Finlepsin® 400 retard

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FINLEPSIN® 400 RETARD (FINLEPSIN® 400 RETARD)

Composition:

Active substance: carbamazepine;

1 tablet contains carbamazepine 400 mg;

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

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties: white or yellowish round flat tablets in the shape of a clover leaf, with bevelled edges, with a cross-shaped score line on both sides and 4 notches on the lateral sides, with a smooth surface, intact edges and uniform external appearance.

Pharmacotherapeutic group. Antiepileptic drugs. ATC code N03AF01.

Pharmacological properties.

Pharmacodynamics.

An anticonvulsant drug, a derivative of tricyclic iminostilbene. Exhibits antiepileptic, neurotropic, and psychotropic activity. The exact mechanism of action of carbamazepine is unknown. The therapeutic effect is primarily due to inhibition of synaptic transmission of excitation, thereby reducing the spread of seizure activity. At higher concentrations, carbamazepine reduces the conduction of seizure discharges. It decreases pain sensations in trigeminal neuralgia. This effect is mediated by 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 shows 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 within 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 plateaus.

When using prolonged-release tablets, lower plasma concentrations of carbamazepine are achieved compared to conventional tablets.

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

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 between 5–18 mcg/mL, pain in trigeminal neuralgia is relieved.

The threshold plasma concentrations of carbamazepine associated with the occurrence of 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. The concentration in saliva 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 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 on monotherapy, approximately 54.6 mL/h/kg; and in patients on combination therapy, approximately 113.3 mL/h/kg. After a single oral dose of carbamazepine, 72% of the dose is excreted via the kidneys 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 (mg/kg body weight) may be required to maintain therapeutic concentrations compared to adults.

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

Patients with renal or hepatic impairment. Data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function 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® 400 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 exacerbation.
• Alcohol withdrawal syndrome.
• Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical).
• Idiopathic glossopharyngeal neuralgia.

Contraindications.

Finlepsin® 400 retard should not be prescribed:

• in cases of known hypersensitivity to carbamazepine or to structurally 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 suppression;
• 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 types of interactions.

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing the formation of the active metabolite of carbamazepine—10,11-epoxide. Concomitant use of CYP3A4 inhibitors 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 a potential decrease in plasma carbamazepine concentration and therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, resulting in increased plasma levels of carbamazepine.

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

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

Drugs that may increase plasma levels of carbamazepine

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 required when co-administering the following drugs:

Analgesics, anti-inflammatory agents: dextropropoxyphene, ibuprofen.

Androgens: danazol.

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

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

Drugs for gastrointestinal disorders: cimetidine, omeprazole.

Muscle relaxants: oxybutynin, dantrolene.

Antiplatelet agents: ticlopidine.

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

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

Since elevated plasma levels of the active metabolite carbamazepine-10,11-epoxide may cause adverse reactions (e.g. dizziness, somnolence, ataxia, diplopia), dosage adjustment of carbamazepine and/or monitoring of plasma carbamazepine levels is required when Finlepsin® 400 retard is co-administered with the following drugs: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, brivaracetam, and valpromide.

Drugs that may decrease plasma levels of carbamazepine

Dosage adjustment of Finlepsin® 400 retard may be necessary when co-administered with the following drugs:

Antiepileptic agents: phenobarbital, fensuximide, 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 anti-asthmatic 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 has been reported to alter 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 drugs

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

Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (long-term 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 mephenytoin.

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

Antihelminthics: 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 anti-asthmatic 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.

Drug 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 preparations or metoclopramide, as well as carbamazepine and neuroleptics (haloperidol, thioridazine), may enhance the severity of neurological side effects (in the case of the latter combination—even at therapeutic plasma levels). Concomitant use of Finlepsin® 400 retard with most diuretics (hydrochlorothiazide, furosemide) may cause symptomatic hyponatremia.

Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g. pancuronium). Increased doses of these agents may be required, and patients need careful monitoring due to the possibility of faster-than-expected termination of neuromuscular blockade. Carbamazepine, like other psychotropic drugs, may reduce tolerance to alcohol; therefore, patients are advised to abstain from alcohol consumption.

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

Contraindicated interaction

Since carbamazepine is structurally similar to tricyclic antidepressants, Finlepsin® 400 retard is not recommended for concomitant use with MAO inhibitors. At least two weeks (or longer, depending on the patient’s clinical condition) should elapse between discontinuation of MAO inhibitors and initiation of carbamazepine therapy.

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 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 spasm.

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

Carbamazepine may enhance 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 of thyroid hormones may be necessary. Thyroid function may change, particularly during concomitant use of carbamazepine and other antiepileptic drugs (e.g. phenobarbital).

Concomitant use of carbamazepine with serotonin reuptake inhibitors (e.g. fluoxetine) may lead to serotonin syndrome.

Finlepsin**®** 400 retard should not be used concomitantly with nefazodone (an antidepressant), as it may cause a significant reduction in plasma concentration of nefazodone and complete loss of its efficacy. Concurrent use of nefazodone and Finlepsin**®** 400 retard increases plasma carbamazepine concentration and decreases concentration 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 yield false-positive results in HPLC (high-performance liquid chromatography) analysis for perphenazine concentration.

Carbamazepine and carbamazepine-10,11-epoxide may yield false-positive results in immunoassay methods using fluorescence polarization for determination of tricyclic antidepressant concentrations.

Special precautions for use

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

General urine analysis and blood urea nitrogen determination are recommended 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 psychosis should be considered, and in elderly patients, the possibility of activation of confusion and development of anxious agitation.

The drug is generally ineffective in absence seizures (petit mal) and myoclonic seizures. Individual cases indicate that seizure exacerbation may occur in patients with atypical absences. Finlepsin® 400 retard should not be used in patients with this type of seizure.

Hematological effects

Use of the drug has been associated with development of agranulocytosis and aplastic anemia; however, due to the extremely low incidence of these conditions, it is difficult to assess the significant risk associated with 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 severe, progressive, or clinically symptomatic leukopenia (e.g., 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 development of aplastic anemia or agranulocytosis. Blood analysis, including platelet count (and possibly reticulocyte count and hemoglobin level), should be performed before and periodically during therapy. Treatment should be discontinued if thrombocytopenia develops, including cases associated with skin bruising or hemorrhages.

Due to the occurrence of the above-mentioned adverse reactions and hypersensitivity reactions, blood morphology, renal and hepatic function, carbamazepine blood concentration, and concentrations of other antiepileptic 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, hepatic failure, erythrocyte count ˂ 4000000/mm³, hematocrit ˂ 32%, hemoglobin concentration below 11 g%, leukocyte count ˂ 2000/mm³, granulocyte count ˂ 1000/mm³ or platelet count ˂ 80000/mm³, or 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 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, the risk may be approximately 10 times higher in patients from certain Asian countries. If signs and symptoms suggestive of serious dermatological reactions (e.g., SJS, Lyell’s syndrome/TEN—such as progressive skin rash with blistering or mucosal changes) develop, carbamazepine should be discontinued immediately and alternative therapy initiated. Patients should be informed about signs and symptoms suggesting hypersensitivity reactions and should be closely monitored for skin reactions. The best outcomes in treating SJS and TEN are achieved through early detection and immediate discontinuation of all drugs likely to be causative. Early discontinuation is associated with a better prognosis.

If a patient develops SJS or TEN related to carbamazepine use, reinitiating carbamazepine therapy is not recommended.

Pharmacogenomics

Growing evidence indicates the influence of various HLA alleles on patient susceptibility to immune-related adverse reactions.

Association with HLA-B*1502

Retrospective studies involving Han Chinese patients have demonstrated a strong correlation between carbamazepine-related skin reactions (SJS/TEN) and the presence of human leukocyte antigen (HLA) allele HLA-B*1502 in these patients. Higher reporting rates of SJS (rare rather than very rare) are 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 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 HLA-B*1502 is low among Caucasian and African populations, indigenous peoples of the Americas, 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 the test for HLA-B*1502 is positive, carbamazepine therapy should not be initiated, except when no other treatment options are available. Patients who have tested negative for HLA-B*1502 have a low risk of developing SJS, although very rare reactions may still occur. Currently, due to lack of data, it is not precisely known whether risks exist for all individuals of Southeast Asian origin.

The HLA-B*1502 allele may be a risk factor for SJS/TEN in Chinese patients receiving other antiepileptic drugs associated with SJS/TEN. Therefore, use of other drugs potentially associated with SJS/TEN should be avoided in patients with the HLA-B*1502 allele if alternative therapy is available. Genetic screening of patients from populations with low HLA-B*1502 allele frequency 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 HLA-B*1502 presence. In Caucasian patients, there is no association between the HLA-B*1502 allele and SJS development.

Association with HLA-A*3101

Human leukocyte antigen may be a risk factor for skin adverse reactions such as SJS, TEN, drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), 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, ≈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%. Insufficient data exist 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 descent or Japanese individuals, the possibility of using carbamazepine should be considered only if benefits outweigh risks.

Limitations of genetic screening

Genetic screening results should not replace appropriate clinical monitoring and patient management. Other potential factors, such as antiepileptic drug dosage, adherence to therapy, and concomitant medications, may also 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

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

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 hypersensitivity syndrome or minor rashes (maculopapular rashes). During carbamazepine therapy, 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 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).

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 discontinued immediately.

Cross-hypersensitivity may occur with carbamazepine and aromatic antiepileptic drugs (e.g., phenytoin, primidone, 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 discontinued immediately. Increased seizure frequency may occur during transition from oral formulations to suppositories.

Hepatic function

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

Some laboratory parameters used to assess liver function may exceed normal limits 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 hepatic metabolic activity is not an indication for carbamazepine discontinuation.

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

Renal function

Assessment of renal function, urine analysis, and blood urea nitrogen determination are recommended at the beginning and periodically during therapy.

Hyponatremia

Cases of hyponatremia are known with carbamazepine use. In patients with pre-existing renal dysfunction associated with low sodium levels or those concomitantly using drugs that lower sodium (e.g., 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 is particularly important for elderly patients. Water intake should be limited in such cases.

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 or urinary retention should be under close monitoring during therapy. In patients with glaucoma, intraocular pressure should be regularly measured.

Psychiatric effects

The potential for activation of latent psychosis should be considered, and in elderly patients, confusion or agitation.

Warning: If carbamazepine is used for the indication "alcohol withdrawal syndrome," it 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 considered during treatment of patients with alcohol withdrawal syndrome using Finlepsin® 400 retard.

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 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 evaluated for suicidal thoughts and behavior, and appropriate treatment initiated if necessary. Patients (and caregivers) should be advised to seek medical help if signs of suicidal thoughts or behavior appear.

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 therapy in a woman of childbearing potential, a pregnancy test should be performed.

Women of childbearing potential must 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 about using other effective contraceptive methods.

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.

Monitoring of plasma drug levels

Although the correlation between dosage and plasma carbamazepine levels, as well as between plasma carbamazepine levels and clinical efficacy and tolerability, is unreliable, monitoring plasma drug levels may be useful in the following cases: sudden increase in seizure frequency, checking patient compliance, during pregnancy, in treatment of children and adolescents; suspected absorption impairment, suspected toxicity, and polypharmacy.

If, in exceptional circumstances, Finlepsin® 400 retard must be used concomitantly with lithium for 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 8 µg/mL, lithium levels should be within the narrow therapeutic range of 0.3–0.8 mEq/L, and the patient should not have received or be receiving neuroleptic treatment within the previous 8 weeks.

Dosage reduction and withdrawal syndrome

Sudden discontinuation of the drug may provoke seizures; therefore, carbamazepine should be tapered gradually over 6 months. If immediate discontinuation is necessary in patients with epilepsy, transition to a new antiepileptic drug should be performed while continuing appropriate medication (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. In patients with conditions or concomitant medications that exacerbate these effects, a full risk assessment for falls 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 must 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 about using other effective contraceptive methods. At least one effective method of contraception (e.g., 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 documented in animals receiving carbamazepine during pregnancy.

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

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

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

For treatment of epilepsy during pregnancy, monotherapy is preferred if possible, as polytherapy 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. Human exposure to carbamazepine during pregnancy is associated with a 2–3 times higher frequency of serious malformations compared to the general population (2–3%). Among 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 for these malformations is recommended. Neurodevelopmental disorders have been reported in children born to women with epilepsy who used carbamazepine alone or in combination with other AEDs during pregnancy. Studies on the risk of neurodevelopmental disorders in children exposed to carbamazepine during pregnancy are conflicting, and 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 may be dose-dependent. If, based on careful risk-benefit assessment, an alternative treatment is unacceptable and carbamazepine therapy continues, monotherapy with the lowest effective dose should be used, and plasma drug level monitoring is recommended. Plasma concentration should be maintained in the lower part of the therapeutic range (4–12 µg/mL) while maintaining seizure control.

It has been reported that some antiepileptic drugs, including carbamazepine, reduce serum folate levels. This deficiency may contribute to increased frequency of congenital malformations in children of women treated for epilepsy. 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 the newborn.

If a woman plans pregnancy, all efforts should be made before conception and discontinuation of 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 therapy and consider alternative treatment options.

Several cases of seizures and/or respiratory depression in newborns, as well as vomiting, diarrhea, and/or poor appetite in newborns, have been associated with maternal 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, failure to gain weight appropriately).

Fertility.

Rare cases of impaired fertility in men and/or abnormal 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) to react quickly (especially at the beginning of therapy or during dose titration, when used in high doses and/or in combination with other central nervous system-acting drugs) may be impaired due to central nervous system adverse reactions (dizziness, somnolence, fatigue). Therefore, patients should be cautious when driving vehicles or operating machinery and in activities requiring balance without support.

This effect is enhanced when combined with alcohol.

Method of Administration and Dosage

Carbamazepine therapy 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® 400 retard is 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). For patients with severe cardiovascular disorders, hepatic or renal disease, and in elderly patients, a lower dose may be sufficient. In most cases, good efficacy is achieved when the daily dose is divided into 4–5 administrations.

Finlepsin® 400 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 dissolution of the prolonged-release tablets.

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

When switching from immediate-release formulations to prolonged-release tablets Finlepsin® 400 retard, 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 therapy, patients belonging to the Han Chinese ethnic group or of Thai origin should, if possible, be tested for the presence of HLA-B*1502, as this allele may predispose to the development of severe carbamazepine-associated Stevens-Johnson syndrome.

Epilepsy

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

Whenever possible, Finlepsin® 400 retard should be used as monotherapy. However, when used in combination with other medicinal products, a similarly gradual dose escalation is recommended. If Finlepsin® 400 retard is added to existing antiepileptic therapy, the dose should be increased gradually, while the doses of concomitant antiepileptic drugs should not be changed or should be adjusted only if necessary.

Treatment must be supervised by a specialist.

Therapeutic drug monitoring (determination of plasma levels of the active substance) may be helpful in determining 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 increase in the dose of the drug.

Adults

Recommended initial dose: 100–200 mg once or twice daily, gradually increasing the dose to achieve the optimal effect. The usual daily dose is 800–1200 mg, divided into two administrations. The maximum daily dose generally should not exceed 1600 mg due to the increased risk of adverse reactions. However, some patients may require doses of Finlepsin® 400 retard up to 1600 mg or even 2000 mg per day.

Elderly Patients

Due to drug interactions and altered pharmacokinetics of antiepileptic drugs, doses of Finlepsin® 400 retard in elderly patients should be selected with caution.

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: dosing as in adults.

Antiepileptic treatment is generally long-term. The dose, duration of treatment, and discontinuation are determined for individual patients by a neurologist. Dose reduction and discontinuation of treatment may be considered only 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. During this period, weight gain should be monitored in children. EEG abnormalities should not increase in severity.

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

Dosage range: 400–1600 mg/day, divided into 2–3 doses. Therapy is usually administered at 400–600 mg/day in 2–3 divided doses.

For treatment of acute manic states, the dose of Finlepsin® 400 retard should be increased rapidly up to 800 mg/day. For maintenance therapy of bipolar disorders, gradual dose escalation with low initial doses is recommended to ensure optimal tolerability. The duration of treatment is determined by the physician.

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 concomitantly with other agents commonly used in the treatment of alcohol withdrawal syndrome. In cases of severe alcohol withdrawal, treatment should be initiated with a combination of Finlepsin® 400 retard and sedative-hypnotic agents (e.g., clomethiazole, chlordiazepoxide), following the dosage recommendations above. After resolution of the acute phase, treatment with Finlepsin® 400 retard may continue as monotherapy. Plasma carbamazepine concentrations should be monitored regularly. Close medical supervision is required, 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 drug dose.

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

The initial dose of Finlepsin® 400 retard is 200–400 mg/day (100 mg twice daily for elderly patients or particularly sensitive individuals). The 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 1600 mg may be required. In some cases, treatment may be continued with a low maintenance dose—0.5 tablet of Finlepsin® 400 retard (corresponding to 200 mg carbamazepine) twice daily (total 400 mg carbamazepine). After pain resolution, the dose should be gradually reduced to the minimum maintenance dose and discontinued after several weeks of treatment if pain does not recur. In case of pain recurrence, treatment should be continued with a maintenance dose.

Children

Due to faster carbamazepine elimination, children may require higher doses (on a per-kilogram basis) compared to adults. This medicinal product formulation should not be administered to children under 6 years of age due to the high dose strength and lack of experience with prolonged-release formulations in this patient group.

Overdose

In cases of poisoning, the possibility of overdose with multiple medicinal products (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 drug concentrations were always >20 µg/mL.

Symptoms. Signs and symptoms of 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, drowsiness, 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 apnea), 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 management 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, including cardiac monitoring and careful correction of electrolyte imbalances.

Special recommendations. In case of arterial hypotension, intravenous dopamine or dobutamine is indicated; cardiac arrhythmias 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 intake should be restricted, and cautious slow intravenous infusion of 0.9% sodium chloride solution should be performed. These measures may help prevent cerebral edema. According to published data, barbiturates are not recommended due to their respiratory depressant effects, especially in children.

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

Recurrence of overdose symptoms on the 2nd and 3rd day 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, such as 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 a temporary reduction in dose. The development of CNS-related adverse reactions may result from relative overdosage or significant fluctuations in plasma concentrations of the active substance. In such cases, monitoring of plasma levels of the active substance is recommended, and the daily dose should be divided into smaller, more frequent doses (e.g., 3–4 times daily).

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

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

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

Endocrine 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 – increased 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, usually without clinical manifestations; isolated cases – increased cholesterol levels, including HDL cholesterol and triglycerides. Decreased plasma vitamin B12 levels 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 disturbances, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness, and paresis; very rare – taste disturbances, neuroleptic malignant 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 new seizures may be provoked.

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

Ear and labyrinth disorders: very rare – hearing disorders, tinnitus, ringing in the ears, hyperacusis, hypoacusis, impaired perception of sound pitch.

Cardiac disorders: rare – disturbances in intracardiac conduction, 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, thoracic and mediastinal disorders: very rare – hypersensitivity reactions affecting 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 – increased gamma-glutamyl transferase (due to induction of liver enzymes), usually without clinical significance; common – increased alkaline phosphatase; uncommon – increased transaminases; rare – jaundice, various forms of hepatitis (cholestatic, hepatocellular, mixed), bile duct disappearance syndrome; 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), photosensitization, erythema multiforme and nodularis, skin pigmentation changes, purpura, acne, increased sweating, alopecia, hirsutism.

Growing evidence supports an association between genetic markers and the occurrence of skin-related adverse reactions such as SJS, TEN, DRESS, AGEP, 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 the development of SJS and TEN is the HLA-B*1502 allele in individuals of Chinese origin (Han ethnic group), Thai origin, or from other Asian countries (see sections "Special precautions" and "Dosage and administration").

Musculoskeletal and connective tissue disorders: rare – muscle weakness; very rare – arthralgia, myalgia, muscle cramps, disturbances in bone metabolism (decreased plasma calcium and 25-hydroxycholecalciferol levels, which may lead to osteomalacia or osteoporosis). Decreased bone mineral density, osteopenia, osteoporosis, 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, impaired kidney function (proteinuria, hematuria, oliguria, dysuria, increased 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 are spontaneous, it is not possible to determine the exact number of affected patients or reliably estimate the frequency of these reactions; therefore, their frequency is classified as "unknown".

Infections and infestations: reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: bone marrow insufficiency.

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: acute generalized exanthematous pustulosis (AGEP), 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.

Keep out of reach of 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 operations.

80 Mogilska Street, 31-546 Kraków, Poland.