Carbamazepine-zdorovya forte

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT KARBAZEPIN-ZDOROV'YA FORTE

Composition:

Active substance: 1 tablet contains carbamazepine 400 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, copovidone, povidone, sodium croscarmellose, calcium stearate, sodium lauryl sulfate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or almost white tablets, flat cylindrical, with a score line and chamfer.

Pharmacotherapeutic group. Antiepileptic drugs. Carboxamide derivatives. ATC code N03A F01.

Pharmacological Properties

Pharmacodynamics. As an anticonvulsant: the drug's spectrum of activity as an antiepileptic agent includes partial seizures (simple and complex), with or without secondary generalization; generalized tonic-clonic seizures; as well as combinations of these seizure types.

The mechanism of action of carbamazepine—the active ingredient of the drug—is only partially understood. Carbamazepine stabilizes overexcited nerve membranes, inhibits the generation of repetitive neuronal discharges, and reduces synaptic transmission of excitatory impulses. The primary mechanism of action is likely prevention of repetitive sodium-dependent action potentials in depolarized neurons through use- and voltage-dependent blockade of sodium channels.

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

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

As a neurotropic agent, the drug is effective in certain neurological disorders. For example, it prevents painful attacks in idiopathic and secondary trigeminal neuralgia. Additionally, the drug is used to relieve neuropathic pain in various conditions, including spinal cord sclerosis, post-traumatic paresthesia, and postherpetic neuralgia. In alcohol withdrawal syndrome, the drug 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.

It has been confirmed that as a psychotropic agent, the drug is effective in affective disorders, specifically: for treatment of acute manic states and for maintenance therapy of bipolar affective (manic-depressive) disorders (either as monotherapy or in combination with neuroleptics, antidepressants, or lithium preparations).

Pharmacokinetics. After oral administration, carbamazepine is almost completely absorbed, although somewhat slowly. Following a single dose of the conventional tablet, C_max in plasma is reached after approximately 12 hours. There are no clinically significant differences in the extent of absorption of the active ingredient after administration of various oral dosage forms of carbamazepine. After a single 400 mg oral dose of the drug, the mean C_max of unchanged active substance reaches approximately 4.5 µg/mL.

Bioavailability of various oral formulations of carbamazepine has been shown to range between 85% and 100%.

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 dosage, and duration of treatment. There are substantial interindividual differences 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 nearly 30% of carbamazepine concentrations.

Bioavailability of different carbamazepine products may vary; this property necessitates avoiding changes in the dosage form, which could lead to reduced therapeutic effect, increased risk of epileptic seizures, or excessive adverse effects.

With complete absorption, the apparent 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%. Concentrations of unchanged carbamazepine in cerebrospinal fluid and saliva are proportional to the unbound fraction of the active substance (20–30%). Carbamazepine concentrations in breast milk amount to 25–60% of its plasma levels.

Carbamazepine is primarily metabolized in the liver via the epoxide pathway, resulting in the formation of major metabolites—the 10,11-trans-diol derivative and its glucuronic acid conjugate. The main isoenzyme responsible for biotransformation of carbamazepine into carbamazepine-10,11-epoxide is cytochrome P450 3A4. 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).

After a single oral dose, the half-life (T_½) of unchanged carbamazepine averages 36 hours; after repeated administration, it averages 16–24 hours (due to autoinduction of hepatic monoxygenase systems), depending on the duration of treatment. In patients concurrently taking other drugs that induce the same hepatic enzyme system (e.g., phenytoin, phenobarbital), the T_½ of carbamazepine averages 9–10 hours.

The mean T_½ of the 10,11-epoxide metabolite in 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. Approximately 2% of the administered dose is excreted unchanged in urine, and about 1% as the pharmacologically active 10,11-epoxide metabolite.

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 differ in elderly patients compared to younger adults.

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

Clinical characteristics.

Indications.

• 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.

The drug 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 an episode.
• Alcohol withdrawal syndrome.
• Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical forms).
• Idiopathic glossopharyngeal neuralgia.

Contraindications. The drug should not be prescribed:

• in cases of known hypersensitivity to carbamazepine or to structurally related medicinal products (such as tricyclic antidepressants), or to any other component of the drug;
• 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 concentrations 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, and thus may reduce plasma concentrations of other drugs that are primarily metabolized via CYP3A4 by inducing their metabolism.

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

Medicinal products that may increase carbamazepine plasma levels. Since elevated plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), dosage adjustment and/or monitoring of plasma levels is required when co-administered with the following drugs:

Analgesics, anti-inflammatory agents: dextropropoxyphene, ibuprofen.

Androgens: danazol.

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

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

Antiepileptic agents: stiripentol, vigabatrin.

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

Antihistamines: loratadine, terfenadine.

Antipsychotic agents: olanzapine, loxapine, quetiapine.

Antituberculosis agents: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular agents: diltiazem, verapamil.

Drugs 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 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 and/or monitoring of plasma levels is required when the drug is co-administered with the following agents:

Antipsychotics: loxapine, quetiapine.

Antiepileptic agents: primidone, progabide, valproic acid, valnoctamide, valpromide, brivaracetam.

Medicinal products that may decrease carbamazepine plasma levels. Dose adjustment of the drug may be necessary when co-administered with the following medicinal products:

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

Antineoplastic agents: cisplatin or doxorubicin.

Antituberculosis agents: rifampicin.

Bronchodilators or antiasthmatic agents: theophylline, aminophylline.

Dermatological agents: isotretinoin.

Interaction with other substances: herbal medicinal products containing St. John’s wort.

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

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

Effect of the drug on plasma levels of concomitantly administered medicinal products. Carbamazepine may reduce plasma levels of certain drugs and diminish or nullify their effects. Dose adjustment of the following drugs may be necessary according to clinical requirements.

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

Antibiotics: doxycycline, rifabutin.

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

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 increases and decreases in plasma phenytoin levels have been reported with carbamazepine, as well as isolated cases of increased plasma levels of mephenytoin.

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.

Neuroleptic agents: 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 (alternative methods of contraception should be considered).

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

Corticosteroids: particularly prednisolone, dexamethasone.

Agents used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

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

Combinations requiring special consideration. Concomitant use of carbamazepine and levetiracetam may increase carbamazepine toxicity.

Concomitant use of carbamazepine and isoniazid may increase isoniazid hepatotoxicity.

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

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

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

Contraindicated interaction. Since carbamazepine is structurally similar to tricyclic antidepressants, it is not recommended to use the drug concomitantly with MAO inhibitors; administration of an MAO inhibitor must be discontinued at least two weeks prior to starting the drug (or earlier, if clinically appropriate).

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

Carbamazepine and 10,11-epoxide may produce false-positive results in immunoassays using fluorescence polarization methodology for the detection of tricyclic antidepressants.

Special precautions for use.

The drug should be prescribed only under medical supervision, only after assessment 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) level determination at the beginning and periodically during therapy.

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

One should bear in mind the possibility of activation of latent psychoses, and in elderly patients – the possibility of activation of confusion and anxious agitation.

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, due to the extremely low frequency of these conditions, it is difficult to assess the significant risk of their development during drug administration. The overall risk in patients who have not received prior therapy is 4.7 cases per 1,000,000 per year for agranulocytosis and 2 cases per 1,000,000 per year for aplastic anemia.

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's condition should be carefully monitored and regular complete blood counts should be performed. Treatment with the drug 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 upon signs of bone marrow suppression.

Temporary or persistent reduction in platelet or white blood cell counts may occur periodically or frequently due to drug intake. 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 the start of therapy and periodically during treatment.

Serious dermatological reactions. Serious dermatological reactions, including Lyell's syndrome (LS) and Stevens-Johnson syndrome (SJS), occur very rarely with the use of the drug. Patients with serious dermatological reactions may require hospitalization, as these conditions can be life-threatening and fatal. Most cases of SJS/LS occur within the first few months of treatment. If signs and symptoms suggestive of serious dermatological reactions (e.g., SJS, LS) develop, the drug should be immediately discontinued and alternative therapy initiated.

Pharmacogenomics. Increasing evidence indicates the influence of different HLA alleles on patient susceptibility to immune-related adverse reactions.

Association with (HLA)-B*1502. Data from retrospective studies in Han Chinese patients have demonstrated a strong correlation between carbamazepine-related skin reactions (SJS/LS) and the presence of human leukocyte antigen (HLA) allele (HLA)-B*1502 in these patients. A higher frequency of SJS reports (rare rather than very rare) is characteristic of certain Asian countries (e.g., Taiwan, Malaysia, and the Philippines), where the (HLA)-B*1502 allele is prevalent in the population. The carrier frequency of this allele among Asian populations is over 15% in the Philippines, Thailand, Hong Kong, and Malaysia; approximately 10% in Taiwan; nearly 4% in Northern China; approximately 2% to 4% in South Asia (including India); and less than 1% in Japan and Korea. The prevalence of the (HLA)-B*1502 allele is low among European and African populations, indigenous peoples of America, and Latin American populations.

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

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

The (HLA)-B*1502 allele may be a risk factor for SJS/LS in Chinese patients receiving other antiepileptic drugs associated with SJS/LS. Therefore, other drugs associated with SJS/LS should be avoided in patients carrying the (HLA)-B*1502 allele if alternative therapy is available. Genetic screening is generally not recommended in patient populations with a low frequency of the (HLA)-B*1502 allele. Screening is generally not recommended in patients already receiving the drug, as the risk of SJS/LS 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 the development of skin adverse reactions such as SJS, LS, DRESS, AGEP, and maculopapular eruptions. 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 regimen, and concomitant therapy, 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. Transient and non-life-threatening mild dermatological reactions, such as isolated macular or maculopapular exanthema, may also occur. These usually resolve within several 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, the patient should be closely monitored so that drug administration 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 anticonvulsant hypersensitivity syndrome or mild rashes (maculopapular eruptions). However, the presence of (HLA)-B*1502 has not been shown to indicate a risk of the aforementioned skin reactions.

Hypersensitivity. The drug may provoke hypersensitivity reactions, including 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), 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 have hypersensitivity reactions to oxcarbazepine.

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

In general, if signs and symptoms suggestive of hypersensitivity occur, the use of the drug should be immediately discontinued.

Seizures. The drug should be used with caution in patients with mixed seizure types, including absence seizures (typical or atypical). Under such circumstances, the drug may provoke seizures. If seizures are provoked, the use of the drug should be immediately discontinued.

An increase in seizure frequency may occur during the transition from oral formulations of the drug 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. In case of acute liver function deterioration or in patients with active liver disease, the drug should be immediately discontinued.

Some laboratory parameters used to assess liver function may be outside the normal range in patients taking carbamazepine, particularly gamma-glutamyl transferase. This is likely due to induction of liver enzymes. Enzyme induction may also lead to a moderate increase in alkaline phosphatase levels. Such an increase in functional activity of hepatic metabolism is not an indication for carbamazepine discontinuation.

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

Renal function. Assessment of renal function and blood urea nitrogen (BUN) level determination are recommended at the beginning and periodically during the course of therapy.

Hyponatremia. Cases of hyponatremia development with carbamazepine use are known. In patients with pre-existing renal dysfunction associated with low sodium levels, or in patients receiving concomitant treatment with drugs that reduce sodium levels (such as diuretics, drugs associated with inadequate antidiuretic hormone secretion), serum sodium levels should be measured before treatment. Subsequently, sodium levels should be measured every 2 weeks, then monthly during the first 3 months of treatment or according to clinical necessity. This particularly applies to elderly patients. 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. The drug exhibits moderate anticholinergic activity. Thus, patients with elevated intraocular pressure and urinary retention should be closely monitored during therapy.

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

Suicidal thoughts and behavior. Several reports of suicidal thoughts and behavior have been recorded in patients receiving antiepileptic drugs. Information from a meta-analysis of data obtained 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.

Therefore, patients should be monitored for suicidal thoughts and behavior, and appropriate treatment should be initiated if necessary. Patients (and caregivers) should be advised to consult a physician if signs of suicidal thoughts and behavior appear.

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

Women of childbearing potential. Carbamazepine may harm the fetus when administered to a pregnant woman. Prenatal exposure to carbamazepine may increase the risk of serious congenital malformations and other adverse outcomes (see section "Use during pregnancy or breastfeeding. Pregnancy. Breastfeeding. Fertility").

If, after careful consideration of alternative treatment options, the benefit of using carbamazepine does not outweigh the potential 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 treatment, a pregnancy test should be considered in women of childbearing age.

Women of childbearing potential must use effective 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 age should consult regarding the use of other effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or breastfeeding. Pregnancy. Breastfeeding. Fertility").

Women of childbearing potential should consult their physician as soon as pregnancy is planned to discuss switching to alternative treatment before conception and discontinuation of contraception (see section "Use during pregnancy or breastfeeding. Pregnancy. Breastfeeding. Fertility").

Women of childbearing potential should be advised to immediately consult a physician if pregnancy occurs or if they 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 drug levels may be useful in the following cases: sudden increase in seizure frequency, checking patient compliance, during pregnancy, in the treatment of children and adolescents; in suspected absorption impairment, suspected toxicity, and when multiple drugs are used.

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

If a patient has intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy.

General risk associated with the use of antiepileptic medicinal products (AEDs).

All women of childbearing potential receiving antiepileptic therapy, and especially women planning pregnancy and pregnant women, should receive medical counseling regarding the potential risk to the fetus from seizures and from the use of antiepileptic medicinal products.

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

If possible, monotherapy is preferred for the treatment of epilepsy during pregnancy, as therapy with multiple AEDs may be associated with a higher risk of congenital malformations.

Risks associated with carbamazepine.

Carbamazepine crosses the placental barrier. Prenatal exposure to carbamazepine may increase the risks of congenital malformations and other adverse developmental outcomes. Exposure to carbamazepine during pregnancy is associated with a 2–3 times higher frequency of serious developmental defects compared to the general population, where the frequency is 2–3%. Such developmental defects as neural tube defects in the fetus, craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, hypoplasia of fingers, and other anomalies affecting various organ systems in children born to mothers who used carbamazepine during pregnancy have been reported. Specialized antenatal monitoring for these developmental defects is recommended. Neurodevelopmental disorders have been reported among children born to women with epilepsy who used carbamazepine alone or in combination with other AEDs during pregnancy. Studies on the risk of neurodevelopmental disorders in children exposed to carbamazepine during pregnancy are conflicting, and the risk cannot be excluded.

If, after careful consideration of alternative treatment options, the benefit does not outweigh the risks, carbamazepine should not be used during pregnancy. The woman should be fully informed and understand the risks of taking carbamazepine during pregnancy.

Data indicate that the risk of developmental defects with carbamazepine use may be dose-dependent. If, based on a careful benefit/risk assessment, no alternative treatment option is suitable and carbamazepine therapy is continued, monotherapy with carbamazepine at the lowest effective dose should be used, and plasma level monitoring should be performed. Plasma concentration can be maintained in the lower part of the therapeutic range of 4 to 12 µg/mL, provided seizure control is maintained.

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

If a woman plans to become pregnant, all efforts should be made before conception and before discontinuation of contraception to switch to appropriate alternative treatment. 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 animals, oral administration of carbamazepine caused developmental defects.

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. Mothers receiving the drug 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.

Women of childbearing potential.

Carbamazepine should not be used in women of childbearing potential except when the potential benefit of carbamazepine use outweighs the potential risk compared to alternative treatment options. The woman should be fully informed and understand the potential risk to the fetus if carbamazepine is taken during pregnancy; therefore, pregnancy planning in advance is important. Before initiating carbamazepine treatment, the possibility of performing a pregnancy test should be considered in women of childbearing potential.

Women of childbearing potential must use effective contraception during and for two weeks after discontinuation of treatment. Due to enzyme induction, carbamazepine may impair the therapeutic effect of hormonal contraceptives (see section "Interaction with other medicinal products and other forms of interaction"); therefore, women of childbearing potential should consult regarding the use of other effective contraceptive methods. At least one effective method of contraception (e.g., intrauterine) or two additional forms of contraception, including a barrier method, should be used. The choice of contraceptive method should consider individual circumstances, with patient involvement in the discussion.

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

Method of administration|use| and dosage. The drug is administered orally; the daily dose is usually divided into two or three administrations. The drug can be taken during, after meals, or between meals with a small amount of liquid, e.g., a glass of water.

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

For dosing requirements of 100 mg, Carbamazepine-Zdorovya should be used.

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

Determining the plasma carbamazepine level may be helpful in selecting the optimal drug dosage.

Especially in combination therapy, therapeutic doses should be calculated based on plasma carbamazepine levels and efficacy.

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

Elderly patients: In elderly patients, the drug dose should be carefully selected due to possible drug interactions.

Children: Treatment may be initiated with 100 mg/day; the dose should be gradually increased by 100 mg each week.

The usual drug dose 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, the dosage is the same as for adults.

If possible, the drug should be administered as monotherapy; however, when used concomitantly with other medicinal products, a gradual dose escalation regimen is recommended.

When adding the drug to ongoing antiepileptic therapy, the dose should be gradually increased without changing the dose of the currently used antiepileptic drug(s), or adjusting it if necessary.

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

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

Idiopathic trigeminal neuralgia and trigeminal neuralgia in multiple sclerosis (typical and atypical). Idiopathic glossopharyngeal neuralgia. The initial dose is 200–400 mg per day (100 mg twice daily for elderly patients). The dose should be slowly increased until pain relief is achieved (usually to a dose of 200 mg three to four times daily). For most patients, a dose of 200 mg three or 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 a faster elimination of carbamazepine, children may require higher doses of the drug (on a per-kilogram basis) compared to adults. The drug may be administered to children aged 5 years and older.

Overdose.

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

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

Respiratory system: Respiratory depression, pulmonary edema.

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

Gastrointestinal tract: Vomiting, gastric retention, decreased motility of the large intestine.

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

Urinary system: Urinary retention, oliguria or anuria, fluid retention; hyperhydration caused by the antidiuretic hormone-like effect of carbamazepine.

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

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

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

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

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

The possibility of recurrent worsening of overdose symptoms on the 2nd and 3rd day after ingestion should be anticipated, due to delayed absorption of the drug.

Adverse Reactions

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

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

Blood and lymphatic system disorders: leucopenia, thrombocytopenia, eosinophilia, leukocytosis, lymphadenopathy, folic acid deficiency, agranulocytosis, aplastic anemia, pancytopenia, erythrocyte aplasia, anemia, megaloblastic anemia, acute intermittent porphyria, mixed porphyria, late cutaneous porphyria, reticulocytosis, hemolytic anemia, bone marrow failure.

Immune system disorders: multiorgan hypersensitivity of delayed type with fever, skin rashes, vasculitis, lymphadenopathy; lymphoma-like signs; arthralgia, leucopenia, eosinophilia, hepatosplenomegaly, altered liver function tests, and vanishing bile duct syndrome (destruction and disappearance of intrahepatic bile ducts), occurring in various combinations. Involvement of other organs (e.g., liver, lungs, kidneys, pancreas, myocardium, colon) may occur; aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactic reaction, angioneurotic edema, hypogammaglobulinemia, drug reaction with eosinophilia and systemic symptoms (DRESS).

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

Metabolism and nutrition disorders: folate deficiency, decreased appetite, acute porphyria (acute intermittent porphyria and mixed porphyria), non-acute porphyria (late cutaneous porphyria), hyperammonemia.

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

Nervous system disorders: dizziness, ataxia, somnolence, general weakness, headache, diplopia, visual accommodation disorders (e.g., blurred vision), abnormal involuntary movements (e.g., tremor, “flapping” tremor, dystonia, tics), nystagmus, orofacial dyskinesia, eye movement disorders, speech disturbances (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness and paresis, taste disturbances, malignant neuroleptic syndrome, aseptic meningitis with myoclonia and peripheral eosinophilia, dysgeusia, sedative effect, memory impairment.

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

Ear and labyrinth disorders: hearing disorders, e.g., tinnitus, increased auditory sensitivity, decreased hearing sensitivity, disturbances in pitch perception.

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

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

Gastrointestinal disorders: nausea, vomiting, dry mouth, diarrhea or constipation, abdominal pain, glossitis, stomatitis, pancreatitis, colitis.

Hepatobiliary disorders: increased gamma-glutamyltransferase levels (due to hepatic enzyme induction), usually not clinically significant; increased alkaline phosphatase levels in blood; increased transaminase levels; hepatitis of cholestatic, parenchymal (hepatocellular), or mixed type; vanishing bile duct syndrome, jaundice, granulomatous hepatitis, liver failure.

Skin and subcutaneous tissue disorders: allergic dermatitis, urticaria, sometimes in severe forms; exfoliative dermatitis, erythroderma, systemic lupus erythematosus, pruritus, Stevens-Johnson syndrome (reported in some Asian countries as a "rare" adverse event), toxic epidermal necrolysis, photosensitivity, erythema multiforme, nodular erythema, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism, acute generalized exanthematous pustulosis (AGEP), lichenoid keratosis, onycomadesis.

Musculoskeletal and connective tissue disorders: muscle weakness, arthralgia, myalgia, muscle cramps, disturbances in bone metabolism (decreased plasma levels of calcium and 25-hydroxycholecalciferol), leading to osteomalacia/osteoporosis, fractures.

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

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

General disorders: very common – general weakness.

Infections and infestations: reactivation of human herpesvirus type 6.

Laboratory and diagnostic test abnormalities: increased gamma-glutamyltransferase levels (due to induction of hepatic enzymes), usually not clinically significant; increased blood alkaline phosphatase, transaminase levels, intraocular pressure; increased blood cholesterol levels, increased high-density lipoprotein levels, increased blood triglyceride levels; changes in thyroid function tests: decreased levels of L-thyroxine (FT4, T4, T3) and increased thyroid-stimulating hormone levels, which usually do not manifest clinically; increased blood prolactin levels, hypogammaglobulinemia, decreased bone mineral density.

Shelf life. 2 years.

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

Keep out of reach of children.

Packaging. Tablets 400 mg, 10×5 in blisters in a box.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Limited Liability Company "FARMEKS GROUP".

Manufacturer's address and location of business activity. Ukraine, 61013, Kharkiv region, Kharkiv, Shevchenka St., 22.

(LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA")

Ukraine, 08301, Kyiv region, Boryspil, Shevchenka St., 100.

(Limited Liability Company "FARMEKS GROUP")