INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FINLEPSIN® 200 RETARD (FINLEPSIN® 200 RETARD)

Composition:

Active substance: carbamazepine;

1 tablet contains carbamazepine 200 mg;

Excipients: ammonium methacrylate copolymer (type B) dispersion, triacetin, talc, methacrylic acid copolymer dispersion, crospovidone, colloidal anhydrous silicon dioxide, magnesium stearate, microcrystalline cellulose.

Pharmaceutical form. Prolonged-release tablets.

Main physico-chemical characteristics: white or yellowish round flat tablets in the shape of a clover leaf, with beveled edges, with a cross-score line on both sides and 4 notches on the lateral sides, with a smooth surface and intact edges and identical external appearance.

Pharmacotherapeutic group. Antiepileptic drugs. ATC code N03AF01.

Pharmacological Properties

Pharmacodynamics

An anticonvulsant drug, a derivative of the tricyclic iminostilbene. Exhibits antiepileptic, neurotropic, and psychotropic activity. The precise mechanism of action of carbamazepine is unknown. The therapeutic effect is primarily due to inhibition of excitatory synaptic transmission, thereby reducing the spread of seizure activity. At higher concentrations, carbamazepine reduces the conduction of seizure discharges. It reduces pain sensations in trigeminal neuralgia. This effect is attributed to inhibition of synaptic transmission of stimuli in the spinal nucleus of the trigeminal nerve.

While reduced release of glutamate and stabilization of neuronal membranes may explain the anticonvulsant action of the drug, the antimanic effect of carbamazepine may be due to inhibition of dopamine and norepinephrine metabolism.

In diabetes insipidus, the drug exerts an antidiuretic effect, probably due to its influence on hypothalamic osmoreceptors.

Pharmacokinetics

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

When using prolonged-release tablets, a lower plasma concentration of carbamazepine is achieved compared to conventional tablets.

Steady-state concentration is reached within 2–8 days.

Regarding therapeutic and toxic plasma concentrations of carbamazepine, 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.

Threshold plasma concentrations of carbamazepine associated with adverse reactions are 8–9 mcg/mL.

70–80% of carbamazepine is bound to plasma proteins. The fraction of unbound (free) carbamazepine remains constant at concentrations 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. Salivary concentration corresponds to the unbound fraction in plasma and shows a significant correlation with plasma drug concentration (approximately 20–30%). If this value is multiplied by 4, it can be used to estimate plasma concentration during therapeutic monitoring.

Carbamazepine crosses the placental barrier and is excreted into breast milk (approximately 58% of the plasma concentration).

After a single dose, carbamazepine is eliminated from plasma with a half-life of 36 hours (range: 18 to 65 hours). During prolonged therapy, 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 on monotherapy, approximately 54.6 mL/h/kg; in patients on combination therapy, approximately 113.3 mL/h/kg. After a single oral dose, 72% of the administered 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, children may require higher doses (mg/kg body weight) 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 renal or hepatic impairment. Data on the pharmacokinetics of carbamazepine in patients with renal or hepatic dysfunction are currently unavailable.

Clinical characteristics.

Indications.

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

Finlepsin® 200 retard can be used as monotherapy or as part of combination therapy.

Acute manic states; maintenance therapy in bipolar affective disorders to prevent exacerbations or to reduce clinical manifestations of an episode.
Alcohol withdrawal syndrome.
Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical forms).
Idiopathic glossopharyngeal neuralgia.

Contraindications.

Finlepsin® 200 retard should not be prescribed:

in patients with known hypersensitivity to carbamazepine or to chemically related medicinal products (such as 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 hepatic porphyria (e.g. acute intermittent porphyria, mixed porphyria, late cutaneous porphyria) in medical history;
in combination with monoamine oxidase inhibitors (MAOIs) and within 14 days after discontinuation of such treatment;
concurrently 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 catalyzing the formation of the active metabolite of carbamazepine—10,11-epoxide. Concomitant use of CYP3A4 inhibitors may increase plasma concentrations of carbamazepine, which in turn may lead to adverse reactions. Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, leading to potential reduction in plasma carbamazepine levels and therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, resulting in increased plasma carbamazepine levels.

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

Medicinal products that may increase carbamazepine plasma levels

Since increased plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), dosage adjustment and/or monitoring of plasma levels should be considered when co-administering 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 carbamazepine plasma levels should be considered when Finlepsin® 200 retard is co-administered with the following agents: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, brivaracetam, and valpromide.

Medicinal products that may decrease carbamazepine plasma levels

Dosage adjustment of Finlepsin® 200 retard may be necessary when co-administered with the following medicinal products.

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

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, the carbamazepine dose should be adjusted accordingly.

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

Effect of carbamazepine on plasma levels of concomitantly administered medicinal products

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

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

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. Under the influence of carbamazepine, plasma concentrations of phenytoin may increase or decrease. In rare cases, this may lead to confusion and even coma. There are 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.

Anthelmintic agents: praziquantel, albendazole.

Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.

Neuroleptic agents: 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 containing estrogens and/or progestogens. In women using hormonal contraceptives, contraceptive efficacy may decrease and breakthrough bleeding may occur. Therefore, alternative contraceptive methods 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 and lithium or metoclopramide, as well as carbamazepine and neuroleptics (haloperidol, thioridazine), may enhance adverse neurological effects (in the latter combination, even at therapeutic plasma levels). Concomitant use of Finlepsin® 200 retard 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 need careful monitoring due to the possibility of faster-than-expected termination of neuromuscular blockade. Carbamazepine, like other psychotropic agents, may reduce alcohol tolerance; 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, patients should be closely monitored for signs and symptoms of thrombosis.

Contraindicated interaction

Since carbamazepine is structurally similar to tricyclic antidepressants, Finlepsin® 200 retard is not recommended for concomitant use with MAO inhibitors. At least 2 weeks (or longer, depending on the patient’s clinical condition) should elapse between the start of carbamazepine and the end of MAOI treatment.

Other interactions

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

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 neuroleptic malignant syndrome or Stevens-Johnson syndrome may increase in patients taking carbamazepine while on neuroleptics.

Carbamazepine may enhance the elimination of thyroid hormones, thereby increasing the requirement for these hormones in patients with hypothyroidism. Thyroid hormone concentrations 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, especially 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**®** 200 retard should not be used in combination with nefazodone (an antidepressant), as it may cause a significant reduction in plasma concentrations of nefazodone and complete loss of its efficacy. Concurrent use of nefazodone and Finlepsin**®** 200 retard increases plasma concentrations of carbamazepine and decreases concentrations of its active metabolite, carbamazepine-10,11-epoxide.

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

Effect on serological tests

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

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

Special precautions for use.

Carbamazepine should be prescribed only under medical supervision, only after evaluation of the benefit/risk ratio, and provided that patients are carefully monitored, particularly those with impaired cardiac, hepatic, or renal function, disorders of sodium metabolism, myotonic dystrophy, a history of hematological adverse reactions to other drugs, or patients with interrupted courses of carbamazepine therapy.

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

Carbamazepine exhibits mild anticholinergic activity; therefore, patients with elevated intraocular pressure should be warned and advised about possible risk factors. The potential for activation of latent psychoses should be considered, and in elderly patients, the possible activation of confusion and development of anxious agitation should be taken into account. The drug is generally ineffective in absence seizures (petit mal seizures) and myoclonic seizures. Individual cases indicate that seizure exacerbation may occur in patients with atypical absences. Finlepsin® 200 retard should not be used in patients with this type of seizure.

Hematological effects. 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 actual 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 with lymphadenopathy and/or flu-like symptoms, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura—they should seek immediate medical attention (blood morphology should be monitored). 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. Blood morphology should be checked before starting treatment, then weekly for one month, and later once a month. After 6 months of treatment, testing 2–4 times per year is sufficient. Carbamazepine therapy should be discontinued if the patient develops serious, progressive leukopenia or leukopenia accompanied by clinical symptoms such as malaise or sore throat. Treatment with carbamazepine should be discontinued upon signs of bone marrow suppression.

Transient or persistent reduction in platelet or leukocyte counts has been observed periodically or frequently with carbamazepine use. However, most of these cases have been confirmed to be 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 thrombocytopenia develops, especially if accompanied by skin bruising or hemorrhages. Due to the occurrence of the adverse reactions mentioned above and hypersensitivity reactions, blood morphology, renal and hepatic function, carbamazepine blood concentration, and concentrations of other antiepileptic drugs during combination therapy should be monitored, particularly 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, hepatic failure, erythrocyte count < 4000000/mm³, hematocrit < 32%, hemoglobin concentration < 11 g%, leukocyte count < 2000/mm³ and correspondingly granulocyte count < 1000/mm³ or platelet count < 80000/mm³, symptomatic hematological 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 potentially 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, such as SJS, Lyell's syndrome/TEN (e.g., progressive skin rash accompanied by blistering or mucosal changes), occur, carbamazepine should be immediately discontinued and alternative therapy initiated. Patients should be informed about signs and symptoms suggestive of 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 better prognosis. If a patient develops SJS or TEN related to carbamazepine use, reinitiating carbamazepine treatment is not recommended.

Pharmacogenomics. Increasing evidence suggests that different HLA alleles influence a patient's susceptibility to immune system-related adverse reactions.

Association with HLA-B*1502

Retrospective studies involving 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 in these patients. A higher frequency of SJS reports (more rare 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 frequency of carriers of this allele among Asian populations is over 15% in the Philippines, Thailand, Hong Kong, and Malaysia, approximately 10% in Taiwan, nearly 4% in Northern China, approximately 2% to 4% in South Asia (including India), and less than 1% in Japan and Korea. The prevalence of the allele HLA-B*1502 is negligible 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 therapy. If testing for the HLA-B*1502 allele is positive, carbamazepine therapy should not be initiated, except in cases where no other treatment options are available. Patients who have been tested and found negative for HLA-B*1502 have a low risk of developing SJS, although very rare cases may still 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 populations with a low frequency 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 occurrence of SJS.

Association with HLA-A*3101

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), maculopapular rash in Caucasian and Japanese individuals. The frequency of the HLA-A*3101 allele varies significantly among ethnic groups. Among Caucasians, it is 2–5%, and in Japanese individuals, 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 origin, whereas the 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 therapy.

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

Limitations of genetic screening

Genetic screening results should not replace appropriate clinical monitoring and management of patients. 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 dosing or after dose reduction. Since early signs of more serious dermatological reactions may be very 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-B*1502 allele in a patient is not a risk factor for less serious skin adverse reactions to carbamazepine, such as antiepileptic drug hypersensitivity syndrome or minor rashes (maculopapular rashes). During carbamazepine treatment, patients should avoid sun exposure due to photosensitivity.

Hypersensitivity. Carbamazepine may provoke hypersensitivity reactions, including drug reaction 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). Other organs may also be affected (lungs, kidneys, pancreas, myocardium, colon).

The presence of the HLA-A*3101 allele is associated with less serious skin adverse reactions to carbamazepine, such as antiepileptic drug hypersensitivity syndrome or minor rashes (maculopapular rashes).

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

Hepatic function. Hepatic function should be assessed at baseline and periodically during therapy, especially in patients with a history of liver disease and in elderly patients. The drug should be immediately discontinued in cases of acute exacerbation of liver function disorders 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 carbamazepine discontinuation.

Severe hepatic reactions due to carbamazepine use are very rare. In case of signs and symptoms of hepatic dysfunction or active liver disease, the patient should be urgently evaluated, and carbamazepine therapy should be suspended until test results are obtained.

Renal function. Assessment of renal function, 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 concurrently using drugs that reduce sodium levels (such as diuretics, 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 measurements during the first 3 months of treatment or as clinically necessary. This particularly applies to elderly patients. In such cases, water intake should be limited.

Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations; therefore, an increased dose of thyroid hormone replacement therapy 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 closely monitored during therapy. In patients with glaucoma, intraocular pressure should be measured regularly.

Psychiatric effects. The potential for activation of latent psychosis should be considered, and in elderly patients, confusion or agitation should be taken into account.

Warning: If carbamazepine is used for the indication "alcohol withdrawal syndrome," the drug should always be administered in a hospital setting.

It should be noted that adverse reactions to carbamazepine may resemble symptoms of alcohol withdrawal, and this should be kept in mind during treatment with Finlepsin® 200 retard in patients with alcohol withdrawal syndrome.

Suicidal thoughts and behavior. Several reports of suicidal thoughts and behavior have been recorded in patients receiving antiepileptic drugs. A meta-analysis of data from placebo-controlled antiepileptic drug trials also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude an increased risk of suicidal thoughts and behavior with carbamazepine.

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 contact a physician if signs of suicidal thoughts or behavior occur.

Endocrine effects. Inter-menstrual bleeding has been observed in women using hormonal contraceptives concurrently 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 benefits are deemed to outweigh 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 therapy 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 transitioning to alternative treatment options before conception and discontinuation of contraception.

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

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

If, in exceptional circumstances, Finlepsin® 200 retard needs to be used concomitantly with lithium for the prevention of manic-depressive episodes (such a need may arise if lithium therapy is ineffective), interaction should be avoided by monitoring carbamazepine plasma concentration. Carbamazepine concentration should be 8 µg/mL, lithium levels should be within the narrow therapeutic range of 0.3 to 0.8 mEq/L, and the patient should not have received neuroleptic treatment in the previous 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 gradually withdrawn over 6 months. If immediate discontinuation is necessary in patients with epilepsy, transition to a new antiepileptic drug should be performed while continuing appropriate therapy (e.g., intravenous, rectal diazepam, or intravenous phenytoin).

Falls. Carbamazepine treatment may be associated with ataxia, dizziness, somnolence, orthostatic hypotension, confusion, or lethargy, which may lead to falls and, consequently, fractures or other injuries. For patients with conditions, diseases, or concomitant drug use that may exacerbate these conditions, a full assessment of fall risk should be regularly performed during long-term carbamazepine therapy.

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 therapy 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 interfere with the therapeutic effect of hormonal contraceptives; therefore, women of childbearing potential should consult their physician about using other effective contraceptive methods. At least one effective method of contraception (such as an intrauterine device) or two complementary methods, 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 retardation, and defects have been observed 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 potential risks to the fetus caused by both seizures and antiepileptic drugs.

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

For the treatment of epilepsy 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. Exposure to 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 (e.g., cleft lip/palate), cardiovascular malformations, hypospadias, finger hypoplasia, and other anomalies affecting various organ systems have been reported. Specialized antenatal monitoring is recommended for these malformations. 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 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, after careful risk-benefit assessment, an alternative treatment option is unacceptable and carbamazepine therapy continues, monotherapy with the lowest effective dose of carbamazepine should be used, and monitoring of drug levels in plasma is recommended. Plasma concentration should 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 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 reassess carbamazepine therapy 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 associated with the use of carbamazepine and other antiepileptic 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 abnormalities in spermatogenesis parameters have been reported.

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

The ability of a patient taking carbamazepine (even when used according to recommendations), particularly at the beginning of therapy or during dose titration, when using high doses and/or in combination with other central nervous system-acting drugs, to react quickly may be impaired due to central nervous system adverse reactions (dizziness, somnolence, fatigue). Therefore, patients should exercise caution when driving vehicles or operating machinery and when performing tasks requiring balance without support.

This effect is enhanced when combined with alcohol.

Method of Administration and Dosage.

Treatment with carbamazepine should be initiated at low doses, which should be individually adjusted according to the patient's clinical condition. The dose should then be gradually increased until the optimal maintenance dose is achieved.

In individual cases, the required dose may significantly differ from the initial treatment doses and maintenance doses (e.g., due to increased or decreased drug metabolism influenced by enzyme-inducing agents or inhibitory substances during combination therapy).

Finlepsin® 200 retard should be administered orally. The daily dose is usually divided into two administrations. The drug may be taken during meals, after meals, or between meals, swallowed with a small amount of liquid (e.g., a glass of water). Lower doses may be sufficient for patients with severe cardiovascular disorders, hepatic disease, renal insufficiency, and elderly patients. In most cases, good efficacy is achieved when the daily dose is divided into 4–5 administrations.

Finlepsin® 200 retard tablets may be split in half. The tablets may be dissolved in water, as the sustained-release properties are preserved in the suspension after dissolving the prolonged-release tablets in water.

The maximum daily dose (in exceptional cases) should not exceed 1600 mg due to the increased risk of adverse reactions following high-dose administration.

When switching from immediate-release formulations to Finlepsin® 200 retard tablets, it is essential to ensure that the corresponding plasma concentration of carbamazepine is achieved.

Under no circumstances should patients discontinue treatment on their own.

Before initiating treatment, patients of Han Chinese ethnicity or Thai origin should, if possible, be tested for the presence of HLA-B*1502, as this allele may trigger the development of severe carbamazepine-associated Stevens-Johnson syndrome.

Epilepsy

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

Whenever possible, Finlepsin® 200 retard should be used as monotherapy. However, when used in combination with other medications, a similar gradual dose escalation is recommended. When adding Finlepsin® 200 retard to existing antiepileptic therapy, the dose should be gradually increased, while the doses of concomitant medications should remain unchanged or be adjusted as necessary.

Treatment must be supervised by a specialist.

Therapeutic drug monitoring—determining the plasma concentration of the active substance—may be helpful in establishing the optimal dose. The therapeutic plasma concentration of the drug ranges from 4 to 12 µg/mL.

In some patients, the use of retard tablets may necessitate an increased dose.

Adults

Recommended initial dose: 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 administrations. Some patients may require doses of Finlepsin® 200 retard up to 1600 mg or even 2000 mg/day.

Elderly Patients

Due to potential drug interactions and altered pharmacokinetics of antiepileptic drugs, Finlepsin® 200 retard doses in elderly patients should be carefully selected.

Children aged 6 years and older

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

Children aged 6 to 10 years: 400–600 mg/day (in 2–3 divided doses).

Children aged 11 to 15 years: 600–1000 mg/day (in 2–5 divided doses).

Children aged 15 years and older: adult dosing applies.

Antiepileptic treatment is generally long-term. The dose, duration of treatment, and discontinuation are determined by a neurologist for each individual patient. Dose reduction and discontinuation may only be considered after achieving a seizure-free period (remission) lasting 2 to 3 years. Treatment should be discontinued gradually over a period of 1 to 2 years. In children, body weight gain should be monitored during this period. EEG abnormalities should not increase.

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

The dose range is 400 to 1600 mg/day, divided into 2–3 administrations. Therapy is usually conducted at a dose of 400–600 mg/day in 2–3 divided doses.

For the treatment of acute manic states, the dose of Finlepsin® 200 retard should be increased rapidly up to 800 mg/day. For maintenance therapy of bipolar disorders, gradual dose escalation starting with low doses is recommended to ensure optimal tolerability. The duration of treatment is determined by the physician.

Lower doses may be sufficient for patients with severe cardiovascular disorders, hepatic disease, renal insufficiency, and elderly patients.

Alcohol withdrawal syndrome

The average dose is 600 mg/day, divided into 3 doses. In severe cases, the dose may be increased during the first few days (e.g., up to 1200 mg/day, divided into 3 doses). Carbamazepine may be used in combination with other agents commonly used in the treatment of alcohol withdrawal syndrome. In cases of severe alcohol withdrawal symptoms, treatment should be initiated with a combination of Finlepsin® 200 retard and sedative-hypnotic agents (e.g., clomethiazole, chlordiazepoxide), following the above dosage recommendations. After the acute phase, treatment with Finlepsin® 200 retard may continue as monotherapy. Plasma carbamazepine concentrations should be regularly monitored. Close medical supervision is essential, as adverse reactions involving the central and peripheral nervous systems may occur.

Treatment of alcohol withdrawal syndrome with carbamazepine should be completed between the 7th and 10th day of therapy by gradually reducing the dose.

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

The initial dose of Finlepsin® 200 retard is 200–400 mg/day (100 mg twice daily for elderly patients or particularly sensitive individuals). This dose should be slowly increased until pain subsides (usually up to 600–800 mg/day, divided into 3–4 doses). For most patients, a dose of 200 mg 3–4 times daily is sufficient to maintain a pain-free state. In some cases, a daily dose of up to 1600 mg may be required. In certain cases, treatment may continue with a low maintenance dose—1 tablet of Finlepsin® 200 retard (corresponding to 200 mg carbamazepine) taken twice daily (totaling 400 mg carbamazepine daily). After pain subsides, the dose should be gradually reduced to the minimum effective maintenance dose and discontinued after several weeks of treatment if pain does not recur. In case of pain recurrence, treatment should continue using the maintenance dose.

Children

Due to faster carbamazepine elimination, children may require higher doses (per kg of body weight) compared to adults. This pharmaceutical form of carbamazepine should not be administered to children under 6 years of age due to the high dose and lack of experience with prolonged-release formulations in this patient group.

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 to 10 g). Plasma drug concentrations were always above 20 µg/mL.

Symptoms. Symptoms and complaints associated with overdose typically reflect impairment of the central nervous, cardiovascular, and respiratory systems.

Central nervous system: CNS depression; disorientation, agitation, restlessness, dizziness, depressed level of consciousness, stupor, somnolence, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (early), hyporeflexia (later); seizures, psychomotor disturbances, myoclonus, opisthotonus, hypothermia, mydriasis, involuntary movements, tremor. EEG abnormalities may include slowing of the background rhythm and presence of slow waves.

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

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

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

Musculoskeletal system: Rhabdomyolysis related to the toxic effect of carbamazepine.

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

Laboratory changes: Hyponatremia, possible metabolic acidosis, hyperglycemia, elevated creatine phosphokinase muscle fraction. Cases of leukocytosis, leukopenia, neutropenia, glucosuria, and ketonuria have been reported.

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 overdose severity.

Gastric evacuation, gastric lavage, and administration of activated charcoal should be performed. 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, with continuous cardiac monitoring and careful correction of electrolyte imbalances.

Special recommendations. In case of arterial hypotension, intravenous 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 (used cautiously due to increased risk of respiratory depression) or paraldehyde should be administered. In case of hyponatremia (water intoxication), fluid restriction and slow, cautious intravenous infusion of 0.9% sodium chloride solution are recommended. These measures may help prevent cerebral edema. According to literature data, barbiturates are not recommended due to their respiratory depressant effects, especially in children.

Hemoadsorption using charcoal sorbents is recommended. Forced diuresis, hemodialysis, and peritoneal dialysis have been reported as ineffective due to the high plasma protein binding of carbamazepine.

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

Adverse Reactions

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

Adverse reactions were observed more frequently during combination therapy than with monotherapy. Depending on the dose and mainly at the beginning of treatment, certain adverse reactions may occur. Generally, they resolve spontaneously within 8–14 days or after temporary dose reduction. The development of adverse CNS reactions may result from relative overdosing or significant fluctuations in plasma concentrations of the active substance. In such cases, monitoring of the plasma level of the active substance is recommended, and the daily dose should be divided into smaller portions (e.g., 3–4 doses).

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

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

Immune system disorders: rare – multi-organ hypersensitivity reaction of delayed type with fever, skin rashes, vasculitis, lymphadenopathy, lymphoma-like signs, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, and abnormal liver function tests occurring in various combinations, vanishing bile duct syndrome (destruction and disappearance of intrahepatic bile ducts). Other organs may also be affected (e.g., liver, lungs, kidneys, pancreas, myocardium, colon). Very rare – aseptic meningitis with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioedema, 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 hyperhydration accompanied by lethargy, vomiting, headache, confusion, and neurological disturbances; very rare – elevated prolactin levels with or without clinical symptoms such as galactorrhea and gynecomastia; abnormal thyroid function tests: decreased levels of thyroxine (FT4, T4, T3) and increased TSH levels, usually without clinical manifestations; in isolated cases – increased cholesterol levels, including HDL cholesterol and triglycerides. Decreased plasma levels of vitamin B12 and increased homocysteine levels under the influence of carbamazepine have also been reported.

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

Psychiatric disorders: rare – hallucinations (visual or auditory), depression, loss of appetite, restlessness, aggressive behavior, agitation, nervous excitement, confusion, mood changes such as depressive or manic mood swings, phobias, disorientation; very rare – activation of latent psychosis, lack of motivation.

Nervous system disorders: very common – general weakness, dizziness, ataxia, somnolence, malaise; common – headache, diplopia, accommodation disorders (blurred vision); uncommon – abnormal reflex movements (e.g., tremor, coarse tremor, dystonia, tics, asterixis), nystagmus; rare – orofacial dyskinesia, thinking disorders, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness, and paresis; very rare – taste disturbances, malignant neuroleptic syndrome, dysgeusia.

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. The severity of absence-type seizures may increase or such seizures may be provoked.

Eye disorders: rare – eye movement disorders; very rare – conjunctivitis, increased intraocular pressure, lens opacities, retinotoxicity.

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

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

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

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

Hepatobiliary disorders: very common – elevated gamma-glutamyl transferase (due to hepatic enzyme induction), usually clinically insignificant; common – elevated alkaline phosphatase; uncommon – elevated transaminases; rare – jaundice, various forms of hepatitis (cholestatic, hepatocellular, mixed), vanishing bile duct syndrome; very rare – granulomatous hepatitis, hepatic failure.

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

Increasing evidence indicates an association between genetic markers and the occurrence of skin-related adverse reactions such as SJS, TEN, DRESS, GEP, and maculopapular rashes. In Japanese and European patients 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 descent (Han ethnic group), Thai descent, or from other Asian countries (see sections "Special precautions for use" and "Dosage and administration").

Musculoskeletal and connective tissue disorders: rare – muscle weakness; very rare – arthralgia, myalgia, muscle cramps, bone metabolism disorders (decreased calcium and 25-hydroxycholecalciferol levels in plasma, which may lead to osteomalacia or osteoporosis). Decreased bone mineral density, osteopenia, osteopor ̈osis, and bone fractures have been reported in patients receiving long-term carbamazepine therapy. The mechanism by which carbamazepine affects bone metabolism is not fully understood.

Renal and urinary disorders: very rare – tubulointerstitial nephritis, renal failure, renal dysfunction (proteinuria, hematuria, oliguria, dysuria, elevated blood urea/azotemia), frequent urination, urinary retention.

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

Injury, poisoning, and procedural complications: isolated cases of falls have been reported (associated with ataxia, dizziness, somnolence, arterial hypotension, confusion, or lethargy due to carbamazepine use).

Adverse reactions identified during post-marketing use (frequency unknown)

The following adverse reactions have been observed during post-marketing use of carbamazepine. Since reports on these reactions are spontaneous, 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.

Nervous system disorders: sedative effect, memory impairment.

Gastrointestinal disorders: colitis.

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

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

Musculoskeletal, connective tissue, and bone disorders: fractures.

Laboratory and diagnostic test abnormalities: decreased bone mineral density.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 30 °C in a place inaccessible to children.

Packaging.

10 tablets per blister. 5, 10, or 20 blisters per carton.

Prescription status. Prescription only.

Manufacturer. TEVA OPERATIONS POLAND SP. Z O.O.

Manufacturer's address and location of business activity.

80 Mogilska Street, 31-546 Kraków, Poland.