day, divided into several doses, gradually increased until symptoms are controlled or until a total daily dose of 1600 mg is reached. The usual dose range is 400–1600 mg/day, divided into several doses.

Patients with Renal or Hepatic Impairment

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

Children

Mesacar® SR tablets may be administered to children aged 5 years and older.

Overdose

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

Central Nervous System: Central nervous system (CNS) depression; confusion, 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, changes in blood pressure (arterial hypotension, sometimes hypertension), cardiac arrhythmias, conduction disturbances with QRS complex widening; syncope associated with cardiac arrest.

Gastrointestinal Tract: Vomiting, gastric retention, reduced intestinal peristalsis.

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 carbamazepine's antidiuretic hormone-like effect.

Laboratory Test Alterations: Hyponatremia, possible metabolic acidosis, hyperglycemia, increased creatine phosphokinase muscle fraction.

Treatment. There is no specific antidote. Initial treatment should be based on the patient's clinical condition. Hospitalization may be necessary. Plasma carbamazepine concentration should be measured to confirm poisoning and assess the degree of overdose.

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

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

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

Side effects.

Summary of safety profile.

At the beginning of treatment with carbamazepine, or when using too high an initial dose, or when treating elderly patients, certain types of adverse reactions occur very commonly or commonly, such as those affecting the central nervous system (dizziness, headache, ataxia, somnolence, general weakness, diplopia), gastrointestinal tract (nausea, vomiting), or allergic skin reactions.

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

There have been reports of decreased bone mineral density, osteopenia, osteoporosis, and fractures in patients receiving long-term carbamazepine therapy. The mechanism by which carbamazepine affects bone metabolism has not been established.

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; common – thrombocytopenia, eosinophilia; rare – lymphadenopathy, leukocytosis; very rare – agranulocytosis, aplastic anaemia, pancytopenia, erythrocyte aplasia, anaemia, megaloblastic anaemia, reticulocytosis, haemolytic anaemia.

Immune system disorders: rare – multi-organ hypersensitivity reaction of delayed type (serum sickness-like) with fever, skin rash, vasculitis, lymphadenopathy; symptoms resembling lymphoma; arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests, and vanishing bile duct syndrome (destruction and disappearance of intrahepatic bile ducts), occurring in various combinations. Other organs may also be involved (e.g., lungs, kidneys, pancreas, myocardium, colon). If such hypersensitivity reactions occur, treatment must be discontinued immediately. very rare – anaphylactic reaction, angioneurotic oedema, hypogammaglobulinaemia.

Endocrine system disorders: common – oedema, fluid retention, weight gain, hyponatraemia 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, and neurological disturbances; very rare – galactorrhoea, gynaecomastia.

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 – hyperammonaemia.

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

Nervous system disorders: very common – ataxia, dizziness, somnolence; common – diplopia, headache; uncommon – abnormal involuntary movements (e.g., tremor, "fluttering" tremor, dystonia, tic), nystagmus; rare – dyskinesia, eye movement disorders, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paraesthesia, paresis; very rare – neuroleptic malignant syndrome (NMS), aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

Eye disorders: common – accommodation disorders (e.g., blurred vision); very rare – lens opacity, conjunctivitis.

Ear and labyrinth disorders: very rare – hearing disorders, such as tinnitus, hyperacusis, hypoacusis, pitch perception disturbances.

Cardiac disorders: rare – disturbances of intracardiac conduction; very rare – arrhythmia, atrioventricular block with syncope, bradycardia, congestive heart failure, exacerbation of ischaemic heart disease.

Vascular disorders: rare – arterial hypertension or arterial hypotension; very rare – circulatory collapse, embolism (e.g., pulmonary embolism), thrombophlebitis.

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

Gastrointestinal disorders: very common – nausea, vomiting; common – dry mouth; uncommon – diarrhoea or constipation; rare – abdominal pain; very rare – glossitis, stomatitis, pancreatitis.

Hepatobiliary disorders: rare – cholestatic, parenchymal (hepatocellular), or mixed type hepatitis, vanishing bile duct syndrome, jaundice; very rare – liver failure, granulomatous hepatitis.

Skin and subcutaneous tissue disorders: very common – urticaria, sometimes severe, allergic dermatitis; uncommon – exfoliative dermatitis; rare – systemic lupus erythematosus, pruritus; very rare – severe skin reactions, such as Stevens–Johnson syndrome (in some Asian countries this adverse event has also been reported with a frequency of "rare"), toxic epidermal necrolysis (see section "Special precautions for use"), photosensitivity reactions, erythema multiforme, nodular erythema, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism.

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

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

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

General disorders: very common – general weakness.

Laboratory and instrumental findings: very common – increased gamma-glutamyl transferase levels (due to hepatic enzyme induction), which is usually clinically insignificant; common – increased alkaline phosphatase levels in blood; uncommon – increased transaminase levels; very rare – increased intraocular pressure, increased blood cholesterol levels, 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 are usually not associated with clinical manifestations; increased blood prolactin levels.

Injury, poisoning and procedural complications: unknown – falls (associated with ataxia, dizziness, somnolence, hypotension, confusion, sedative effect during carbamazepine treatment) (see section "Special precautions for use").

Additional adverse reactions based on spontaneous reports (frequency unknown).

Information on the adverse reactions listed below was obtained during the post-marketing period from spontaneous reports and publications. As these reports are spontaneous, it is impossible to determine the exact number of affected 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.

Immune system disorders: drug reaction with eosinophilia and systemic symptoms (DRESS).

Metabolism disorders: hyperammonaemia.

Nervous system disorders: sedative effect, memory impairment.

Gastrointestinal disorders: colitis.

Skin and subcutaneous tissue disorders: acute generalized exanthematous pustulosis (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal and connective tissue disorders: fractures.

Laboratory and instrumental findings: decreased bone mineral density.

Growing evidence links genetic markers with the occurrence of skin-related adverse reactions such as SJS/TEN, DRESS, AGEP, and maculopapular rash. It has been reported that in patients of European descent and Japanese patients, these reactions are associated with carbamazepine use and the presence of the HLA-A*3101 allele. Another marker, HLA-B*1502, has been shown to be strongly associated with SJS/TEN among Han Chinese, Thai, and certain other Asian populations (see sections "Dosage and administration" and "Special precautions for use").

Reporting suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals, pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature 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.

LLC "KUSUM PHARM".

Manufacturer's address and place of business.

54 Skryabina Street, Sumy, Sumy Oblast, 40020, Ukraine.