INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FІNLEPСIN® (FINLEPSIN®)

Composition:

Active substance: carbamazepine;

1 tablet contains carbamazepine 200 mg;

Excipients: microcrystalline cellulose, gelatin, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white, round tablets with a bevel on both sides and a deep dividing line on one side, convex on the reverse side, with smooth surface, intact edges, and uniform external appearance.

Pharmacotherapeutic group.

Antiepileptic agents. Carboxamide derivatives. Carbamazepine. ATC code N03A F01.

Pharmacological properties.

Pharmacodynamics.

As an anticonvulsant agent: the spectrum of activity of Finlepsin® includes 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 of the drug—is only partially understood. Carbamazepine stabilizes overexcited neuronal membranes, inhibits the generation of repetitive neuronal discharges, and reduces synaptic transmission of excitatory impulses. It is highly likely that the primary mechanism of action may be prevention of repeated formation of sodium-dependent action potentials in depolarized neurons through use- and voltage-dependent blockade of sodium channels. While reduced glutamate release and neuronal membrane stabilization may explain the anticonvulsant effect of the drug, the antimanic effect of carbamazepine may be due to inhibition of dopamine and norepinephrine metabolism.

When carbamazepine is used as monotherapy in patients with epilepsy (especially in children and adolescents), psychotropic effects of the drug have been observed, partially manifested as a beneficial impact on symptoms of anxiety and depression, as well as reduced irritability and aggressiveness. According to several studies, the effect of carbamazepine on cognitive function and psychomotor performance was dose-dependent and either questionable or negative. In other studies, a positive effect of the drug on parameters characterizing attention, learning ability, and memory was observed.

As a neurotropic agent, Finlepsin® is effective in certain neurological disorders; for example, it prevents painful attacks in idiopathic and secondary trigeminal neuralgia. Additionally, carbamazepine is used to alleviate neuropathic pain in various conditions, including spinal cord spasticity, post-traumatic paresthesias, and postherpetic neuralgia. In alcohol withdrawal syndrome, carbamazepine increases the seizure threshold (which is reduced in this condition) and reduces the severity of clinical manifestations such as excitability, tremor, and gait disturbances. In patients with central diabetes insipidus, carbamazepine reduces diuresis and sensation of thirst.

It has been confirmed that as a psychotropic agent, Finlepsin® is effective in affective disorders, specifically: for treatment of acute manic states and for maintenance therapy of bipolar affective (manic-depressive) disorders (both as monotherapy and in combination with neuroleptic agents, antidepressants, or lithium salts).

Pharmacokinetics.

Absorption. After oral administration, carbamazepine is absorbed slowly and almost completely. The elimination half-life is 8.5 hours, with a wide range (approximately 1.72–12 hours). After a single dose, maximum plasma concentration of carbamazepine is reached in adults within 4–16 hours (very rarely after 35 hours) and in children approximately within 4–6 hours. Plasma carbamazepine concentration does not show a linear relationship with dose, and with higher doses, the plasma concentration curve plateaus.

Steady-state concentration is achieved within 2–8 days. There is no close correlation between the dose of carbamazepine and steady-state plasma concentration.

Therapeutic and toxic plasma concentrations of carbamazepine are reported as follows: seizures may cease at plasma levels of 4–12 mcg/mL. Plasma concentrations exceeding 20 mcg/mL may worsen the clinical condition.

At plasma concentrations of the active substance of 5–18 mcg/mL, pain in trigeminal neuralgia is relieved.

70–80% of carbamazepine is bound to plasma proteins. The fraction of unbound (free) carbamazepine remains constant even at plasma concentrations of up to 50 mcg/mL.

48–53% of the pharmacologically active metabolite, carbamazepine-10,11-epoxide, is bound to plasma proteins. The concentration of carbamazepine in cerebrospinal fluid is 33% of the plasma concentration.

Carbamazepine crosses the placental barrier and is excreted into breast milk.

After a single dose, carbamazepine is eliminated from plasma with an elimination half-life of 36 hours. During long-term treatment, the half-life decreases by 50% due to induction of hepatic microsomal enzymes.

In healthy individuals, total plasma clearance is approximately 19.8 mL/h/kg; in patients receiving monotherapy, it is approximately 54.6 mL/h/kg; in patients receiving combination therapy, it is approximately 113.3 mL/h/kg. After a single oral dose of carbamazepine, 72% of the dose is excreted in urine as metabolites. The remaining 28% is excreted in feces, partly in unchanged form. Only 2–3% of the substance excreted in urine is unchanged carbamazepine.

Pharmacokinetic characteristics in specific patient populations.

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

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

Patients with renal or hepatic impairment. Data on the pharmacokinetics of carbamazepine in patients with renal or hepatic dysfunction are currently unavailable.

Clinical characteristics.

Indications.

Epilepsy:
- complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization;
- generalized tonic-clonic seizures;
- mixed seizure types.

Finlepsin® can be used as monotherapy or in combination with other antiepileptic drugs.

Acute manic states; maintenance therapy in bipolar affective disorders for prevention of relapses or for reduction of clinical manifestations during exacerbations.
Alcohol withdrawal syndrome.
Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical forms).
Idiopathic glossopharyngeal neuralgia.

Contraindications.

Finlepsin® should not be prescribed:

in patients with known hypersensitivity to carbamazepine or to structurally related medicinal products (e.g., tricyclic antidepressants), or to any of the excipients;
in patients with atrioventricular block;
in patients with a history of bone marrow depression;
in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria);
in combination with monoamine oxidase inhibitors (MAOIs), or within 14 days after discontinuation of MAOIs;
in combination with voriconazole, as treatment may be ineffective.

Interaction with other medicinal products and other forms of interaction.

Cytochrome P450 3A4 (CYP3A4) is the main enzyme responsible for the formation of the active metabolite of carbamazepine, carbamazepine-10,11-epoxide. Concomitant use of CYP3A4 inhibitors may increase plasma concentrations of carbamazepine, potentially leading to adverse reactions. Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, resulting in potentially reduced plasma concentrations and therapeutic efficacy of carbamazepine. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, leading to increased plasma levels of carbamazepine.

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

Human microsomal epoxide hydrolase is the enzyme responsible for the formation of 10,11-trans-dihydrodiol derivatives of carbamazepine. Concomitant use of inhibitors of human microsomal epoxide hydrolase may lead to increased plasma concentrations of carbamazepine-10,11-epoxide.

Medicinal products that may increase plasma carbamazepine levels

Since increased plasma levels of carbamazepine may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), dosage adjustment and/or monitoring of plasma levels is recommended when Finlepsin® is 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, viloxazine, trazodone.

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: terfenadine, loratadine.

Antipsychotics: olanzapine, loxapine, quetiapine.

Antituberculosis agents: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular agents: verapamil, diltiazem.

Agents for gastrointestinal disorders: cimetidine, omeprazole.

Muscle relaxants: oxybutynin, dantrolene.

Antiplatelet agents: ticlopidine.

Other substances: nicotinamide (in adults, only at high doses), grapefruit juice.

Medicinal products that may increase plasma levels of the active metabolite carbamazepine-10,11-epoxide

Since elevated plasma levels of the active metabolite carbamazepine-10,11-epoxide may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia), dosage adjustment and/or monitoring of plasma levels of carbamazepine is recommended when Finlepsin® is used concomitantly with the following agents: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, brivaracetam, and valpromide.

Medicinal products that may decrease plasma carbamazepine levels

Dosage adjustment of Finlepsin® may be required when used concomitantly with the following medicinal products:

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

Antineoplastic agents: doxorubicin, cisplatin.

Antituberculosis agents: rifampicin.

Bronchodilators or antiasthmatic agents: theophylline, aminophylline.

Dermatological agents: isotretinoin.

Others: products containing St. John’s wort (Hypericum perforatum).

Mefloquine may exhibit antagonistic properties against the antiepileptic effect of carbamazepine. Therefore, carbamazepine dosage should be adjusted accordingly.

Isotretinoin alters the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; plasma concentration of carbamazepine should be monitored.

Effect of carbamazepine on plasma levels of concomitantly administered medicinal products

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

Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long-term concomitant use of carbamazepine with paracetamol [acetaminophen] may be associated with hepatotoxicity), tramadol, phenazone (antipyrine).

Antibiotics: doxycycline, rifabutin.

Anticoagulants: oral anticoagulants (e.g., warfarin, phenprocoumon, dicoumarol, acenocoumarol).

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

Antiemetics: aprepitant.

Antiepileptic agents: clobazam, clonazepam, eslicarbazepine, ethosuximide, felbamate, primidone, lamotrigine, oxcarbazepine, tiagabine, topiramate, valproic acid, zonisamide. Plasma concentrations of phenytoin may increase or decrease under the influence of carbamazepine. In rare cases, this may lead to confusion or even coma. There are a few reports of increased plasma concentrations of mefenytoin.

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

Anthelmintics: praziquantel, albendazole.

Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.

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

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

Anxiolytics: midazolam, alprazolam.

Bronchodilators or antiasthmatic agents: theophylline.

Contraceptives: hormonal contraceptives. In women using hormonal contraceptives, contraceptive efficacy may be reduced and intermenstrual bleeding may occur unexpectedly. Therefore, alternative methods of contraception should be considered.

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

Corticosteroids: prednisolone, dexamethasone.

Agents used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

Others: buprenorphine, gestrinone, tibolone, toremifene, mianserin, sertraline.

Combinations requiring special consideration

Concomitant use of carbamazepine and levetiracetam may increase carbamazepine toxicity.

Concomitant use of carbamazepine and isoniazid may increase isoniazid hepatotoxicity.

Concomitant use of carbamazepine with lithium or metoclopramide, and with neuroleptics (haloperidol, thioridazine), may increase the risk of adverse neurological effects (in the latter case, even at therapeutic plasma levels).

Combined use of Finlepsin® with most diuretics (hydrochlorothiazide, furosemide) may cause symptomatic hyponatremia.

Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g., pancuronium). Higher doses of these agents may be required, and patients should be closely monitored due to the possibility of unexpectedly rapid termination of neuromuscular blockade.

Carbamazepine, like other psychotropic agents, 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 reduce plasma concentrations of direct oral anticoagulants, thereby increasing the risk of thrombosis. Therefore, if concomitant use is necessary, careful monitoring for signs and symptoms of thrombosis is required.

Other interactions

Neurotoxic effects may be enhanced when carbamazepine is used concomitantly with lithium salts. Close monitoring of plasma concentrations of both agents is required. Patients should not use neuroleptics within 8 weeks prior to or during treatment with carbamazepine.

Particular attention should be paid to the following symptoms of neurotoxicity: unsteady gait, ataxia, horizontal nystagmus, hyperreflexia, muscle spasms.

Literature reports indicate that the risk of developing malignant neuroleptic syndrome or Stevens-Johnson syndrome may increase in patients taking neuroleptics while receiving carbamazepine.

Carbamazepine may enhance the elimination of thyroid hormones, thereby increasing the requirement for thyroid hormones in patients with hypothyroidism. Plasma concentrations of thyroid hormones should be measured at the beginning and end of treatment in patients receiving thyroid hormone replacement therapy. Dose adjustment may be necessary. Thyroid function may change, particularly during concomitant use of carbamazepine and other antiepileptic drugs (e.g., phenobarbital).

Serotonin syndrome may develop when carbamazepine is used concomitantly with serotonin reuptake inhibitors (e.g., fluoxetine).

Finlepsin**®** should not be used in combination with nefazodone (an antidepressant), as it may cause a significant reduction in plasma concentration of nefazodone and complete loss of its efficacy. When nefazodone and Finlepsin**®** are taken concomitantly, plasma concentration of carbamazepine increases and concentration of its active metabolite, carbamazepine-10,11-epoxide, decreases.

Concomitant use of carbamazepine with antiarrhythmic agents, cyclic antidepressants, or erythromycin increases the risk of cardiac conduction disturbances.

Contraindicated interaction

Since carbamazepine is structurally similar to tricyclic antidepressants, Finlepsin® should not be used concomitantly with monoamine oxidase inhibitors (MAOIs). At least two weeks (or longer, depending on the patient's clinical condition) should elapse between discontinuation of MAOIs and initiation of carbamazepine therapy.

Effect on serological tests

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

Carbamazepine and carbamazepine-10,11-epoxide may produce false-positive results in immunoassays using fluorescence polarization techniques for determination of tricyclic antidepressant concentrations.

Special precautions for use.

Carbamazepine should be prescribed only under medical supervision, only after evaluation of the benefit/risk ratio and with careful monitoring of patients with impaired cardiac, hepatic, or renal function, disturbances in sodium metabolism, myotonic dystrophy, history of hematological adverse reactions to other drugs, or patients with interrupted courses of carbamazepine therapy.

It is recommended to perform urinalysis and blood urea nitrogen (BUN) measurement at the beginning and periodically during therapy.

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

One should bear in mind the possibility of activation of latent psychosis, and in elderly patients, the possible development of confusion and anxious agitation.

The drug is generally ineffective in absence seizures (petit mal seizures) and myoclonic seizures. Individual cases indicate that seizure frequency may increase in patients with atypical absences. Finlepsin® should not be used in patients with absence seizures.

Hematological effects. Cases of agranulocytosis and aplastic anemia have been associated with the use of carbamazepine; however, due to the extremely low incidence of these conditions, it is difficult to assess the significant risk associated with carbamazepine use.

Patients should be informed about early signs of toxicity and symptoms of possible hematological disorders, as well as symptoms of dermatological and hepatic reactions. Patients should be warned that if any of the following reactions occur—fever, sore throat, skin rash, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura—they should seek immediate medical attention.

A complete blood count should be performed before starting treatment, then monitored monthly with weekly intervals during the first month, and later once a month. After 6 months of treatment, performing 2–4 analyses per year is sufficient. If the number of leukocytes or platelets significantly decreases during therapy, the patient's condition should be closely monitored, and regular complete blood counts should be performed. Carbamazepine therapy should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical manifestations such as fever or sore throat. Carbamazepine use should be discontinued upon signs of bone marrow suppression.

Transient or persistent reduction in platelet or leukocyte counts may occur periodically or frequently with carbamazepine use. However, most of these cases have been confirmed as temporary and do not indicate the development of aplastic anemia or agranulocytosis. Blood analysis, including platelet count (and possibly reticulocyte count and hemoglobin level), should be performed before starting therapy and periodically during treatment. Treatment should be discontinued if leukopenia (mainly neutropenia), thrombocytopenia—especially when accompanied by allergy symptoms, elevated body temperature, sore throat, skin bruising, or hemorrhages—occurs.

Due to the occurrence of the adverse reactions mentioned above and hypersensitivity reactions, hematological parameters, renal and liver function, carbamazepine plasma concentration, and concentrations of other anticonvulsant drugs during combination therapy should be monitored, especially during long-term treatment.

Blood tests at short intervals (weekly) are required in case of: elevated body temperature, infection, skin rash, fatigue, sore throat, oral ulcers, bruising, increased aminotransferase activity, leukocyte count ˂ 3000/mm³ or granulocyte count ˂ 1500/mm³, platelet count ˂ 125000/mm³, reticulocyte count ˂ 0.3% = 20000/mm³, plasma iron concentration ˃ 150 µg%.

Discontinuation of carbamazepine is required in case of: bruising or purpuric bleeding, liver failure, erythrocyte count ˂ 4000000/mm³, hematocrit ˂ 32%, hemoglobin concentration below 11 g%, leukocyte count ˂ 2000/mm³ and correspondingly granulocyte count ˂ 1000/mm³ or platelet count ˂ 80000/mm³, symptomatic hematopoietic disorders.

Serious dermatological reactions. Serious dermatological reactions, including toxic epidermal necrolysis (TEN) or Lyell’s syndrome and Stevens-Johnson syndrome (SJS), occur very rarely with carbamazepine use. Patients with serious dermatological reactions may require hospitalization, as these conditions can be life-threatening and fatal. Most cases of SJS/TEN occur within the first few months of carbamazepine treatment. It is estimated that these dermatological reactions occur in 1–6 per 10,000 new patients in countries with predominantly Caucasian populations. However, in patients from certain Asian countries, the risk may be approximately 10 times higher. If signs and symptoms suggestive of serious dermatological reactions (e.g., SJS, Lyell’s syndrome/TEN—such as progressive skin rash accompanied by blistering or mucosal changes) occur, carbamazepine use should be immediately discontinued and alternative therapy initiated. Patients should be informed about signs and symptoms indicating possible hypersensitivity reactions and should be carefully monitored for skin reactions.

The best outcomes in treating SJS and TEN are achieved through early detection and immediate discontinuation of all potentially causative drugs. Early discontinuation is associated with a better prognosis.

If a patient develops SJS or TEN associated with carbamazepine use, reinitiating carbamazepine treatment should not be attempted.

Pharmacogenomics

Growing evidence indicates that different HLA alleles influence a patient's susceptibility to immune system-related adverse reactions.

Association with (HLA)-B*1502

Retrospective studies in Han Chinese patients have demonstrated a strong correlation between carbamazepine-associated skin reactions (SJS/TEN) and the presence of human leukocyte antigen (HLA) allele (HLA)-B*1502 in these patients. 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 frequency of carriers of this allele among Asian populations exceeds 15% in the Philippines, Thailand, Hong Kong, and Malaysia, approximately 10% in Taiwan, nearly 4% in Northern China, approximately 2–4% in South Asia (including India), and less than 1% in Japan and Korea. The prevalence of the (HLA)-B*1502 allele is low among Caucasian and African populations, indigenous peoples of America, and Latin American populations.

In patients considered genetically at risk, testing for the presence of the (HLA)-B*1502 allele should be performed before initiating carbamazepine treatment. If the patient tests positive for the (HLA)-B*1502 allele, carbamazepine treatment should not be initiated, except when no other therapeutic options are available. Patients who have been tested and found negative for (HLA)-B*1502 have a low risk of developing SJS, although such reactions may very rarely occur.

Currently, due to lack of data, it is not precisely known whether all individuals of Southeast Asian origin are at risk.

The (HLA)-B*1502 allele may be a risk factor for SJS/TEN in Chinese patients receiving other antiepileptic drugs that may be associated with SJS/TEN. Therefore, the use of other drugs potentially associated with SJS/TEN should be avoided in patients carrying the (HLA)-B*1502 allele if alternative therapy is available. Genetic screening of patients from ethnic groups with a low prevalence of the (HLA)-B*1502 allele is generally not recommended. Screening is generally not recommended in individuals already receiving carbamazepine, as the risk of SJS/TEN is significantly limited to the first few months regardless of the presence of the (HLA)-B*1502 allele in the patient's genes.

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

Association with (HLA)-A*3101

Human leukocyte antigen may be a risk factor for skin adverse reactions such as SJS, TEN, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), maculopapular rashes in individuals of European descent and Japanese.

The frequency of the HLA-A*3101 allele varies significantly among ethnic groups. Among Europeans, it is 2–5%, and among Japanese, it is approximately 10%.

The presence of the HLA-A*3101 allele may increase the risk of skin reactions (mostly mild) from 5% overall among all patient groups to 26% in individuals of European descent, whereas absence of this allele may reduce the aforementioned risk from 5% to 3.8%.

There is insufficient data to support recommendations for HLA-A*3101 screening before initiating carbamazepine treatment.

If testing reveals the presence of the HLA-A*3101 allele in patients of European descent or Japanese, the possibility of using carbamazepine should be considered only if benefits outweigh the risks.

Limits of genetic screening

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

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

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

During carbamazepine treatment, patients should avoid sun exposure due to photosensitivity.

Hypersensitivity. Carbamazepine may provoke hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), multiple delayed-type hypersensitivity reactions with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, altered liver function tests, and vanishing bile duct syndrome (including destruction and disappearance of intrahepatic bile ducts), which may manifest in various combinations.

Other organs may also be affected (lungs, kidneys, pancreas, myocardium, colon).

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

In general, if signs and symptoms indicating hypersensitivity occur, carbamazepine use should be immediately discontinued.

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

Seizures. Carbamazepine should be used with caution in patients with mixed seizure types, including absences (typical or atypical). In such cases, the drug may provoke seizures. If seizures are provoked, carbamazepine use should be immediately discontinued. Increased seizure frequency may occur when switching from oral formulations to suppositories.

Liver function. Liver function should be assessed at baseline and periodically during therapy, especially in patients with a history of liver disease and in elderly patients. If acute liver dysfunction occurs or in patients with active liver disease, the drug should be immediately discontinued.

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 hepatic enzyme induction. 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 and symptoms of hepatic dysfunction or active liver disease occur, the patient should be urgently evaluated, and carbamazepine treatment should be suspended until evaluation results are obtained.

Renal function. Renal function assessment, urinalysis, and blood urea nitrogen (BUN) measurement are recommended at the beginning and periodically during the course of therapy.

Hyponatremia. Cases of hyponatremia have been reported with carbamazepine use. In patients with pre-existing renal dysfunction associated with low sodium levels, or in patients receiving concomitant therapy with drugs that lower sodium levels (such as diuretics, drugs associated with inappropriate antidiuretic hormone secretion), serum sodium levels should be measured before treatment. Subsequently, sodium levels should be measured every 2 weeks, then monthly during the first 3 months of treatment or according to clinical necessity. This particularly applies to elderly patients. In such cases, water intake should be limited.

Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations; therefore, an increase in thyroid hormone replacement therapy dosage may be necessary for patients with hypothyroidism.

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

Psychiatric effects. The possibility of activation of latent psychosis and, in elderly patients, confusion or agitation should be kept in mind.

Warning: If carbamazepine is used to prevent seizures in alcohol withdrawal syndrome, the drug should always be administered in a hospital setting.

It should be remembered that adverse reactions of carbamazepine may resemble symptoms of alcohol withdrawal. This should be considered during Finlepsin® treatment of patients with alcohol withdrawal syndrome.

Suicidal thoughts and behavior. Several reports of suicidal thoughts and behavior have been documented in patients receiving antiepileptic drugs. A meta-analysis of data from placebo-controlled antiepileptic drug trials also showed a small increased risk of suicidal thoughts and behavior. The mechanism underlying 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.

Endocrine effects. Intermenstrual bleeding has been observed in women using hormonal contraceptives concomitantly with carbamazepine.

Women of childbearing potential. Carbamazepine may harm the fetus when used during pregnancy. Prenatal exposure to carbamazepine may increase the risk of serious congenital malformations and other adverse developmental outcomes.

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 must be fully informed about the potential risk to the fetus if carbamazepine is used during pregnancy.

Before initiating carbamazepine treatment in a woman of childbearing potential, a pregnancy test should be performed.

Women of childbearing potential should be advised to consult their physician as soon as they plan pregnancy to discuss switching to alternative treatment options before conception and discontinuation of contraception.

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

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 drug levels may be useful in the following cases: sudden increase in seizure frequency, checking patient compliance, during pregnancy, in the treatment of children and adolescents; when absorption impairment is suspected, suspected toxicity, and when multiple drugs are used.

If, in exceptional circumstances, Finlepsin® must be used concomitantly with lithium for the prevention of manic-depressive episodes (this may be necessary if lithium therapy is ineffective), interaction should be avoided by monitoring carbamazepine plasma concentration. Carbamazepine concentration should be maintained at 8 µg/mL, lithium levels should be kept within narrow therapeutic ranges of 0.3–0.8 mEq/L, and the patient should not have received neuroleptic treatment in the preceding 8 weeks and should not be receiving it currently.

Dose reduction and withdrawal syndrome. Abrupt discontinuation of the drug may provoke seizures; therefore, carbamazepine should be tapered gradually over 6 months. If immediate discontinuation is necessary, transition to a new antiepileptic drug in patients with epilepsy should be performed on a background of appropriate medication (e.g., intravenous, rectal diazepam, or intravenous phenytoin).

Falls. Carbamazepine treatment may be associated with ataxia, dizziness, somnolence, hypotension, confusion, or lethargy, which may lead to falls and, consequently, fractures or other injuries. In patients with conditions or states predisposing to these disturbances, or when using drugs that exacerbate these conditions, a full risk assessment for falls should be regularly performed during long-term carbamazepine treatment.

Use during pregnancy or breastfeeding.

Women of childbearing potential. Carbamazepine should not be used in women of childbearing potential, except when potential benefit outweighs risks and after careful consideration of alternative treatment options. The woman must be fully informed and understand the risk of potential fetal harm if carbamazepine is used during pregnancy, and thus understand the importance of pregnancy planning. Before initiating carbamazepine treatment in a woman of childbearing potential, a pregnancy test should be performed.

Women of childbearing potential should use an effective method of contraception during treatment and for two weeks after discontinuation of treatment. Due to enzyme induction, carbamazepine may impair the therapeutic effect of hormonal contraceptives; therefore, women of childbearing potential should consult their physician regarding the use of other effective contraceptive methods. At least one effective method of contraception (such as an intrauterine device) or two complementary methods of contraception, including a barrier method, should be used. The choice of contraceptive method should consider individual circumstances with patient involvement in the discussion.

Pregnancy. Reports of fetal death, growth impairment, and defects have been documented in animals receiving carbamazepine during pregnancy.

Risk associated with the use of antiepileptic drugs (AEDs) in general

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

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

For epilepsy treatment during pregnancy, monotherapy is preferred if possible, as treatment with multiple AEDs may be associated with a higher risk of congenital malformations than monotherapy, depending on the specific antiepileptic drugs used.

Risks associated with carbamazepine

Carbamazepine crosses the human placenta. Prenatal exposure to carbamazepine may increase the risk of congenital malformations and other adverse developmental outcomes. The impact of carbamazepine during human pregnancy is associated with a 2–3 times higher frequency of serious malformations compared to the general population, where the frequency is 2–3%. In children of women who used carbamazepine during pregnancy, malformations such as neural tube defects (spina bifida), craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, finger hypoplasia, and other anomalies affecting various organ systems have been reported. Specialized antenatal monitoring for these malformations is recommended. Neurodevelopmental impairments 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 impairments in children exposed to carbamazepine during pregnancy are conflicting, and risk cannot be excluded.

Carbamazepine should not be used during pregnancy, except when potential benefit outweighs risks after careful consideration of alternative treatment options. The woman must be fully informed and understand the risks of using carbamazepine during pregnancy.

Data suggest that the risk of congenital malformations with carbamazepine use may be dose-dependent. If, based on a careful risk-benefit assessment, an alternative treatment option is unacceptable and carbamazepine treatment continues, monotherapy with the lowest effective carbamazepine dose should be used, and monitoring of the drug plasma level is recommended. Plasma concentration should be maintained in the lower part of the therapeutic range (4–12 µg/mL), provided seizure control is maintained.

It has been reported that some antiepileptic drugs, such as carbamazepine, reduce serum folate levels. This deficiency may contribute to an increased frequency of congenital malformations in children of women receiving epilepsy treatment. Folic acid supplementation is recommended before and during pregnancy. To prevent coagulation disorders in newborns, vitamin K1 is also recommended for the mother during the last weeks of pregnancy and for newborns.

If a woman plans pregnancy, all efforts should be made before conception and before discontinuing contraception to switch to an appropriate alternative drug. If a woman becomes pregnant while taking carbamazepine, she should be referred to a specialist to re-evaluate carbamazepine treatment and consider alternative treatment options.

Several cases of seizures and/or respiratory depression in newborns, as well as several cases of vomiting, diarrhea, and/or poor appetite in newborns, have been reported and associated with the use of carbamazepine and other anticonvulsant drugs. These may also be manifestations of neonatal withdrawal syndrome.

Breastfeeding. Carbamazepine passes into breast milk (25–60% of plasma concentration). The benefits of breastfeeding versus the remote possibility of adverse effects in the infant should be carefully weighed. Breastfeeding may be allowed for mothers receiving carbamazepine only if the infant is monitored for possible adverse reactions (e.g., excessive drowsiness, allergic skin reactions, inadequate weight gain).

Fertility. Very rare cases of impaired fertility in men and/or abnormal spermatogenesis parameters have been reported.

Ability to affect reaction speed when driving or operating machinery.

The ability of a patient taking carbamazepine (even when used according to recommendations) to react quickly (especially at the beginning of therapy or during dose titration, when used at high doses and/or in combination with other central nervous system (CNS)-acting drugs) may be impaired due to CNS-related adverse reactions (dizziness, somnolence, fatigue). Therefore, patients should exercise caution when driving a vehicle or operating machinery and when working in positions requiring balance. It should be remembered that alcohol consumption further reduces attention and prolongs reaction time.

Method of Administration and Dosage.

Finlepsin® should be administered orally. The daily dose is usually divided into 2–3 doses. The drug may be taken during meals, after meals, or between meals, with a small amount of liquid (e.g., a glass of water). A Finlepsin® tablet may be split in half. For patients with severe cardiovascular disorders, hepatic disease, renal insufficiency, or for elderly patients, a lower dose may be sufficient. In most cases, good efficacy is achieved when the daily dose is divided into 4–5 doses. Before initiating treatment, patients of Han Chinese ethnicity or Thai descent should, if possible, be tested for the presence of HLA-B*1502, as this allele may provoke the development of severe carbamazepine-associated Stevens–Johnson syndrome.

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

Epilepsy

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

Whenever possible, Finlepsin® should be prescribed as monotherapy. However, when used in combination with other medications, a similarly gradual dose escalation is recommended. If Finlepsin® is added to existing antiepileptic therapy, the dose should be increased gradually, while the doses of concomitantly administered drugs should not be changed or, if necessary, adjusted.

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

Particularly in cases of combination therapy, therapeutic doses should be based on plasma carbamazepine levels and clinical efficacy. Therapeutic levels of carbamazepine range from 4 to 12 μg/mL.

Adults and children aged 15 years and older

Recommended initial dose: 100–200 mg once or twice daily. The dose should then be gradually increased to achieve optimal effect. The usual daily dose is 800–1200 mg. Some patients may require doses of Finlepsin® up to 1600 mg or even 2000 mg per day. The daily dose usually does not exceed 1600 mg, as the risk of adverse reactions increases.

Elderly patients

Due to drug interactions and altered pharmacokinetics of antiepileptic agents, Finlepsin® doses in elderly patients should be selected with caution.

Children aged 6 years and older

Treatment may begin with a dose of 100 mg daily, increasing gradually by 100 mg each week.

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

Children aged 6 to 10 years: 400–600 mg per day (in 2–3 doses).
Children aged 11 to 15 years: 600–1000 mg per day (in 3–5 doses).

Acute manic states and maintenance treatment of affective (bipolar) disorders

Dosage range: 400–1600 mg per day. Generally, therapy should be administered at 400–600 mg per day in 2–3 divided doses.

For treatment of acute manic states, the dose of Finlepsin® should be increased relatively quickly. For maintenance therapy of bipolar disorders, gradual dose escalation with small increments is recommended to ensure optimal tolerability.

Alcohol withdrawal syndrome

The average dose is 200 mg three times daily. In severe cases, during the first few days, the dose may be increased (e.g., to 400 mg three times daily). In cases of severe alcohol withdrawal, treatment should begin with a combination of Finlepsin® and sedative-hypnotic agents (e.g., clomethiazole, chlordiazepoxide), following the dosage recommendations above. After the acute phase, treatment with Finlepsin® may continue as monotherapy.

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

Initial dose of Finlepsin®: 200–400 mg per day (100 mg twice daily for elderly patients). The dose should be gradually increased until pain subsides (usually to 200 mg three to four times daily). For most patients, a dose of 200 mg three to four times daily is sufficient to maintain a pain-free state. In some cases, a daily dose of 1600 mg may be required. After pain cessation, the dose should be gradually reduced to the lowest effective maintenance dose.

Children

Due to faster elimination of carbamazepine in children, higher doses (on a per-kilogram basis) may be required compared to adults. Carbamazepine in this pharmaceutical form may be administered to children aged 6 years and older.

Overdose.

In cases of poisoning, the possibility of overdose with multiple drugs (e.g., in suicide attempts) should be considered.

Symptoms of carbamazepine overdose have been observed only after ingestion of very high doses (4–10 g). Plasma concentrations of the drug were always found to be >20 μg/mL.

Symptoms. Symptoms and complaints occurring in overdose typically reflect involvement of the central nervous, cardiovascular, and respiratory systems.

CNS effects: dizziness, CNS depression; disorientation, depressed level of consciousness, drowsiness, stupor, anxiety, agitation, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (early), hyporeflexia (later); seizures, psychomotor disturbances, involuntary movements, tremor, myoclonus, opisthotonus, hypothermia, mydriasis; possible EEG abnormalities, such as slowing of the basic rhythm and presence of slow waves.

Respiratory system: respiratory depression (sometimes respiratory arrest), pulmonary edema.

Cardiovascular system: tachycardia, arterial hypotension, occasionally arterial hypertension, cyanosis, rhythm and conduction disturbances with widening of the QRS complex; atrioventricular block; cardiac arrest associated with loss of consciousness.

Gastrointestinal tract: nausea, vomiting, delayed gastric emptying, reduced colonic motility.

Musculoskeletal system: isolated cases of rhabdomyolysis related to the toxic effect of carbamazepine have been reported.

Urinary system: urinary retention, oliguria or anuria; fluid retention; water intoxication due to an antidiuretic hormone-like effect of carbamazepine.

Laboratory findings: hyponatremia, possible metabolic acidosis, hyperglycemia, elevated creatine phosphokinase muscle fraction. Cases of leukocytosis, leukopenia, neutropenia, glucosuria, and ketonuria have been observed.

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

Gastric evacuation, gastric lavage, and administration of activated charcoal are recommended. Late gastric evacuation may lead to delayed absorption and recurrence of intoxication symptoms during recovery. Symptomatic and supportive treatment should be provided in an intensive care unit, with continuous cardiac monitoring and careful correction of electrolyte imbalances.

Special recommendations. In case of arterial hypotension, intravenous administration of dopamine or dobutamine is indicated. Cardiac rhythm disturbances should be treated individually. In case of seizures, benzodiazepines (e.g., diazepam) or other anticonvulsants such as phenobarbital (with caution due to increased risk of respiratory depression) or paraldehyde should be administered. In case of hyponatremia (water intoxication), fluid intake should be restricted and 0.9% sodium chloride solution should be administered slowly and cautiously by intravenous infusion. These measures may help prevent cerebral edema. According to literature data, barbiturates are not recommended due to their respiratory depressant effects, especially in children.

Hemoperfusion using carbon sorbents is recommended. Forced diuresis, hemodialysis, and peritoneal dialysis have been reported as ineffective, as carbamazepine is highly protein-bound in plasma.

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

Side effects.

Depending on the dose and mainly at the beginning of treatment, certain adverse reactions may occur. Generally, they resolve spontaneously within a few days or after temporary dose reduction. Adverse reactions observed occurred more frequently during combination therapy than with monotherapy.

At the beginning of carbamazepine treatment, or when using a very high initial dose, or when treating elderly patients, very common or common undesirable reactions may occur, for example, involving the CNS (dizziness, headache, ataxia, somnolence, general weakness, diplopia), the gastrointestinal tract (nausea, vomiting), or allergic skin reactions.

The development of adverse CNS reactions may result from relative overdosage or significant fluctuations in plasma concentration of the active substance. In such cases, monitoring of the active substance level in plasma is recommended, and the daily dose should be divided into smaller fractions (e.g., 3–4 doses).

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

Blood and lymphatic system disorders: very common – leukopenia; common – thrombocytopenia, eosinophilia; rare – leukocytosis, lymphadenopathy, folate deficiency; very rare – agranulocytosis, aplastic anemia, pancytopenia, erythroblastopenia, anemia, megaloblastic anemia, acute intermittent porphyria, mixed porphyria, late cutaneous porphyria, reticulocytosis, hemolytic anemia.

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

Endocrine system disorders: common – edema, fluid retention, weight gain, hyponatremia, and decreased plasma osmolality due to carbamazepine’s antidiuretic hormone (ADH)-like effect, which in isolated cases may lead to water intoxication accompanied by lethargy, vomiting, headache, confusion, and neurological disturbances; very rare – elevated blood prolactin levels with or without clinical symptoms such as galactorrhea and gynecomastia; abnormal thyroid function tests: decreased levels of L-thyroxines (FT4, T4, T3) and increased thyroid-stimulating hormone, usually without clinical manifestations; abnormalities in bone metabolism parameters (decreased levels of calcium and 25-hydroxycholecalciferol in plasma), leading to osteomalacia/osteoporosis; increased cholesterol levels, including high-density lipoproteins, cholesterol, and triglycerides. Carbamazepine may reduce serum folate levels. Decreased serum vitamin B12 levels and increased homocysteine levels under carbamazepine influence have also been reported.

Metabolism and nutrition disorders: rare – folate deficiency, decreased appetite; very rare – acute porphyria (acute intermittent and mixed porphyria), non-acute porphyria (late cutaneous porphyria); frequency not known – hyperammonemia.

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

Nervous system disorders: very common – dizziness, ataxia, somnolence, general weakness, increased fatigue; common – headache; uncommon – abnormal involuntary movements (e.g., tremor, asterixis, dystonia, tics), nystagmus; rare – orofacial dyskinesia, impaired thinking, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness, and paresis; very rare – taste disturbances, dysgeusia, malignant neuroleptic syndrome. There have been reports that carbamazepine may exacerbate symptoms of multiple sclerosis. As with other antiepileptic drugs, carbamazepine may increase the frequency of epileptic seizures. Absence seizures (a specific type of epileptic seizure originating in both brain hemispheres) may be exacerbated or provoked.

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

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

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

Respiratory system disorders: very rare – hypersensitivity reactions involving the lungs, characterized by fever, dyspnea, pneumonitis or pneumonia; pulmonary fibrosis. In case of such hypersensitivity reactions, the drug should be discontinued.

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

Hepatobiliary disorders: very common – increased gamma-glutamyl transferase levels (due to hepatic enzyme induction), usually without clinical significance; common – increased alkaline phosphatase levels; uncommon – increased transaminase levels; rare – cholestatic, parenchymal (hepatocellular), or mixed-type hepatitis, vanishing bile duct syndrome, jaundice; very rare – granulomatous hepatitis, hepatic failure.

Skin and subcutaneous tissue disorders: very common – allergic dermatitis, urticaria, sometimes in severe forms; uncommon – exfoliative dermatitis, erythroderma; rare – systemic lupus erythematosus, pruritus; very rare – Stevens-Johnson syndrome (in some Asian countries, this adverse event has also been reported with a frequency of "rare"), toxic epidermal necrolysis (Lyell's syndrome), photosensitivity, erythema multiforme, nodular erythema, skin pigmentation disorders, purpura, acne, increased sweating, alopecia, hirsutism.

Increasing evidence supports an association between genetic markers and skin-related adverse reactions such as SJS, TEN, DRESS, DRESS, and maculopapular rashes. In patients of Japanese and European origin carrying the HLA-A*3101 allele, such reactions have been observed after carbamazepine administration. Another marker strongly associated with SJS and TEN is the HLA-B*1502 allele in individuals of Chinese (Han ethnic group), Thai, or other Asian descent (see sections "Special precautions" and "Dosage and administration").

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

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

Reproductive system disorders: very rare – sexual dysfunction/impotence/erectile dysfunction, impaired fertility in males, decreased libido, impaired spermatogenesis (with reduced number and/or motility of spermatozoa).

General disorders: very common – general weakness.

Injuries, poisonings, procedural complications: isolated cases of falls have been reported (associated with ataxia, dizziness, somnolence, arterial hypotension, confusion, or lethargy related to carbamazepine use).

Adverse reactions based on spontaneous reports (frequency unknown)

The following adverse reactions have been observed during post-marketing use of carbamazepine. Since these reports are spontaneous, it is impossible to determine the exact number of affected patients or reliably estimate the incidence; therefore, their frequency is classified as "unknown."

Infections and infestations: reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: bone marrow failure.

Nervous system disorders: sedative effect, memory impairment.

Gastrointestinal disorders: colitis.

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

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

Musculoskeletal and connective tissue disorders: fractures.

Laboratory test abnormalities: decreased bone mineral density.

Shelf life. 3 years.

Storage conditions. The medicinal product does not require special storage conditions. Keep out of reach of children.

Packaging.

10 tablets per blister. 5 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Teva Operations Poland Sp. z o.o.

Manufacturer's location and address of its business operations.

80 Mogilska Street, 31-546 Kraków, Poland.