Zeptol

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

Composition:

Active substance: carbamazepine;

1 tablet contains 200 mg of carbamazepine;

Excipients: microcrystalline cellulose, povidone (K-30), colloidal anhydrous silicon dioxide, hypromellose, corn starch, talc, magnesium stearate, sodium starch glycolate (type A), sodium lauryl sulfate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, round, flat tablets with beveled edges, a score line on one side, and the inscription "ZEPTOL 200" on the other.

Pharmacotherapeutic group. Antiepileptic drugs.

ATC code N03AF01.

Pharmacological Properties.

Pharmacodynamics.

As an anticonvulsant agent, carbamazepine is effective in focal (partial) seizures (simple and complex), whether or not accompanied by secondary generalization, in generalized tonic-clonic seizures, and also in combination of these seizure types.

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

As a 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 syringomyelia, 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 manifestations such as agitation, tremor, and gait disturbances. In patients with central diabetes insipidus, carbamazepine reduces diuresis and sensation of thirst.

It has been confirmed that as a psychotropic agent, carbamazepine is effective in affective disorders, namely: for treatment of acute manic states, for maintenance therapy of bipolar affective (manic-depressive) disorders (as monotherapy or in combination with neuroleptics, antidepressants, or lithium salts), in schizoaffective psychoses, manic psychoses (in combination with neuroleptics), and in acute polymorphic schizophrenia (rapid cycling episodes). The mechanism of action of carbamazepine—the active substance—is only partially understood.

Carbamazepine stabilizes membranes of overexcited nerve fibers, inhibits the generation of repetitive neuronal discharges, and reduces synaptic transmission of excitatory impulses. It has been established that the primary mechanism of action is prevention of repeated sodium-dependent action potentials in depolarized neurons by blocking sodium channels. The anticonvulsant effect of the drug is primarily due to reduced glutamate release and stabilization of neuronal membranes, whereas the antimanic effect may be attributed to inhibition of dopamine and norepinephrine metabolism.

Pharmacokinetics.

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

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

Steady-state plasma concentrations of the drug are achieved within 1–2 weeks, depending on individual metabolic characteristics (autoinduction of hepatic enzyme systems by carbamazepine, heteroinduction by other concurrently administered drugs), as well as the patient's condition, drug dosage, and duration of treatment. Considerable interindividual variations in steady-state concentrations within the therapeutic range are 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 nearly 30% of carbamazepine concentrations.

Distribution. Assuming 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%. The concentration of unchanged carbamazepine in cerebrospinal fluid and saliva is proportional to the fraction of unbound (free) active substance (20–30%). Carbamazepine concentration in breast milk ranges from 25% to 60% of its plasma level.

Metabolism. Carbamazepine is metabolized primarily 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 biotransformation of carbamazepine into carbamazepine-10,11-epoxide is cytochrome P450 3A4. These metabolic reactions also produce a "minor" metabolite, 9-hydroxymethyl-10-carbamoylacridan. After a single oral dose of carbamazepine, approximately 30% of the active substance is excreted in urine as end products of epoxide metabolism. Other important biotransformation pathways lead to the formation of various monohydroxylated derivatives and the N-glucuronide of carbamazepine, formed with the participation of uridine diphosphate-glucuronosyltransferase (UGT2B7).

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

The mean elimination half-life of the 10,11-epoxide metabolite from plasma is approximately 6 hours after a single oral dose 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. Nearly 2% of the administered dose is excreted unchanged in urine, and approximately 1% as the pharmacologically active metabolite, 10,11-epoxide.

Pharmacokinetic characteristics in specific patient populations.

Elderly patients. There are no data indicating that the pharmacokinetics of carbamazepine change 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 as well as part of combination therapy.

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

Contraindications.

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 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 their 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 the development of adverse reactions. Concomitant use of CYP3A4 inducers may enhance the metabolism of carbamazepine, resulting in potentially reduced plasma concentrations of carbamazepine and diminished 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 by CYP3A4 through induction of 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 carbamazepine plasma levels.

Since elevated plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), dosage adjustment of Zepin 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.

Antiepileptics: stiripentol, vigabatrin.

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

Antihistamines: loratadine, terfenadine.

Antipsychotics: olanzapine, loxapine, quetiapine.

Antituberculosis agents: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular agents: diltiazem, verapamil.

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

Drugs that may decrease carbamazepine plasma levels.

Dosage adjustment may be necessary when co-administered with the following drugs.

Antiepileptic agents: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic carbamazepine levels, it is recommended to adjust phenytoin plasma concentration to 13 µg/mL before 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 (Hypericum perforatum).

Mefloquine may exhibit antagonistic properties against the antiepileptic effect of Zepin. 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 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.

Anthelmintics: praziquantel, albendazole.

Antineoplastic agents: imatinib, cyclophosphamide, lapatinib, temsirolimus.

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

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

Anxiolytics: alprazolam, midazolam.

Bronchodilators or antiasthmatic agents: theophylline.

Contraceptives: hormonal contraceptives (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 drugs: 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 enhance the hepatotoxicity of isoniazid.

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

Combination 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 require close monitoring due to the possibility of faster-than-expected termination of neuromuscular blockade.

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

Contraindicated interactions.

Since carbamazepine is structurally similar to tricyclic antidepressants, Zepin is not recommended for concomitant use with monoamine oxidase inhibitors (MAO inhibitors); treatment with an MAO inhibitor should be discontinued at least two weeks prior to initiating Zepin (or earlier, if clinically feasible).

Effect on serological tests.

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

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

Special precautions for use.

Zepitol 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, patients with a history of adverse hematological reactions to other drugs, and patients with interrupted treatment courses.

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

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

One should bear in mind the potential activation of latent psychosis. In elderly patients, possible activation of confusion and anxious agitation should be considered.

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

Hematological effects. The use of the drug has been associated with the development of agranulocytosis and aplastic anemia; however, due to the extremely low incidence of these conditions, it is difficult to assess the risk associated with drug administration.

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, angina, skin rash, oral ulcers, easy bruising, petechiae, or hemorrhagic purpura—they should immediately contact a physician.

If leukocyte or platelet counts significantly decrease during therapy, the patient's condition should be carefully monitored and complete blood counts should be performed regularly. Treatment with Zepitol should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical manifestations such as fever or sore throat. The drug should be discontinued if signs of bone marrow suppression appear.

Transient or persistent reduction in platelet or white blood cell counts may frequently occur with Zepitol use. However, these phenomena are usually transient and do not indicate the development of aplastic anemia or agranulocytosis. Blood tests, including platelet count (and possibly reticulocyte count and hemoglobin level), should be performed before initiating therapy and periodically during treatment.

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

Pharmacogenomics.

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

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. 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 prevalence of carriers of this allele among the Asian population is over 15% in the Philippines, Thailand, Hong Kong, and Malaysia, approximately 10% in Taiwan, nearly 4% in Northern China, approximately 2–4% in South Asia (including India), and less than 1% in Japan and Korea. The prevalence of the HLA-B*1502 allele is negligible among European and African populations, indigenous peoples of America, and Latin American populations.

In patients who genetically belong to high-risk groups, testing for the presence of the HLA-B*1502 allele should be performed before initiating Zepitol therapy. If testing confirms the presence of HLA-B*1502, treatment with the drug 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 still very rarely occur.

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

The HLA-B*1502 allele may be a risk factor for SJS/TEN development in Chinese patients receiving other antiepileptic drugs associated with SJS/TEN. Therefore, the use of other drugs associated with SJS/TEN should be avoided in patients carrying the HLA-B*1502 allele, if alternative therapy is available. Genetic screening is generally not recommended for patients from ethnic groups with a low prevalence of the HLA-B*1502 allele. Screening is generally not recommended for patients already receiving Zepitol, as the risk of SJS/TEN is largely confined to the first few months, regardless of the presence of the HLA-B*1502 allele.

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, 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, the use of the drug should be avoided.

Limitations of genetic screening

Genetic screening results should not replace appropriate clinical monitoring and patient management. Other potential factors, such as antiepileptic drug dosage, adherence to therapy, and concomitant medications, may also play a role in the development of these severe cutaneous adverse reactions. The impact of other diseases and the level of skin disorder monitoring has 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 at the same dose or after dose reduction. Since early signs of more serious dermatological reactions may be difficult to distinguish from mild transient reactions, patients should be closely monitored so that the drug can be discontinued immediately if the reaction worsens.

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

Hypersensitivity. Zepitol 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).

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

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

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

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

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

An increase in seizure frequency may occur when switching from oral formulations to suppositories.

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

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

Severe hepatic reactions due to carbamazepine use are very rare. If signs of hepatic dysfunction or active liver disease occur, the patient should be urgently evaluated and treatment with Zepitol suspended.

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 have been reported with carbamazepine use. In patients with renal impairment associated with low sodium levels, as well as in patients receiving concomitant medications that lower 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 indicated. 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. Zepitol exhibits moderate anticholinergic activity. Therefore, patients with elevated intraocular pressure or urinary retention should be closely monitored during therapy.

Psychiatric effects. The potential for activation of latent psychosis should be considered; in elderly patients, confusion or agitation may occur.

Suicidal thoughts and behavior. There have been several reports of suicidal thoughts and behavior in patients receiving antiepileptic drugs. Therefore, patients should be monitored for suicidal thoughts and behavior, and appropriate treatment should be initiated if necessary. Patients (and caregivers) should be advised to contact a physician if signs of suicidal thoughts or behavior occur.

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

Plasma drug level monitoring. Although the correlation between dosage and plasma carbamazepine levels, as well as between plasma carbamazepine levels and clinical efficacy and tolerability, is not well established, monitoring plasma drug levels may be appropriate in the following cases: sudden increase in seizure frequency, patient compliance assessment, during pregnancy, in the treatment of children and adolescents; suspected absorption impairment, suspected toxicity, and when multiple drugs are used.

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

Dose reduction and withdrawal syndrome. Abrupt discontinuation of the drug may provoke seizures; therefore, carbamazepine should be discontinued gradually over 6 months. If immediate discontinuation is necessary, transition to a new antiepileptic drug in patients with epilepsy should be performed while continuing appropriate medication therapy.

Women of childbearing potential

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

Carbamazepine should not be used in women of childbearing potential unless, after careful consideration of alternative treatment options, the benefit is deemed to outweigh the risks.

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 potential.

Women of childbearing potential must use effective contraception during treatment and for two weeks after discontinuation of carbamazepine. Due to enzyme induction, carbamazepine may impair the therapeutic effect of hormonal contraceptives; therefore, women of childbearing potential should be advised to use 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 contact their physician immediately if they become pregnant or suspect they may be pregnant while taking carbamazepine.

Use during pregnancy or breastfeeding.

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

All women of childbearing potential receiving antiepileptic therapy, and 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 treatment 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 developmental outcomes. Exposure to carbamazepine during pregnancy is associated with a 2–3 times higher frequency of serious congenital malformations compared to the general population (2–3%). Reported malformations include neural tube defects, craniofacial defects such as cleft lip/palate, cardiovascular malformations, hypospadias, hypoplasia of fingers, and other anomalies occurring in various organ systems of the fetus whose mother used carbamazepine during pregnancy. Specialized prenatal monitoring for these malformations is recommended. Neurodevelopmental disorders have been reported in children born to women with epilepsy who used carbamazepine alone or in combination with other AEDs during pregnancy. Studies on the risk of neurodevelopmental disorders in children exposed to carbamazepine in utero are conflicting, and the risk cannot be excluded.

Unless, after careful consideration of alternative treatment options, the benefit is deemed to outweigh the risks, carbamazepine should not be used in women during pregnancy. The woman should be fully informed and understand the risks of taking carbamazepine during pregnancy.

Available data suggest that the risk of congenital malformations with carbamazepine use may be dose-dependent. If, after careful evaluation of alternative treatment options and their benefit-risk ratio, they are found unsuitable and carbamazepine treatment continues, monotherapy and the lowest effective dose of carbamazepine should be used, and plasma level monitoring is recommended. Plasma concentrations can be maintained in the lower part of the therapeutic range (4–12 mcg/mL), provided seizure control is maintained.

If a woman plans pregnancy, 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.

Monitoring and prevention. Folic acid deficiency is known to develop during pregnancy. Antiepileptic drugs may increase the risk of folic acid deficiency; therefore, supplementation with folic acid is recommended before and during pregnancy.

Newborns. To prevent bleeding disorders in newborns, vitamin K1 is recommended for women in the last weeks of pregnancy and for newborns.

There have been several reports of seizures and/or respiratory depression in newborns, as well as several cases of vomiting, diarrhea, 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 except when the potential benefit-risk ratio outweighs 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 should be done in advance. 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 their physician 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.

Lactation period. Carbamazepine passes into breast milk (25–60% of plasma concentration). The benefits of breastfeeding versus the potential risk of adverse effects in the infant should be carefully weighed. Mothers receiving Zepitol may breastfeed provided the infant is monitored for possible adverse reactions (e.g., excessive drowsiness, allergic skin reactions).

Fertility.

Cases of impaired fertility in men and/or abnormal spermatogenesis parameters have been reported.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

Zepitol 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 initiating treatment, patients who potentially belong to populations carrying the HLA-A*3101 allele should, if possible, be tested for the presence of this allele, as its presence may increase the risk of developing severe adverse reactions, including skin reactions.

Epilepsy

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

Therapeutic drug monitoring of carbamazepine plasma levels may be helpful in determining the optimal dosage. Particularly in cases of combination therapy, therapeutic doses should be carefully adjusted 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 optimal effect is achieved. The usual daily dose often ranges between 800–1200 mg. Some patients may require doses up to 1600 mg or even 2000 mg per day.

Elderly patients: In elderly patients, dosage should be carefully adjusted due to the potential for drug interactions.

Children: Treatment may be initiated with a dose of 100 mg/day, gradually increased by 100 mg each week.

The usual dosage is 10–20 mg/kg body weight per day, administered in several divided doses.

For children aged 15 years, the dosage should be prescribed as for adults.

If possible, the drug should be prescribed as monotherapy, but when used in combination with other medicinal products, a gradual dose escalation regimen of the drug is recommended.

When prescribing Zeprol in addition to ongoing antiepileptic therapy, the dose of the drug should be gradually increased without changing the dose of the currently used antiepileptic drug(s), or, if necessary, with dose adjustment.

Acute manic states and maintenance therapy in bipolar affective disorders

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

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 severe alcohol withdrawal, treatment should be initiated with a combination of the drug and sedative-hypnotic agents (e.g., with clomethiazole, chlordiazepoxide), following the above-mentioned dosage recommendations. After completion of the acute phase, the drug may be continued as monotherapy.

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

The initial dose of Zeprol is 200–400 mg per day (100 mg twice daily for elderly patients). The dose should be slowly increased until pain subsides (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 1600 mg may be required. After pain subsides, 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. Zeprol tablets 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; disorientation, depressed level of consciousness, drowsiness, agitation, hallucinations, coma; blurred vision, slurred speech, dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (initially), 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 due to the antidiuretic hormone-like effect of carbamazepine.

Laboratory findings: Hyponatremia, possible metabolic acidosis, hyperglycemia, increased 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 should be 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, including cardiac function monitoring and 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; in case of hyponatremia (water intoxication), fluid restriction and slow, cautious intravenous infusion of 0.9% sodium chloride solution. These measures may help prevent cerebral edema.

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

Recurrence of overdose symptoms on the 2nd and 3rd days 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, as well as during treatment of elderly patients, certain types of adverse reactions may occur, for example, from the central nervous system (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 dose reduction. Development of adverse reactions from the CNS may result from relative overdose or significant fluctuations in plasma concentrations 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 individual doses (e.g., 3–4 doses).

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

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

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 galactorrhea, gynecomastia, bone metabolism disorders (decreased plasma calcium and 25-hydroxycholecalciferol levels), leading to osteomalacia/osteoporosis; in isolated 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; activation of psychosis.

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 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.

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

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

Cardiac disorders: disturbances in intracardiac conduction; arterial hypertension or arterial 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: hypersensitivity reactions in the lungs characterized by fever, dyspnea, pneumonitis or pneumonia.

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

Hepatobiliary disorders: increased gamma-glutamyltransferase levels (due to induction of liver enzymes), usually without clinical significance; increased alkaline phosphatase levels in blood; increased transaminase levels; hepatitis of cholestatic, parenchymal (hepatocellular), or mixed type; vanishing bile duct syndrome, jaundice; granulomatous hepatitis, hepatic failure.

Skin and subcutaneous tissue disorders: allergic dermatitis, urticaria, sometimes in severe forms; exfoliative dermatitis, erythroderma; systemic lupus erythematosus, pruritus; Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity, erythema multiforme and nodular erythema, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism.

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

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

Reproductive system and breast disorders: sexual dysfunction/impotence/erectile dysfunction, impaired spermatogenesis (with reduced number/motility of spermatozoa).

General disorders: general weakness.

Investigations: increased gamma-glutamyltransferase levels (due to induction of liver enzymes), usually without clinical significance; 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 levels, which usually do not present with clinical symptoms; increased blood prolactin levels, hypogammaglobulinemia.

Adverse reactions based on spontaneous reports.

Infections and infestations: reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: bone marrow insufficiency.

Nervous system disorders: sedative effect, memory impairment.

Gastrointestinal disorders: colitis.

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

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

Musculoskeletal and connective tissue disorders: fractures.

Investigations: decreased bone mineral density.

Shelf life. 5 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging.

10 tablets per strip, 10 strips per cardboard package.

Prescription status. Prescription only.

Manufacturer.

San Pharmaceuticals Industries Ltd.

Manufacturer's address and place of business.

Survey No. 214, Plot No. 20, Gavt. Indl. Area, Phase II, Piparia, Silvassa – 396230, U.T. Dadra and Nagar Haveli, India.