Carbamazepine-darnitsa

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARBAZEPIN-DARNITSA (CARBAMAZEPINE-DARNITSA)

Composition:

Active substance: carbamazepine;

One tablet contains carbamazepine 200 mg;

Excipients: microcrystalline cellulose, potato starch, povidone, colloidal anhydrous silicon dioxide, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: tablets of white or white with creamy-pinkish hue, flat cylindrical shape, with bevel and score line.

Pharmacotherapeutic group. Antiepileptic drugs. Carbamazepine. ATC code N03AF01.

Pharmacological Properties

Pharmacodynamics

As an anticonvulsant, carbamazepine is effective in focal (partial) seizures (simple and complex), with or without secondary generalization, generalized tonic-clonic seizures, and combinations of these seizure types.

The mechanism of action of carbamazepine has been only partially elucidated. Carbamazepine stabilizes overexcited nerve membranes, prevents repetitive neuronal discharges, and reduces synaptic transmission of excitatory impulses. The primary mechanism of action is likely the prevention of repetitive sodium-dependent action potentials in depolarized neurons by voltage- and use-dependent blockade of sodium channels.

Reduction in glutamate release and neuronal membrane stabilization may explain the anticonvulsant effect of the drug. The antimanic effect of carbamazepine may be attributed to inhibition of dopamine and norepinephrine metabolism.

In clinical studies, when carbamazepine was used as monotherapy in patients with epilepsy (particularly in children and adolescents), psychotropic effects of the drug were observed, including a beneficial impact on symptoms of anxiety and depression, as well as reduced irritability and aggression. According to several studies, the effect of carbamazepine on cognitive function and psychomotor performance was dose-dependent and either questionable or negative. In other studies, a positive effect of the drug on parameters related to attention, learning ability, and memory was observed.

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

Carbamazepine has been confirmed as an effective psychotropic agent in affective disorders: for the treatment of acute manic episodes and for maintenance therapy of bipolar affective (manic-depressive) disorders (as monotherapy or in combination with neuroleptics, antidepressants, or lithium preparations).

Pharmacokinetics

Absorption. After oral administration, carbamazepine is almost completely absorbed, although somewhat slowly. Following a single dose, maximum plasma concentration (Cmax) is reached within 12 hours. No clinically significant differences in the extent of absorption of the active substance have been observed after administration of various oral dosage forms of carbamazepine. After a single 400 mg dose, the mean Cmax of unchanged active substance reaches approximately 4.5 µg/mL.

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

Steady-state plasma concentrations are achieved within 1–2 weeks, depending on individual metabolic characteristics (autoinduction of hepatic enzyme systems by carbamazepine, heteroinduction by concomitantly administered drugs), as well as the patient's condition, drug dose, and duration of treatment. There are substantial individual variations in steady-state concentrations within the therapeutic range: in most patients, these values range from 4 to 12 µg/mL (17–50 µmol/L). Concentrations of carbamazepine-10,11-epoxide (a pharmacologically active metabolite) reach up to approximately 30% of carbamazepine concentrations.

The bioavailability of different carbamazepine formulations may vary, which could lead to reduced efficacy, risk of epileptic seizures during treatment, or increased incidence of adverse effects.

Distribution. With complete absorption, the volume of distribution of carbamazepine ranges from 0.8 to 1.9 L/kg. Carbamazepine crosses the placental barrier. Plasma protein binding of carbamazepine is 70–80%. The concentration of unchanged carbamazepine in cerebrospinal fluid and saliva is proportional to the unbound fraction of the active substance (20–30%). The concentration of carbamazepine in breast milk is 25–60% of its plasma level.

Metabolism. Carbamazepine is primarily metabolized in the liver via the epoxide pathway, resulting in the formation of the main metabolites—10,11-trans-dihydrodiol derivative and its glucuronic acid conjugate. The primary isoenzyme responsible for the biotransformation of carbamazepine into carbamazepine-10,11-epoxide is cytochrome P450 3A4. These metabolic reactions also produce a "minor" metabolite—9-hydroxymethyl-10-carbamoylacridan. After a single oral dose of carbamazepine, approximately 30% of the active substance is excreted in urine as end products of epoxide metabolism. Other important biotransformation pathways lead to the formation of various monohydroxylated derivatives and the N-glucuronide of carbamazepine, formed with the participation of uridine diphosphate-glucuronosyltransferase (UGT2B7).

Elimination. After a single oral dose, the elimination half-life of unchanged carbamazepine averages 36 hours; after repeated dosing, it averages 16–24 hours (due to autoinduction of the hepatic monoxygenase system), depending on the duration of treatment. In patients concurrently taking other drugs that induce the same hepatic enzyme system (e.g., phenytoin, phenobarbital), the half-life of carbamazepine averages 9–10 hours. The mean elimination half-life of the 10,11-epoxide metabolite from plasma is approximately 6 hours after a single oral dose.

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

Pharmacokinetic characteristics in specific patient populations

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

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

Patients with renal or hepatic impairment. Currently, there are no pharmacokinetic data available for carbamazepine in patients with impaired renal or hepatic function.

Clinical characteristics.

Indications.

• Epilepsy:

− complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization;

− generalized tonic-clonic seizures;

− mixed forms of seizures.

Carbamazepine may be used as monotherapy or in combination therapy.

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

Contraindications.

The medicinal product should not be prescribed:

− in cases of known hypersensitivity to carbamazepine or to pharmacologically related substances (such as tricyclic antidepressants), or to any other component of the medicinal product;

− in atrioventricular block;

− to patients with a history of bone marrow depression;

− to patients with hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria) in their medical history;

− in combination with monoamine oxidase inhibitors (MAO inhibitors).

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 the development of adverse reactions. Concomitant use of CYP3A4 inducers may enhance the metabolism of carbamazepine, leading to a potential decrease in serum carbamazepine concentration and therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, leading to increased plasma levels of carbamazepine.

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

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

Medicinal products that may increase plasma levels of carbamazepine.

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 performed when co-administered with the following medicinal products:

Analgesics, anti-inflammatory agents: dextropropoxyphene, ibuprofen.

Androgens: danazol.

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

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

Antiepileptics: stiripentol, vigabatrin.

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

Antihistamines: loratadine, terfenadine.

Antipsychotics: olanzapine, loxapine, quetiapine.

Antituberculosis agents: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular agents: diltiazem, verapamil.

Agents for gastrointestinal disorders: cimetidine, omeprazole.

Muscle relaxants: oxybutynin, dantrolene.

Antiplatelet agents: ticlopidine.

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

Medicinal products that may increase plasma levels of the active metabolite of 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), plasma levels of carbamazepine should be monitored and/or dosage adjusted accordingly when co-administered with the following agents: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, valpromide, brivaracetam.

Medicinal products that may decrease plasma levels of carbamazepine.

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

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

Antineoplastic agents: cisplatin or doxorubicin.

Antituberculosis agents: rifampicin.

Bronchodilators or antiasthmatic agents: theophylline, aminophylline.

Dermatological agents: isotretinoin (alters bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; plasma concentration of carbamazepine should be monitored).

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

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

Effect of carbamazepine on plasma levels of concomitantly administered medicinal products.

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

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

Antibiotics: doxycycline, rifabutin.

Anticoagulants: oral anticoagulants (e.g., warfarin, phenprocoumon, dicoumarol, acenocoumarol). Concomitant use may lead to reduced concentrations of oral anticoagulants, increasing the risk of thrombosis. Therefore, if concomitant use is necessary, more careful monitoring of signs and symptoms of thrombosis is recommended.

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

Antiemetics: aprepitant.

Antiepileptic agents: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Both increased and decreased plasma levels of phenytoin have been reported with carbamazepine, as well as isolated cases of increased plasma levels of mefenytoin. In rare cases, this may lead to confusion or even coma.

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

Anthelmintics: praziquantel, albendazole.

Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.

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

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

Anxiolytics: alprazolam, midazolam.

Bronchodilators or antiasthmatic agents: theophylline.

Contraceptives: hormonal contraceptives (CYP3A4 substrates).

Carbamazepine is a strong inducer of CYP3A4. Carbamazepine may increase the metabolism of certain hormonal contraceptives (via induction of CYP3A4), such as oral and subdermal implanted contraceptives, leading to significantly lower hormone concentrations in plasma. This may result in contraceptive failure or breakthrough bleeding. Alternative methods to oral and subdermal implanted contraceptives, which are significantly affected by CYP3A4 induction, should be considered, or alternatives to carbamazepine should be evaluated (see sections "Special instructions" and "Use during pregnancy or breastfeeding").

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

Corticosteroids: prednisolone, dexamethasone.

Agents used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

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

Combinations of medicinal products requiring special consideration.

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

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

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

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

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

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

Contraindicated interactions.

Since carbamazepine is structurally similar to tricyclic antidepressants, it is not recommended to use it concomitantly with MAO inhibitors; treatment with an MAO inhibitor should be discontinued at least two weeks prior to starting carbamazepine (or earlier if clinically justified).

Treatment in combination with voriconazole may be ineffective.

Effect on serological tests.

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

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

Special precautions for use.

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

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

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

One should bear in mind the possibility of activation of latent psychosis, and in elderly patients, the possibility of anxiety, agitation, and exacerbation of confusion.

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.

Hematological effects. Agranulocytosis and aplastic anemia have been associated with the use of the drug. However, since such conditions occur very rarely, it is difficult to assess the significance of the risk. It is known that the overall risk of developing agranulocytosis in the general population not receiving carbamazepine treatment reaches 4.7 cases per 1 million population per year, and the risk of aplastic anemia is 2 cases per 1 million population per year.

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

If leukocyte or platelet counts significantly decrease during therapy, the patient should be monitored and complete blood counts should be regularly checked. Carbamazepine therapy should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical manifestations such as fever or sore throat. The drug should be discontinued if signs of bone marrow suppression occur.

Temporary 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 transient 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.

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 require hospitalization, as these conditions may be life-threatening and potentially fatal. Most cases of SJS/TEN occur within the first few months of carbamazepine treatment. If signs or symptoms suggestive of serious dermatological reactions (e.g., SJS, Lyell’s syndrome/TEN) develop, carbamazepine should be immediately discontinued and alternative therapy initiated.

Pharmacogenomics.

Increasing evidence indicates the influence of various HLA alleles on a patient's susceptibility to immune-related adverse reactions.

Association with (HLA)-B*1502

Retrospective studies in Han Chinese patients have demonstrated a strong correlation between carbamazepine-related skin reactions (SJS/TEN) and the presence of human leukocyte antigen (HLA) allele (HLA)-B*1502 in these patients. A higher frequency of reported SJS cases (rare to very rare) is typical for certain Asian countries (e.g., Taiwan, Malaysia, and the Philippines), where the (HLA)-B*1502 allele is prevalent in the population. The frequency of carriers of this allele among the Asian population is over 15% in the Philippines, Thailand, Hong Kong, and Malaysia, approximately 10% in Taiwan, nearly 4% in Northern China, approximately 2–4% in South Asia (including India), and less than 1% in Japan and Korea. The prevalence of the (HLA)-B*1502 allele is low among European 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 the drug. If the patient's test for (HLA)-B*1502 is positive, treatment should not be started unless no other therapeutic options are available. Patients who have been tested and found negative for (HLA)-B*1502 have a low risk of developing SJS, although such reactions may still very rarely occur.

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

The (HLA)-B*1502 allele may be a risk factor for SJS/TEN in Chinese patients receiving other antiepileptic drugs associated with SJS/TEN. Therefore, other drugs associated with SJS/TEN should be avoided in patients carrying the (HLA)-B*1502 allele if alternative therapy is available. Genetic screening of patients from ethnic groups with low (HLA)-B*1502 allele frequency is generally not performed, nor is it routinely performed in patients already receiving carbamazepine, since the risk of SJS/TEN is significantly limited to the first few months of treatment, regardless of the presence of the (HLA)-B*1502 allele in the patient's genes.

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

Association with HLA-A*3101

Human leukocyte antigen may be a risk factor for serious dermatological reactions such as SJS, TEN, drug reaction with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), and maculopapular rash. If testing reveals the presence of the HLA-A*3101 allele, the use of the drug should be avoided.

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 influence 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 difficult to distinguish from mild transient reactions, patients should be closely monitored so that the drug can be immediately discontinued if the reaction worsens with continued use.

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

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

The presence of the HLA-A*3101 allele in patients is associated with less severe adverse skin reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or mild rashes (maculopapular eruptions).

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

Cross-hypersensitivity may occur with the use of carbamazepine and phenytoin.

If signs and symptoms indicating hypersensitivity occur, the drug should be immediately discontinued.

Seizures. Carbamazepine should be used with caution in patients with mixed seizure types, including absences (typical or atypical). In such cases, carbamazepine may provoke seizures. If seizures are provoked, the drug should be immediately discontinued.

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

Liver function. Liver function should be assessed at baseline and periodically during therapy, especially in patients with a history of liver disease and in elderly patients. The drug should be immediately discontinued in patients with acute exacerbation of liver dysfunction or 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 hepatic metabolic activity is not an indication for carbamazepine discontinuation.

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

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

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

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

Anticholinergic effects. The drug exhibits moderate anticholinergic activity. Therefore, patients with elevated intraocular pressure or urinary retention should be closely monitored during therapy.

Psychiatric effects. One should consider the possibility of activation of latent psychosis, and in elderly patients, confusion or agitation.

Suicidal thoughts and behavior. There have been several reports of suicidal thoughts and behavior in patients receiving antiepileptic drugs. A meta-analysis of data from placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude an increased risk of suicidal thoughts and behavior with carbamazepine use. Therefore, patients should be evaluated for suicidal thoughts and behavior and, if necessary, appropriate treatment should be initiated. Patients (and caregivers) should be advised to consult a physician if signs of suicidal thoughts or behavior occur.

Endocrine effects. Due to hepatic enzyme induction, carbamazepine may reduce the therapeutic effect of estrogen and/or progesterone-containing drugs. This may lead to reduced contraceptive efficacy, symptom recurrence, breakthrough bleeding, or spotting. Women taking carbamazepine who require hormonal contraception should receive a preparation containing at least 50 mcg of estrogen, or alternative non-hormonal contraceptive methods should be considered.

Women of childbearing potential. Carbamazepine may harm the fetus when used during pregnancy.

Pregnancy registries and epidemiological data indicate a potential association between carbamazepine use during pregnancy and serious congenital malformations, including neural tube defects and malformations of other organ systems (e.g., craniofacial defects and cardiovascular malformations). These data suggest that teratogenic effects associated with antiepileptic drugs may be more prevalent with combination therapy compared to monotherapy.

Prenatal exposure to carbamazepine may increase the risk of serious congenital malformations and other adverse developmental outcomes.

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

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

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

Women of childbearing potential should use effective contraception during treatment and for two weeks after discontinuation. Due to enzyme induction, carbamazepine may impair the effectiveness of hormonal contraceptives; therefore, women of childbearing potential should consult their physician about using other effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or lactation").

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

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

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 levels may be useful in the following cases: sudden increase in seizure frequency, assessment of patient compliance, during pregnancy, in the treatment of children and adolescents, suspected malabsorption, suspected toxicity, and when using multiple drugs.

Dose reduction and drug discontinuation. Abrupt discontinuation of the drug may provoke seizures; therefore, carbamazepine should be tapered gradually over 6 months. If abrupt discontinuation is necessary, patients with epilepsy should be transitioned to a new antiepileptic drug while continuing appropriate therapy (e.g., intravenous or rectal diazepam, or intravenous phenytoin).

Important information on excipients.

This medicinal product contains sodium compounds; therefore, caution is advised when administering it to patients on a sodium-restricted diet.

Use during pregnancy or lactation.

Pregnancy.

General risk associated with antiepileptic drugs (AEDs). All women of childbearing potential taking antiepileptic therapy, especially those planning pregnancy and pregnant women, should be informed about the potential risk to the fetus from both seizures and AEDs.

Abrupt discontinuation of AEDs should be avoided, as it may lead to seizures, which can have serious consequences for the woman and the unborn child. If possible, monotherapy is preferred for epilepsy treatment during pregnancy, as treatment with multiple AEDs may be associated with a higher risk of congenital malformations.

Risks associated with carbamazepine.

Embryo-fetal toxicity. Carbamazepine may cause harm to the fetus when administered to a pregnant woman (see section "Special precautions for use"). Carbamazepine crosses the placental barrier. In animals, prenatal exposure to carbamazepine may increase the risk of congenital malformations and other adverse developmental outcomes. Exposure to carbamazepine during pregnancy is associated with a 2–3 times higher frequency of serious malformations compared to the general population (2–3%). Malformations reported include neural tube defects, craniofacial defects (e.g., cleft lip/palate), cardiovascular malformations, hypospadias, finger hypoplasia, and other anomalies) affecting various fetal organ systems in mothers who used carbamazepine during pregnancy. Specialized antenatal monitoring for these malformations is recommended. Neurodevelopmental disorders have been reported in children born to women with epilepsy who used carbamazepine alone or in combination with other AEDs during pregnancy. Available data suggest that teratogenic effects associated with anticonvulsant drugs may be more prevalent with combination therapy compared to monotherapy. Studies on the risk of neurodevelopmental disorders in children exposed to carbamazepine during pregnancy are conflicting, and the risk cannot be excluded.

According to study data, the risk of malformations with carbamazepine use may depend on the dose. If, after careful benefit/risk assessment, no alternative treatment option is suitable and carbamazepine treatment continues, monotherapy with the lowest effective carbamazepine dose should be used, and monitoring of its plasma levels is recommended.

Plasma concentration can be maintained in the lower part of the therapeutic range (4–12 mcg/mL), provided seizure control is maintained.

Unless a careful evaluation of alternative treatment options concludes that benefits outweigh risks, carbamazepine should not be used during pregnancy. The woman should be fully informed and understand the risks of taking carbamazepine during pregnancy.

Women of childbearing potential.

Carbamazepine should not be used in women of childbearing potential, except when the potential benefit outweighs risks compared to alternative treatment options.

Women who may become pregnant should be informed about the potential increased risk of serious congenital malformations with carbamazepine use during pregnancy; therefore, pregnancy planning in advance is important. The risks and benefits of using carbamazepine should be evaluated and discussed with the patient to determine whether alternative therapy should be considered. Before initiating carbamazepine therapy, a pregnancy test should be considered in women of childbearing potential. Women should use effective contraception during and for two weeks after discontinuation of treatment. Due to enzyme induction, carbamazepine may reduce the effectiveness of hormonal contraceptives; therefore, women should consult their physician about using other effective contraceptive methods. Women with reproductive potential should be advised to consistently use effective non-hormonal contraception or barrier methods during carbamazepine treatment (see sections "Interaction with other medicinal products and other forms of interaction"). At least one effective method of contraception (e.g., intrauterine device) or two additional forms of contraception, including a barrier method, should be used. The choice of contraceptive method should consider individual circumstances, with patient involvement in the discussion.

If a woman plans to become pregnant, all efforts should be made before conception and discontinuation of contraception to switch to appropriate alternative therapy. If a woman becomes pregnant while taking carbamazepine, she should be referred to a specialist to reassess the treatment method and consider alternative options.

In animal studies, carbamazepine use at clinically relevant doses during pregnancy resulted in fetal developmental toxicity, including increased incidence of fetal malformations.

Monitoring and prevention. Folate deficiency may occur during pregnancy. Antiepileptic drugs may increase the risk of folate deficiency; therefore, folic acid supplementation is recommended before and during pregnancy.

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

There have been several reports of seizures and/or respiratory depression in newborns, as well as cases of vomiting, diarrhea, and/or poor appetite in newborns associated with the use of the drug and other anticonvulsant medications.

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

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

Ability to affect reaction speed when driving or operating machinery.

The patient's ability to react quickly (especially at the beginning of therapy or during dose titration) may be impaired due to dizziness and drowsiness; therefore, patients should exercise caution when driving or operating machinery.

Method of Administration and Dosage

Carbamazepine should be administered orally; the daily dose of the medicinal product should be divided into 2–3 doses. The medicinal product can be taken independently of food intake, swallowing with a small amount of liquid, for example, a glass of water.

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

Epilepsy

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

Determining the plasma carbamazepine concentration may be helpful in establishing the optimal dose of the medicinal product. Especially in cases of combination therapy, therapeutic doses should be determined based on plasma carbamazepine levels and treatment efficacy.

Adults: the recommended initial dose of the medicinal product is 100–200 mg once or twice daily. The dose should then be gradually increased until the optimal effect is achieved. The daily dose often reaches 800–1200 mg. Some patients may require a dose of up to 1600 mg or even 2000 mg per day.

Elderly patients: due to the possibility of drug interactions, the dose of the medicinal product should be carefully selected in elderly patients.

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

The usual dose of the medicinal product is 10–20 mg/kg body weight per day (administered in several doses).

Child's age	Daily dose
5−10 years	400−600 mg (in 2−3 doses)
10−15 years	600−1000 mg (in 2−5 doses)

For children aged 15 years and older – dosage as in adults.

Carbamazepine should preferably be administered as monotherapy; however, when used concomitantly with other medicinal products, a gradual dose escalation regimen as described below is recommended.

When carbamazepine is added to ongoing antiepileptic therapy, the dose should be gradually increased without altering the dose of the current antiepileptic drug(s), or with dose adjustment if necessary.

Acute manic episodes and maintenance therapy in bipolar affective disorders
Dosage range: 400 to 1600 mg per day; usually 400 to 600 mg per day, divided into 2–3 doses. For acute mania, a relatively rapid dose escalation is recommended, whereas for optimal tolerability during maintenance therapy in bipolar disorders, gradual dose escalation in small increments is advised.

Alcohol withdrawal syndrome
Average dose: 200 mg three times daily. In severe cases, the dose may be increased during the first few days (up to 400 mg three times daily). In severe alcohol withdrawal, treatment should be initiated with a combination of the medicinal product and sedative-hypnotic agents (e.g., clomethiazole, chlordiazepoxide), following the dosage recommendations above. After resolution of the acute phase, the medicinal product may be continued as monotherapy.

Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical). Idiopathic glossopharyngeal neuralgia
Initial dose: 200–400 mg per day (100 mg twice daily for elderly patients). The dose should be slowly increased until pain subsides (usually to 200 mg three to four times daily). For most patients, a dose of 200 mg three to four times daily is sufficient to maintain a pain-free state. In some cases, a daily dose of up to 1600 mg may be required. After pain relief is achieved, the dose should be gradually reduced to the minimum effective maintenance dose.

Children

Due to faster elimination of carbamazepine in children, higher doses (on a mg/kg basis) may be required compared to adults.

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

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

Carbamazepine-Darnytsia tablets may be administered to children aged 5 years and older.

Overdose.

Symptoms. Signs and symptoms of overdose typically reflect central nervous system (CNS), cardiovascular, and respiratory system involvement.

CNS: CNS depression; confusion, depressed level of consciousness, drowsiness, agitation, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (early), hyporeflexia (later), seizures, psychomotor disturbances, myoclonus, hypothermia, mydriasis.

Respiratory system: Respiratory depression, pulmonary edema.

Cardiovascular system: Tachycardia, arterial hypotension, occasionally arterial hypertension, conduction disturbances with QRS complex widening; syncope associated with cardiac arrest, accompanied by loss of consciousness.

Gastrointestinal tract: Vomiting, gastric retention, reduced colonic motility.

Musculoskeletal system: Isolated cases of rhabdomyolysis associated with toxic effects of carbamazepine have been reported.

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

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

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

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

Special recommendations. In case of arterial hypotension, intravenous dopamine or dobutamine should be administered; in case of cardiac arrhythmias, treatment should be individually tailored; in case of seizures, benzodiazepines (e.g., diazepam) or other anticonvulsants such as phenobarbital (with caution due to increased risk of respiratory depression) or paraldehyde should be administered; in case of hyponatremia (water intoxication), fluid intake should be restricted and cautious slow intravenous infusion of 0.9% sodium chloride solution should be performed. These measures may help prevent cerebral edema.

Hemoperfusion using charcoal sorbents is recommended. Forced diuresis and peritoneal dialysis have been reported as ineffective.

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

Adverse Reactions

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

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

Adverse reactions are listed according to the following frequency categories: 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; not known (frequency cannot be estimated from available data).

Eye disorders: very rare – accommodation disorders (e.g., blurred vision), lens opacity, conjunctivitis, increased intraocular pressure.

Ear and labyrinth disorders: very rare – hearing disturbances, such as tinnitus, increased or decreased hearing sensitivity, impaired perception of sound pitch.

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

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

Hepatobiliary disorders: very common – increased levels of gamma-glutamyl transferase (GGT) (due to induction of liver enzymes), which is usually clinically insignificant; common – increased alkaline phosphatase levels in blood; uncommon – increased transaminase levels; rare – cholestatic, parenchymal (hepatocellular), or mixed-type hepatitis, bile duct disappearance syndrome, jaundice; very rare – granulomatous hepatitis, hepatic failure.

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

Endocrine disorders: common – edema, fluid retention, weight gain, hyponatremia and decreased plasma osmolality due to an antidiuretic hormone-like effect, which in isolated cases may lead to hyperhydration accompanied by lethargy, vomiting, headache, confusion, and neurological disturbances; very rare – increased blood prolactin levels, with or without manifestations such as galactorrhea, gynecomastia, disturbances in bone metabolism (decreased plasma calcium and 25-hydroxycholecalciferol levels), leading to osteomalacia/osteoporosis; isolated cases – increased cholesterol concentration, including high-density lipoprotein cholesterol and triglycerides.

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

Nervous system disorders: very common – dizziness, ataxia, somnolence, general weakness, lethargy; common – headache, diplopia, accommodation disorders (e.g., blurred vision); uncommon – abnormal involuntary movements (e.g., tremor, "fluttering" tremor, dystonia, twitching), nystagmus; rare – orofacial dyskinesia, eye movement disorders, speech disturbances (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness, and paresis; very rare – taste disturbances, malignant neuroleptic syndrome, aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia.

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

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

Blood and lymphatic system disorders: very common – leukopenia; common – thrombocytopenia, eosinophilia; rare – leukocytosis, lymphadenopathy, folic acid deficiency; very rare – agranulocytosis, aplastic anemia, pancytopenia, erythroblastic aplasia, anemia, megaloblastic anemia, acute intermittent porphyria, mixed 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, altered liver function tests, and bile duct disappearance syndrome (destruction and loss of intrahepatic bile ducts), occurring in various combinations. Other organs may also be affected (e.g., liver, lungs, kidneys, pancreas, myocardium, colon); very rare – aseptic meningitis with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioneurotic edema, hypogammaglobulinemia.

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, photosensitivity, erythema multiforme, nodular erythema, hyperemia, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism.

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

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

General disorders and administration site conditions: very common – general weakness.

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

Adverse reactions based on spontaneous reports (frequency unknown)

The following adverse reactions have been reported during post-marketing use of the medicinal product from spontaneous reports and literature sources. As these reports are spontaneous, it is not possible to determine the exact number of affected patients or reliably estimate the frequency of occurrence; therefore, their frequency is classified as "not known."

Infections and infestations: reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: bone marrow failure.

Nervous system disorders: sedative effect, memory impairment.

Gastrointestinal disorders: colitis.

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

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

Musculoskeletal disorders: fractures.

Investigations: decreased bone mineral density.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister pack; 2 or 5 blisters per carton.

Prescription category. Prescription only.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and location of business activity.

13, Borispilska Street, Kyiv, 02093, Ukraine.