Carbamazepine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CARBAMAZEPINE (CARBAMAZEPINE)

Composition:

Active substance: carbamazepine;

1 tablet contains 200 mg of carbamazepine;

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

Pharmaceutical form. Tablets.

Main physico-chemical properties: single-layer, round-shaped tablets with flat upper and lower surfaces and beveled edges, with a score line, white or white with a yellowish tinge. When broken, a relatively homogeneous structure is visible under magnification.

Pharmacotherapeutic group. Antiepileptic drugs. Carbamazepine.

ATC code N03AF01.

Pharmacological Properties.

Pharmacodynamics.

As an anticonvulsant agent. The antiepileptic activity spectrum of carbamazepine 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 carbamazepine—is only partially understood. Carbamazepine stabilizes overexcited nerve membranes, inhibits repetitive neuronal firing, and reduces synaptic transmission of excitatory impulses. The primary mechanism of action may involve prevention of repetitive sodium-dependent action potentials in depolarized neurons by voltage- and use-dependent blockade of sodium channels.

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

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

As a neurotropic 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 tabes, post-traumatic paresthesias, and postherpetic neuralgia. In alcohol withdrawal syndrome, carbamazepine increases the seizure threshold (which is lowered in this condition) and reduces the severity of clinical symptoms such as agitation, tremor, and gait disturbances. In patients with central diabetes insipidus, carbamazepine reduces diuresis and thirst.

As a psychotropic agent, carbamazepine is effective in affective disorders, specifically: treatment of acute manic states, and maintenance therapy of bipolar affective (manic-depressive) disorders (as monotherapy, as well as in combination with neuroleptics, antidepressants, or lithium salts).

Pharmacokinetics.

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

The bioavailability of various oral formulations of carbamazepine has been shown to range between 85–100%.

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, dosage, and duration of treatment. Substantial interindividual variability in steady-state concentrations within the therapeutic range is observed: 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 nearly 30% of carbamazepine concentrations.

The bioavailability of different carbamazepine products may vary; this property necessitates avoiding changes in the dosage form, which could lead to reduced efficacy, occurrence of epileptic seizures, or excessive adverse effects.

Distribution. 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 concentration in breast milk ranges from 25–60% of its plasma levels.

Metabolism. Carbamazepine is primarily metabolized in the liver via the epoxide pathway, resulting in the formation of major metabolites—10,11-trans-diol derivative and its glucuronic acid conjugate. The main 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, as well as 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 administration, it averages 16–24 hours (due to autoinduction of hepatic mono-oxygenase systems), depending on treatment duration. In patients concurrently receiving other drugs that induce the same hepatic enzyme system (e.g., phenytoin, phenobarbital), the half-life of carbamazepine averages 9–10 hours.

The average elimination half-life of the 10,11-epoxide metabolite from plasma is approximately 6 hours after a single oral dose of the epoxide.

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 in urine as unchanged drug, and about 1% 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 (on a mg/kg basis) 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 seizure types.

Carbamazepine may be used as monotherapy or as part of combination therapy.

• Acute manic episodes; 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.

Should not be prescribed:

• in patients with known hypersensitivity to carbamazepine or to structurally related medicinal products (such as tricyclic antidepressants), or to any other component of the drug;
• in patients with atrioventricular block;
• in patients with a history of bone marrow depression;
• in patients with hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria) in medical history;
• in combination with monoamine oxidase inhibitors (MAO inhibitors).

Interaction with other medicinal products and other forms of interaction.

Cytochrome P450 3A4 (CYP3A4) is the main enzyme catalyzing the formation of the active metabolite of carbamazepine—10,11-epoxide. Concomitant use of CYP3A4 inhibitors may increase plasma concentrations of carbamazepine, which in turn may lead to adverse reactions. Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, resulting in decreased serum concentrations of carbamazepine and reduced 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 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.

Drugs that may increase plasma levels of carbamazepine.

Since elevated plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), dosage adjustment of carbamazepine and/or monitoring of its plasma levels should be performed when used concomitantly 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.

Agents for gastrointestinal disorders: cimetidine, omeprazole.

Muscle relaxants: oxybutynin, dantrolene.

Antiplatelet agents: ticlopidine.

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

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

Since elevated plasma levels of carbamazepine-10,11-epoxide may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), the dose of carbamazepine should be adjusted accordingly and/or its plasma levels monitored when used concomitantly with the following substances.

Antipsychotic agents: loxapine, quetiapine.

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

Drugs that may decrease plasma levels of carbamazepine.

Dosage adjustment of carbamazepine may be necessary when used concomitantly with the following drugs.

Antiepileptic agents: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic carbamazepine concentrations, it is recommended to adjust phenytoin plasma concentrations 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 products containing St. John’s wort (Hypericum perforatum).

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

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

Effect of carbamazepine on plasma levels of concomitantly administered drugs.

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

Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol (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 increased and decreased plasma levels of phenytoin have been reported with carbamazepine, as well as isolated cases of increased plasma levels of mefenytin.

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

Antihelminthic agents: 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 (e.g., prednisolone, dexamethasone).

Agents used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.

Thyroid agents: levothyroxine.

Interaction with other drugs: 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 carbamazepine with neuroleptics (haloperidol, thioridazine), may increase the risk of neurological side effects (even at therapeutic plasma levels in the latter combination).

Combined 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 drugs, may reduce tolerance to alcohol; patients are advised to avoid alcohol consumption.

Concomitant use is contraindicated.

Since carbamazepine is structurally similar to tricyclic antidepressants, it should not be used concomitantly with monoamine oxidase inhibitors (MAO inhibitors). Treatment with an MAO inhibitor should be discontinued at least two weeks (or earlier, if clinically feasible) before starting carbamazepine.

Effect on serological tests.

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

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

Special precautions for use.

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

It is recommended to perform urinalysis and blood urea nitrogen determination 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 psychoses, and in elderly patients – the possibility of activation of confusion and anxious agitation.

The drug is generally ineffective in absence seizures (petit mal) and myoclonic seizures. Individual cases indicate that seizure exacerbation may occur in patients with atypical absences.

Haematological effects. Agranulocytosis and aplastic anaemia have been associated with the use of carbamazepine; however, due to the extremely low frequency of these conditions, it is difficult to assess the actual risk of carbamazepine use. For untreated patients, the overall risk of agranulocytosis is 4.7 cases per 1,000,000 per year, and of aplastic anaemia – 2 cases per 1,000,000 per year.

Patients should be informed about early signs of toxicity and symptoms of possible haematological disorders, as well as symptoms of dermatological and hepatic reactions. The patient should be warned that if any of the following reactions occur – fever, angina, skin rashes, oral ulcers, easy bruising, petechiae, or haemorrhagic purpura – they should immediately consult a physician.

If the number of leukocytes or platelets significantly decreases during therapy, a complete blood count should be performed and the patient's condition should be carefully monitored. Treatment with carbamazepine should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical manifestations such as fever or sore throat; as well as in case of signs of bone marrow suppression.

Transient or persistent reduction in platelet or leukocyte counts has been reported in connection with carbamazepine use. However, in most cases, this reduction was temporary and did not indicate the development of aplastic anaemia or agranulocytosis. Blood analysis, including platelet count (and possibly reticulocyte count and haemoglobin level), should be performed before the start of therapy and periodically during its course.

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

Pharmacogenomics.

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

Association with (HLA)-B*1502

Retrospective studies in Han Chinese patients have demonstrated a strong correlation between carbamazepine-associated skin reactions (SJS/TEN) and the presence of human leukocyte antigen (HLA) allele (HLA)-B*1502 in these patients. A higher incidence of SJS (rare rather than very rare) is characteristic of certain Asian countries (e.g., Taiwan, Malaysia, and the Philippines), where the (HLA)-B*1502 allele is prevalent in the population. The frequency of carriers of this allele among 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% 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 carbamazepine therapy. If testing for the (HLA)-B*1502 allele yields a positive result, carbamazepine therapy should not be initiated, except in cases where no other therapeutic options are available. Patients who have been tested and found negative for (HLA)-B*1502 have a low risk of developing SJS, although such reactions may very rarely occur.

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

The presence of the (HLA)-B*1502 allele is a risk factor for SJS/TEN development in Chinese patients receiving other antiepileptic drugs that may be associated with SJS/TEN. Therefore, other drugs that may be 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 nationalities with a low frequency of the (HLA)-B*1502 allele is generally not necessary. In most cases, screening of patients already receiving carbamazepine is not recommended, as the risk of SJS/TEN is significantly limited to the first few months, regardless of the presence of the (HLA)-B*1502 allele in the patient's genes.

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

Association with HLA-A*3101

Human leukocyte antigen is a risk factor for the development of skin adverse reactions such as SJS, TEN, drug rash 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, carbamazepine use should be avoided.

Limitations of genetic screening

Results of genetic screening should not replace appropriate clinical monitoring and patient management. Other potential factors, such as antiepileptic drug dosage, adherence to therapy, and concomitant therapy, 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, the patient should be closely monitored so that the drug can be discontinued immediately if the reaction worsens.

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

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

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

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

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

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

An increase in seizure frequency may occur during the 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. If liver function impairment worsens or if the disease progresses to an active phase, the drug should be discontinued immediately.

Some laboratory test parameters used to assess liver function may be outside the normal range in patients taking carbamazepine, particularly gamma-glutamyl transferase (GGT) levels. This is likely due to enzyme induction in the liver. 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 discontinuation of carbamazepine.

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

Kidney function. Assessment of kidney function and blood urea nitrogen determination are recommended at the beginning and periodically during the course of therapy.

Hyponatremia. Cases of hyponatremia have been reported with carbamazepine use. In patients with pre-existing renal dysfunction associated with low sodium levels, and in patients receiving 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 as clinically necessary. This particularly applies to elderly patients. In such cases, water intake should be limited.

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

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

Psychiatric effects. The possibility of activation of latent psychosis should be considered; in elderly patients – confusion or agitation.

Suicidal thoughts and behaviour. Several reports have documented suicidal thoughts and behaviour in patients receiving antiepileptic drugs. A meta-analysis of data from placebo-controlled trials of antiepileptic drugs also showed a slight increase in the risk of suicidal thoughts and behaviour. The mechanism of this risk is unknown, and available data do not exclude an increased risk of suicidal thoughts and behaviour with carbamazepine treatment.

Therefore, patients should be screened for suicidal thoughts and behaviour, and appropriate treatment should be prescribed if necessary. Patients (and caregivers) should be advised to consult a physician if signs of suicidal thoughts or behaviour appear.

Endocrine effects. Due to enzyme induction in the liver, 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 blood spotting. Women taking carbamazepine for whom hormonal contraception is necessary should receive a preparation containing at least 50 mcg of estrogen, or alternative non-hormonal contraceptive methods should be considered for such patients.

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

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

Unless a careful evaluation of alternative treatment options determines 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 starting carbamazepine therapy, a pregnancy test should be considered in women of childbearing potential.

Women of childbearing potential should 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 potential should consult about using other effective contraceptive methods (see sections "Interaction with other medicinal products and other forms of interaction" and "Use during pregnancy or breastfeeding").

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

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

Dose reduction and withdrawal syndrome. Abrupt discontinuation of the drug may provoke seizures; therefore, carbamazepine should be gradually withdrawn over 6 months. If immediate discontinuation is necessary, patients with epilepsy should be switched to another antiepileptic drug while continuing appropriate therapy.

Use during pregnancy or breastfeeding.

Pregnancy

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

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

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 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 risk of congenital malformations and other adverse outcomes. Exposure to carbamazepine during pregnancy is associated with a frequency of serious congenital malformations 2–3 times higher than in the general population, where it is 2–3%. Reported malformations include fetal neural tube defects, craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, digital hypoplasia, and other anomalies affecting various organ systems of the fetus when the mother used carbamazepine during pregnancy. Specialized antenatal monitoring for these malformations is recommended. Neurodevelopmental disorders have been reported in children whose mothers used carbamazepine alone or in combination with other AEDs during pregnancy for epilepsy treatment. Studies on the risk of nervous system disorders in children whose mothers received carbamazepine during pregnancy are conflicting, and the risk cannot be excluded.

Unless a careful evaluation of alternative treatment options determines that benefits outweigh risks, carbamazepine should not be used in pregnant women. The woman should be fully informed and understand the risks of taking carbamazepine during pregnancy. Data suggest that the risk of malformations with carbamazepine use may depend on the dose. If, after careful benefit/risk assessment, alternative therapy is not suitable and carbamazepine treatment continues, the lowest effective dose of carbamazepine as monotherapy should be used, and plasma levels should be monitored. Plasma concentration can be maintained at the lower end of the therapeutic range of 4 to 12 mcg/mL, provided seizure control is maintained.

Monitoring and prevention. 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 the fetus if the mother has epilepsy. Folic acid is recommended for women of childbearing potential before and during pregnancy.

If a woman plans to become pregnant, all efforts should be made before conception and 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.

Newborns. To prevent coagulation disorders in the child, vitamin K1 is also recommended for the mother during the last weeks of pregnancy and for newborns.

There have been several reported cases of seizures and/or respiratory depression in newborns, as well as several cases of vomiting, diarrhoea and/or poor appetite in newborns, associated with the use of carbamazepine and other anticonvulsant drugs.

Women of childbearing potential

Carbamazepine should not be used in women of childbearing potential who do not use contraception, except in cases where the potential benefit/risk of carbamazepine therapy outweighs that of alternative treatment options. The woman should be fully informed and understand the potential risk to the fetus if she takes carbamazepine during pregnancy; therefore, it is important to plan pregnancy in advance. Before starting carbamazepine therapy, the possibility of performing a pregnancy test should be considered in women of childbearing potential.

Women of childbearing potential should 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 about using 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.

When choosing a contraceptive method, individual circumstances should be evaluated, involving the patient in the discussion.

Breastfeeding. Carbamazepine passes into breast milk (25–60% of plasma concentration). The benefits of breastfeeding and the likelihood 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 vehicles or operating machinery.

The ability of a patient taking carbamazepine to react quickly (especially at the beginning of therapy or during dose titration) may be impaired due to dizziness and drowsiness; therefore, the patient should be cautious when driving a vehicle or operating machinery.

Dosage and Administration

Carbamazepine is administered orally; the daily dose is usually divided into two or three doses. The drug may be taken during, after meals, or between meals with a small amount of liquid, for example, a glass of water.

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

Epilepsy

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

Monitoring plasma carbamazepine levels may be helpful in determining the optimal dosage.

Particularly in combination therapy, therapeutic doses should be determined based on plasma carbamazepine levels and clinical 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 daily dose often reaches 800–1200 mg. Some patients may require a carbamazepine dose up to 1600 mg or even 2000 mg per day.

Elderly patients: due to the possibility of drug interactions, carbamazepine dosage in elderly patients should be carefully titrated.

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

The usual dosage is 10–20 mg/kg body weight per day (divided into 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, administer the adult dosage.

Carbamazepine should be prescribed as monotherapy whenever possible. However, when used concomitantly with other medicinal products, a gradual dose escalation regimen similar to that used for monotherapy is recommended.

When adding Carbamazepine to ongoing antiepileptic therapy, the dose should be gradually increased without altering the dose of the currently used antiepileptic drug(s); dose adjustment of carbamazepine may be necessary if required.

Acute manic episodes and maintenance treatment in bipolar affective disorders

Dosage range: approximately 400 to 1600 mg daily, usually 400 to 600 mg daily, divided into 2–3 doses. In acute manic states, a relatively rapid dose escalation is recommended, whereas for optimal tolerability during maintenance therapy in bipolar disorders, gradual 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 (e.g., up to 400 mg three times daily). In cases of severe alcohol withdrawal symptoms, treatment should be initiated with a combination of Carbamazepine and sedative-hypnotic agents (e.g., clomethiazole, chlordiazepoxide), following the dosage recommendations outlined above. After completion of the acute phase, Carbamazepine may be continued as monotherapy.

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

Initial dose of Carbamazepine is 200–400 mg daily (100 mg twice daily in elderly patients). The dose should be slowly increased until pain relief is achieved (usually up to 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 Carbamazepine up to 1600 mg may be required. After pain relief is achieved, the dose should be gradually reduced to the lowest effective maintenance dose.

Children

Due to a faster elimination of carbamazepine in children, higher doses (on a mg/kg basis) may be required compared to adults. Carbamazepine tablets may be administered to children aged 5 years and older.

Overdose.

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

Central nervous system (CNS): CNS depression; disorientation, impaired 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 leading to loss of consciousness.

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

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

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

Laboratory findings: 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 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 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 restriction and slow, cautious intravenous infusion of 0.9% sodium chloride solution are indicated. These measures may help prevent cerebral edema.

Hemoperfusion using carbon 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 drug.

Adverse Reactions

At the beginning of treatment with Carbamazepine, or when using too high an initial dose, or when treating elderly patients, certain types of adverse reactions may occur, for example, from the CNS (dizziness, headache, ataxia, somnolence, general weakness, diplopia), from the gastrointestinal tract (nausea, vomiting), or allergic skin reactions.

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

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

Immune system disorders: delayed-type multiorgan hypersensitivity 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. Other organs may also be affected (e.g., liver, lungs, kidneys, pancreas, myocardium, colon); 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 reduced 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 manifestations such as galactorrhea, gynecomastia, disturbances in bone metabolism (reduced plasma calcium and 25-hydroxycholecalciferol levels), leading to osteomalacia/osteoporosis; 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 (frequency "unknown").

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

Nervous system disorders: dizziness, ataxia, somnolence, general weakness, headache, diplopia; abnormal involuntary movements (e.g., tremor, "fluttering" tremor, dystonia, tics), nystagmus, orofacial dyskinesia, eye movement disorders, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness and paresis, taste disturbances, malignant neuroleptic syndrome, aseptic meningitis with myoclonus 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, impaired perception of sound pitch.

Cardiac and vascular disorders: intracardiac conduction disturbances, 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-glutamyl transferase levels (due to hepatic enzyme induction), usually not clinically significant; increased blood alkaline phosphatase levels, elevated transaminase levels, cholestatic, parenchymal (hepatocellular), or mixed-type hepatitis, vanishing bile duct syndrome, jaundice, granulomatous hepatitis, hepatic failure.

Skin and subcutaneous tissue disorders: allergic dermatitis, urticaria (sometimes severe), exfoliative dermatitis, erythroderma, systemic lupus erythematosus, pruritus, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, erythema multiforme and nodular erythema, skin pigmentation disorders, purpura, acne, hyperhidrosis, increased hair loss, hirsutism, acute generalized exanthematous pustulosis (AGEP), lichenoid keratosis, onychomadesis.

Musculoskeletal and connective tissue disorders: muscle weakness, arthralgia, myalgia, muscle spasms, disturbances in bone metabolism (reduced plasma calcium and 25-hydroxycholecalciferol levels, which may lead to osteomalacia or osteoporosis), fractures.

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

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

General disorders: general weakness.

Infections and infestations: reactivation of human herpesvirus type 6.

Laboratory and diagnostic test abnormalities: increased gamma-glutamyl transferase levels (due to hepatic enzyme induction), usually not clinically significant; increased blood alkaline phosphatase levels, increased transaminase levels, 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, usually without clinical manifestations; increased blood prolactin levels, hypogammaglobulinemia, decreased bone mineral density.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister pack, 2 or 5 blisters per cardboard box;

50 tablets in a container, 1 container per cardboard box.

Prescription category.

Prescription only.

Manufacturer/Marketing Authorization Holder.

JSC "Tekhnolog".

Manufacturer's address and place of business.

8 Staroprizhna Street, Uman, Cherkasy region, 20300, Ukraine.