INSTRUCTIONS for medical use of the medicinal product TEGRETOL® (TEGRETOL®)

Composition:

Active substance: carbamazepine;

One tablet contains 200 mg of carbamazepine;

Excipients: microcrystalline cellulose; sodium carmellose (low-substituted sodium carboxymethylcellulose); magnesium stearate; colloidal anhydrous silicon dioxide.

Dosage form. Tablets.

Main physico-chemical properties: white, round, flat tablets with bevelled edges; engraved with "CG" on one side and "G/K" and a score line on the other.

Pharmacotherapeutic group. Antiepileptic drugs. ATC code N03AF01.

Pharmacological Properties

Pharmacodynamics

As an anticonvulsant agent, the antiepileptic drug Tegretol® is effective in partial seizures (simple and complex), with or without secondary generalization, as well as in generalized tonic-clonic seizures and in combinations of these seizure types.

In clinical studies, when Tegretol® was used as monotherapy in patients with epilepsy (especially in children and adolescents), psychotropic effects of the drug were observed, partially manifested as a positive influence on symptoms of anxiety and depression, as well as reduced irritability and aggressiveness.

As a neurotropic agent, Tegretol® is effective in certain neurological disorders. For example, it prevents painful attacks in idiopathic and secondary trigeminal neuralgia. Furthermore, Tegretol® is used to alleviate neuropathic pain under various conditions. In alcohol withdrawal syndrome, Tegretol® increases the seizure threshold (which is reduced in this condition) and reduces the severity of clinical manifestations such as agitation, tremor, and gait disturbances.

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

Pharmacokinetics

Absorption. After tablet administration, carbamazepine is almost completely absorbed, although somewhat slowly. After a single dose of the conventional tablet, maximum plasma concentration (C_max) is reached within 12 hours.

Bioavailability of different oral dosage forms of Tegretol® has been shown to range between 85–100%.

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

When doses up to 300 mg of carbamazepine are administered, approximately 75% of the ingested dose reaches the systemic circulation within 6 hours. Therefore, the maximum recommended daily dose for this dosage form is 250 mg four times daily.

Plasma concentrations. No clinically significant differences in the extent of absorption of the active substance have been observed after administration of different oral dosage forms of the drug. After a single oral dose of a tablet containing 400 mg of carbamazepine, the mean C_max of unchanged active substance reaches approximately 4.5 µg/mL.

Significant 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) are nearly 30% of carbamazepine concentrations.

Steady-state plasma concentration of the drug is achieved within 1–2 weeks, depending on individual metabolic characteristics (autoinduction of hepatic enzyme systems by carbamazepine, heteroinduction by concomitantly administered drugs), as well as the patient's condition, drug dosage, and duration of treatment.

Distribution. Plasma protein binding of carbamazepine ranges from 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 amounts to 25–60% of its plasma level. Carbamazepine crosses the placental barrier. Assuming complete absorption, the apparent volume of distribution ranges from 0.8 to 1.9 L/kg.

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 first step involves oxidation to carbamazepine-10,11-epoxide, primarily mediated by cytochrome P450 3A4 isoenzyme. Human microsomal epoxide hydrolase is believed to be responsible for the formation of the pharmacologically active carbamazepine-10,11-epoxide, which is almost completely transformed into the 10,11-trans-diol derivative and its glucuronides. 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).

Carbamazepine induces its own metabolism.

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 monooxygenase system), depending on the duration of treatment. In patients concurrently receiving 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 in urine as unchanged drug, approximately 1% as the pharmacologically active metabolite 10,11-epoxide, and approximately 30% as carbamazepine-10,11-trans-diol and other inactive metabolites.

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. There are no data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function.

Clinical characteristics.

Indications.

Epilepsy:
- complex or simple partial seizures (with or without loss of consciousness), with or without secondary generalization;
- generalized tonic-clonic seizures;
- mixed seizure types.
- Tegretol® can be used both as monotherapy and in combination therapy.
- Tegretol is generally ineffective in absence seizures (a mild form of epileptic seizure) and myoclonic seizures. (See "Special precautions for use.").
Acute manic states; maintenance therapy in bipolar affective disorders to prevent relapses or to reduce clinical manifestations of exacerbations.
Alcohol withdrawal syndrome.
Idiopathic trigeminal neuralgia and trigeminal neuralgia associated with multiple sclerosis (typical and atypical forms).
Idiopathic glossopharyngeal neuralgia.

Contraindications.

Tegretol® is contraindicated:

in patients with known hypersensitivity to carbamazepine or oxcarbazepine, 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 suppression;
in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, mixed porphyria, late cutaneous porphyria);
in combination with monoamine oxidase inhibitors (MAOIs).

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 administration of CYP3A4 inhibitors or epoxide hydrolase inhibitors with carbamazepine may lead to increased plasma concentrations of carbamazepine, which in turn may result in adverse reactions. Therefore, dosage adjustment of Tegretol® and monitoring of plasma levels are recommended. Concomitant use of CYP3A4 inducers may enhance carbamazepine metabolism, potentially leading to decreased plasma concentrations of carbamazepine and reduced therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, resulting in increased plasma levels of carbamazepine. Therefore, dosage adjustment of Tegretol® may be necessary.

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

Human microsomal epoxide hydrolase is the enzyme responsible for the conversion of carbamazepine-10,11-epoxide into 10,11-trans-diol derivatives. Concomitant administration of inhibitors of human microsomal epoxide hydrolase (e.g., valproic acid) may lead to increased plasma concentrations of carbamazepine-10,11-epoxide.

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

Medicinal products that may increase carbamazepine plasma levels.

Since elevated plasma levels of carbamazepine may lead to adverse reactions (such as dizziness, somnolence, ataxia, diplopia), dosage of Tegretol® should be appropriately adjusted and/or plasma levels monitored when co-administered with the following medicinal products.

Analgesics, anti-inflammatory agents: dextropropoxyphene, ibuprofen.

Androgens: danazol.

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

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

Antiepileptics: stiripentol, vigabatrin.

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

Antihistamines: terfenadine.

Antipsychotics: olanzapine, loxapine, quetiapine.

Antituberculosis agents: isoniazid.

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

Carbonic anhydrase inhibitors: acetazolamide.

Cardiovascular agents: diltiazem, verapamil.

Gastrointestinal agents: cimetidine, omeprazole.

Muscle relaxants: oxybutynin, dantrolene.

Antiplatelet agents: ticlopidine.

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

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

Elevated plasma levels of the active metabolite carbamazepine-10,11-epoxide may lead to adverse reactions (e.g., dizziness, somnolence, ataxia, diplopia, blurred vision, nystagmus). Therefore, dosage of Tegretol® should be appropriately adjusted and/or plasma levels monitored when co-administered with medicinal products that increase plasma levels of this metabolite, such as: brivaracetam, loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide, and valpromide.

Medicinal products that may decrease carbamazepine plasma levels.

Dosage adjustment of Tegretol® may be required when co-administered with the following medicinal products.

Antiepileptic agents: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin and 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 preparations containing St. John’s wort (Hypericum perforatum).

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

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 Tegretol® on plasma levels of concomitantly administered medicinal products.

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

Analgesics, anti-inflammatory agents: buprenorphine, methadone, paracetamol, phenazone (antipyrine), tramadol.

Antibiotics: doxycycline, rifabutin.

Anticoagulants: oral anticoagulants (e.g., warfarin, phenprocoumon, dicoumarol, acenocoumarol, rivaroxaban, dabigatran, apixaban, edoxaban).

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

Antiemetics: aprepitant.

Antiepileptic agents: brivaracetam, clobazam, clonazepam, eslicarbazepine, ethosuximide, felbamate, lamotrigine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Reports exist of both increased and decreased plasma levels of phenytoin due to carbamazepine, as well as isolated cases of increased plasma levels of mephenytoin. To avoid phenytoin intoxication and subtherapeutic carbamazepine concentrations, the recommended plasma concentration of phenytoin should not exceed 13 µg/mL before initiating carbamazepine therapy. Isolated reports describe increased plasma concentrations of mephenytoin during carbamazepine treatment, which in rare cases may lead to confusion and even coma.

Antifungal agents: itraconazole, voriconazole, ketoconazole.

Anthelmintics: albendazole, praziquantel.

Antineoplastic agents: cyclophosphamide, imatinib, lapatinib, temsirolimus.

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

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, including prednisolone, dexamethasone.

Agents used for erectile dysfunction: tadalafil.

Immunosuppressants: cyclosporine, everolimus, sirolimus, tacrolimus.

Thyroid agents: levothyroxine. Carbamazepine is expected to enhance thyroid hormone elimination and increase thyroid hormone requirements in patients with hypothyroidism. Therefore, thyroid function should be monitored in patients receiving replacement therapy both at the beginning and end of Tegretol® treatment.

If necessary, the dose of thyroid hormones should be adjusted. Thyroid function may change, particularly when carbamazepine is used concomitantly with other anticonvulsants (e.g., phenobarbital).

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

Combinations requiring special consideration.

Long-term use of carbamazepine with paracetamol (acetaminophen) may be associated with the development of hepatotoxicity.

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

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

Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.

Concomitant use of carbamazepine with lithium or metoclopramide, as well as with neuroleptics (haloperidol, thioridazine), may lead to enhanced neurological side effects (in the case of the latter combination—even at therapeutic plasma levels). Therefore, careful monitoring of clinical symptoms is required. At least 8 weeks should elapse after discontinuation of previous neuroleptic treatment. Concomitant therapy should also be avoided. Patients should be monitored for the development of neurotoxic symptoms such as unsteady gait, ataxia, horizontal nystagmus, increased proprioceptive muscle reflexes, and muscle spasms (fasciculations).

According to published data, adding carbamazepine to ongoing neuroleptic therapy may increase the risk of neuroleptic malignant syndrome or Stevens-Johnson syndrome.

When isotretinoin (an acne treatment) is used concomitantly with carbamazepine, plasma levels of carbamazepine should be monitored.

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

Carbamazepine may reduce the effectiveness of hormonal contraceptives, and breakthrough bleeding may occur during their use. Therefore, either the contraceptive should contain more than 50 µg of estrogen, or non-hormonal methods of contraception should be recommended.

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

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

Carbamazepine may reduce plasma levels of bupropion and increase levels of the metabolite hydroxybupropion, thereby reducing the clinical efficacy and safety of bupropion.

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

Contraindicated interactions.

Since carbamazepine is structurally similar to tricyclic antidepressants, Tegretol® is contraindicated for concomitant use with monoamine oxidase inhibitors (MAOIs); treatment with an MAOI inhibitor must be discontinued before starting Tegretol® (at least two weeks prior, or earlier if clinically justified).

Effect on serological testing.

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 immunoassays using fluorescence polarization techniques for tricyclic antidepressants.

Special precautions.

General.

Tegretol® should be used only under medical supervision, only after assessment of the benefit/risk ratio and with careful monitoring of patients with cardiac, hepatic or renal disorders, history of adverse hematological reactions to other drugs, disorders of sodium metabolism, and patients with interrupted courses of Tegretol® therapy.

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

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

The possibility of activation of latent psychoses should be considered. In elderly patients, the possibility of activation of confusion and anxious agitation should be taken into account.

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

Hematological effects.

The use of Tegretol® has been associated with the development of agranulocytosis and aplastic anemia; however, due to the extremely low frequency of these conditions, it is difficult to assess the actual risk associated with Tegretol® use. The overall risk in untreated patients is 4.7 cases per 1,000,000 per year for agranulocytosis and 2 cases per 1,000,000 per year for aplastic anemia.

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

If leukocyte or platelet counts significantly decrease during therapy, the patient's condition should be closely monitored, and regular complete blood counts should be performed. Treatment with Tegretol® should be discontinued if the patient develops serious, progressive leukopenia, especially if accompanied by clinical symptoms such as fever or sore throat. Tegretol® therapy should be discontinued upon signs of bone marrow suppression.

Temporary or persistent reduction in platelet or white blood cell counts may occur periodically or frequently during Tegretol® therapy. However, most of these cases have been shown to be transient and do not indicate the development of aplastic anemia or agranulocytosis. Blood tests, including platelet count (and possibly reticulocyte count, hemoglobin level, and serum iron level), should be performed before starting therapy and periodically during treatment.

Serious dermatological reactions. Serious dermatological reactions, including toxic epidermal necrolysis (TEN) or Lyell’s syndrome, and Stevens-Johnson syndrome (SJS), occur very rarely with Tegretol®. Patients with serious dermatological reactions may require hospitalization, as these conditions can be life-threatening and fatal. Most cases of SJS/TEN occur within the first few months of Tegretol® treatment. It is estimated that these dermatological reactions occur in 1–6 per 10,000 new patients in countries with predominantly Caucasian populations. However, the risk may be approximately 10 times higher in patients from certain Asian countries. If symptoms suggestive of serious dermatological reactions (e.g., SJS, Lyell’s syndrome/TEN) develop, Tegretol® should be immediately discontinued and alternative therapy initiated.

Pharmacogenomics.

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

Association with (HLA)-B*1502

Retrospective studies in Han Chinese patients have demonstrated a strong correlation between carbamazepine-related skin reactions (SJS/TEN) and the presence of human leukocyte antigen (HLA) allele (HLA)-B*1502. The prevalence of this HLA-B*1502 allele ranges from 2% to 12% in Han Chinese patients and is approximately 8% in Thai patients. A higher frequency of SJS reports (rare rather than very rare) is characteristic of certain Asian countries (e.g., Taiwan, Malaysia, and the Philippines), where the (HLA)-B*1502 allele is prevalent. The carrier frequency of this allele exceeds 15% in the populations of the Philippines and certain Malaysian populations. Prevalence of 2% and 6% has been reported in Korea and India, respectively. The prevalence of the (HLA)-B*1502 allele is negligible in Caucasian, African, Native American, and Latin American populations (<1%).

The allele prevalence stated in this document represents the percentage of chromosomes in specific populations carrying the respective allele. Thus, the percentage of patients carrying at least one copy of the allele on either of their two chromosomes (i.e., "carrier frequency") is nearly twice the allele prevalence. Therefore, the percentage of patients at risk is nearly twice the allele prevalence.

For patients considered genetically at risk, testing for the presence of the (HLA)-B*1502 allele should be performed before initiating Tegretol® therapy. If the patient tests positive for (HLA)-B*1502, Tegretol® therapy should not be initiated, except when no other therapeutic options are available. When assessing risk, it should be remembered that the HLA-B*1502 allele is also a risk factor for other antiepileptic drugs. 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.

It has been established that identifying patients carrying the HLA-B*1502 allele and avoiding carbamazepine use in these Han Chinese patients reduces the incidence of carbamazepine-induced SJS/TEN.

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

The (HLA)-B*1502 allele may be a risk factor for SJS/TEN in Chinese patients receiving other antiepileptic drugs associated with SJS/TEN. Therefore, other drugs potentially 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 of nationalities with a low frequency of the (HLA)-B*1502 allele. Screening is generally not recommended for patients already receiving Tegretol®, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of the presence of the (HLA)-B*1502 allele.

Genetic screening results should not replace appropriate clinical monitoring, as many HLA-B*1502 carriers do not develop SJS/TEN, while other patients without genetic risk factors may develop SJS/TEN for other reasons. The situation is similar for carriers of the HLA-A*3101 allele receiving Tegretol®. Such patients do not necessarily develop SJS/TEN, DRESS, AGEP, or maculopapular rash. However, serious skin adverse reactions may occur in patients without the HLA-A*3101 allele for other reasons. To date, no studies have been conducted on how other factors (such as dosage, treatment adherence, concomitant medications, and comorbidities) contribute to the development of these serious dermatological reactions.

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 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, Tegretol® use should be avoided.

Retrospective analyses in Japanese and Northern European patients have demonstrated an association between severe skin reactions (Stevens-Johnson syndrome, Lyell’s syndrome, drug rash with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, and maculopapular rash) in carriers of the HLA-A*3101 allele of the human leukocyte antigen (HLA) gene and carbamazepine use.

The prevalence of this allele varies among different ethnic groups: approximately 2–5% in European populations, about 10% in Japanese. The prevalence is less than 5% in populations of Australia, Asia, Africa, and North America. In Western European populations, the prevalence of the HLA-A*3101 allele is estimated at approximately 6.7%, depending on the geographical region, with exceptions ranging from 5% to 12%. Prevalence exceeding 15% has been established in certain South American ethnic groups (Argentina and Brazil), Native North American populations (Navajo and Sioux tribes, Seri in Mexico), and South India (Tamil Nadu).

Before initiating Tegretol® therapy, screening for the HLA-A*3101 allele is recommended in potential carriers (e.g., Japanese, Caucasians, Native Americans, Latin Americans, South Indian, and Arab patients) (see section "Dosage and administration"). The drug should be used in carriers of this allele only when the benefit of therapy outweighs the potential risk. Screening for the HLA-A*3101 allele is generally not required in patients who have already received Tegretol® for a prolonged period, as SJS/TEN, AGEP, DRESS, and maculopapular rash are typically observed only within the first few months of therapy.

Limitations of genetic screening

Genetic screening results should not replace appropriate clinical monitoring and patient management. Other potential factors, such as antiepileptic drug dosage, treatment adherence, and concomitant therapy, may 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-serious dermatological reactions, such as isolated macular or maculopapular exanthema, may also occur. These usually resolve within a few days or weeks, either with continued dosing or after dose reduction. Since early signs of more serious dermatological reactions may be difficult to distinguish from mild transient reactions, patients should be closely monitored so that drug use can be immediately discontinued if the reaction worsens.

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

Hypersensitivity.

Type I (immediate-type) hypersensitivity reactions have occurred with Tegretol®, including rash, pruritus, urticaria, and angioedema (affecting the larynx, glottis, lips, and eyelids), as well as cases of fatal or life-threatening anaphylaxis. If such reactions occur during Tegretol® use, the drug should be discontinued and alternative therapy initiated.

Tegretol® may provoke delayed-type IVb hypersensitivity reactions, including drug rash with eosinophilia and systemic symptoms (DRESS), multiple delayed hypersensitivity reactions with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, altered liver function tests, and vanishing bile duct syndrome (including destruction and disappearance of intrahepatic bile ducts), 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 (Trileptal®).

Cross-hypersensitivity may occur with carbamazepine and aromatic antiepileptic drugs (e.g., phenytoin, primidone, and phenobarbital).

In general, if symptoms suggestive of hypersensitivity occur, Tegretol® should be immediately discontinued.

Seizures. Since carbamazepine may cause or exacerbate absence seizures, Tegretol® should be used with caution in patients with mixed seizure types that include absence seizures (typical or atypical). In such cases, the drug may provoke seizures. If seizures are provoked, Tegretol® therapy should be immediately discontinued.

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. The drug should be immediately discontinued in case of acute exacerbation of liver function disorders or during the active phase of liver disease.

Kidney function. Assessment of kidney function and blood urea nitrogen (BUN) levels is recommended at the beginning and periodically during therapy.

Hyponatremia. Cases of hyponatremia have been reported with carbamazepine use. In patients with pre-existing renal dysfunction associated with low sodium levels, or in patients receiving concomitant medications that reduce sodium levels (such as diuretics or drugs associated with inappropriate antidiuretic hormone secretion), serum sodium levels should be measured before treatment. Subsequently, sodium levels should be measured every 2 weeks, then monthly during the first 3 months of treatment or as clinically indicated. These risk factors (diuretic use, drug-induced hyponatremia, cranial trauma, initially low sodium levels) should be particularly considered in elderly patients. If hyponatremia occurs, water restriction is an important countermeasure if clinically indicated.

Hypothyroidism. Carbamazepine may reduce thyroid hormone concentrations, necessitating an increase in thyroid hormone replacement therapy dosage in patients with hypothyroidism. Therefore, monitoring of thyroid function is recommended to determine the appropriate dose of replacement hormone therapy.

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

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

Suicidal thoughts and behavior. There have been several reports of suicidal thoughts and behavior in patients receiving antiepileptic drugs. A meta-analysis of data from placebo-controlled trials of antiepileptic drugs also showed a small increased risk of suicidal thoughts and behavior. The mechanism of this risk is unknown, and available data do not exclude an increased risk of suicidal thoughts and behavior with carbamazepine use.

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

Pregnancy. Congenital malformations and nervous system disorders may occur when carbamazepine is used during pregnancy. For epilepsy treatment during pregnancy, carbamazepine should be used only if the potential benefit justifies the potential risk. For psychiatric indications and neuropathic pain, carbamazepine should not be used; alternative treatments should be considered for such patients.

Pregnant women and women planning pregnancy should be adequately counseled regarding the potential teratogenic risk to the unborn child.

Women planning pregnancy should use reliable contraception during carbamazepine therapy and for 2 weeks after the last dose.

Hormonal contraceptives. Breakthrough bleeding has been reported in women using hormonal contraceptives. Tegretol may negatively affect the efficacy of hormonal contraceptives. Therefore, women of reproductive age should be advised to use alternative non-hormonal contraceptive methods during Tegretol therapy.

Endocrine effects. Due to hepatic enzyme induction, Tegretol® 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. Female patients taking Tegretol® who require hormonal contraception should receive a preparation containing at least 50 mcg of estrogen, or alternative effective and reliable non-hormonal contraceptive methods should be considered during Tegretol® therapy.

Plasma level monitoring. Although the correlation between dosage and plasma carbamazepine levels, as well as between plasma carbamazepine levels and clinical efficacy and tolerability, is unreliable, monitoring plasma drug levels may be useful in the following cases: sudden increase in seizure frequency, assessment of patient compliance, during pregnancy, in pediatric and adolescent patients; suspected absorption impairment, suspected toxicity, and when multiple drugs are used.

Dose reduction and drug discontinuation. Abrupt discontinuation of Tegretol® may provoke seizures. If immediate discontinuation of therapy is necessary, patients with epilepsy should be transitioned to a new antiepileptic drug while continuing appropriate medication therapy.

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

Falls. Tegretol® therapy has been associated with ataxia, dizziness, somnolence, orthostatic hypotension, confusion, or lethargy (see "Adverse reactions"), which may lead to falls and, consequently, fractures or other injuries. In patients experiencing these conditions or taking medications that exacerbate them, a comprehensive fall risk assessment should be regularly performed during long-term Tegretol® therapy.

Other

During carbamazepine therapy, patients should avoid exposure to strong sunlight due to the risk of photosensitization.

The medicinal product Tegretol contains less than 1 mmol (23 mg) of sodium per tablet and is therefore considered practically sodium-free.

Use during pregnancy or breastfeeding.

In animal studies, oral administration of carbamazepine caused developmental defects.

Due to enzyme induction, Tegretol® may counteract the therapeutic effect of drugs containing estrogens and/or progestogens, potentially leading to contraceptive failure. Therefore, women planning pregnancy should use alternative effective and reliable contraceptive methods during Tegretol therapy.

Pregnancy

There is clear evidence of risk to the human fetus. Therefore, Tegretol® should not be used during pregnancy unless absolutely necessary (see section "Special precautions, Pregnancy").

It should be noted that developmental disorders, including congenital malformations, occur 2–3 times more frequently in children of women with epilepsy than in healthy individuals. The extent to which these effects are attributable to carbamazepine or the underlying disease is not fully established.

According to the North American Pregnancy Registry, the prevalence of serious structural anomalies requiring surgical, medical, or cosmetic correction, diagnosed within 12 weeks after birth, was 3.0% (95% CI [confidence interval] 2.1–4.2%) among 1,033 pregnant women who took carbamazepine as monotherapy during the first trimester, compared to 1.1% (95% CI 0.37–2.6%) among pregnant women who did not take any antiepileptic drugs (relative risk 2.7; 95% CI 1.0–7.0%).

According to the European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), the prevalence of major congenital malformations was 5.5% (95% CI: 4.5–6.6) among 1,957 pregnancies exposed to carbamazepine. Major congenital malformations were recorded within 12 months after birth. Compared to lamotrigine, levetiracetam, and oxcarbazepine, carbamazepine was associated with an increased risk of serious congenital malformations (lamotrigine — OR [odds ratio]: 2.68, 95% CI: 1.71–4.19; levetiracetam — OR: 2.41, 95% CI: 1.33–4.38; oxcarbazepine — OR: 2.37, 95% CI: 1.17–4.80). Nervous system disorders have been reported in children of women with epilepsy who received carbamazepine alone or in combination with other antiepileptic drugs during pregnancy. Data on the risk of neurodevelopmental disorders (such as autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), intellectual disability, psychomotor delay, cognitive disorders, learning disabilities, schizophrenia, etc.) in children exposed to carbamazepine in utero are conflicting, and this risk cannot be excluded.

Children of mothers with epilepsy are predisposed to intrauterine developmental disorders, including congenital malformations. It has been reported that carbamazepine, like most antiepileptic drugs, may increase the frequency of these disorders, although convincing evidence from controlled monotherapy studies is lacking. However, intrauterine developmental disorders and congenital malformations associated with Tegretol® use have been reported, including spina bifida and other congenital anomalies such as craniofacial defects, cardiovascular malformations, hypospadias, and developmental anomalies of various organ systems.

Specifically, from the 20th to the 40th day of pregnancy, the drug dose should be minimal. Developmental anomalies are likely related to peak plasma levels. Therefore, during this period, the total daily dose should be divided into several doses throughout the day. Plasma level monitoring is recommended. Plasma concentrations should be maintained at the lower end of the therapeutic range (4–12 mcg/mL), provided seizure control is maintained. Data suggest that the risk of malformations with carbamazepine is dose-dependent; at doses <400 mg/day, the frequency of developmental anomalies was lower than with higher carbamazepine doses.

Throughout pregnancy and after delivery, patients should remain under medical supervision (plasma level monitoring and EEG). Plasma concentration should be maintained at the lower end of the therapeutic range (3–7 mcg carbamazepine/mL). The risk of malformations increases with combination therapy; therefore, combination with other antiepileptic drugs or other medications should be avoided to further reduce risk.

Monotherapy is recommended. Data indicate that the risk of malformations with carbamazepine in polytherapy may vary depending on concomitant drugs and may be higher with combinations including valproate.

Due to carbamazepine's enzyme-inducing properties, folic acid supplementation (prevention of neural tube defects) is recommended before and during pregnancy.

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

Newborns. To prevent coagulation disorders in newborns, vitamin K1 is recommended for mothers 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 vomiting, diarrhea, and/or poor appetite in newborns, associated with Tegretol® and other anticonvulsant use.

Breastfeeding. Adverse effects in offspring have been observed in rat studies when dams were administered carbamazepine. Carbamazepine passes into breast milk (25–60% of plasma concentration). The benefits of breastfeeding versus the remote possibility of adverse effects in the infant should be carefully weighed. The benefits of breastfeeding generally outweigh the risk of adverse effects. Breastfeeding should be discontinued if the infant fails to gain weight adequately, is excessively sleepy, or develops allergic skin reactions. Cholestatic hepatitis has been reported in children exposed to carbamazepine prenatally or via breast milk; therefore, monitoring for hepatobiliary adverse effects in such children is recommended. Mothers receiving Tegretol® 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. However, a causal relationship with Tegretol® has not yet been established.

Ability to affect reaction speed when driving or operating machinery.

The patient's ability to react quickly (especially at the beginning of therapy or during dose adjustment) may be reduced both due to seizures caused by the disease and due to adverse effects resulting from Tegretol® use, such as dizziness, somnolence, ataxia, diplopia, accommodation disorders, and visual disturbances. Therefore, patients should exercise caution when driving or operating machinery.

Method of Administration and Dosage

Tegretol® should be administered orally; the daily dose is usually divided into two or three doses. Tablets (whole tablets or, if prescribed, half tablets) should be swallowed whole, without chewing, with a small amount of liquid. The medication may be taken during, after, or between meals, together with a small amount of liquid, for example, a glass of water.

Before initiating treatment, patients who are potentially carriers of the HLA-A*3101 allele based on their ancestry should, whenever possible, be tested for the presence of this allele, as its presence may provoke severe adverse reactions, such as skin reactions.

Epilepsy

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

Determining plasma levels of carbamazepine may be helpful in establishing the optimal dosage.

Particularly in combination therapy, therapeutic doses should be determined based on plasma carbamazepine levels and clinical efficacy.

Experience has shown that therapeutic levels of carbamazepine range between 4–12 μg/mL.

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; a common daily dose is 400 mg twice or three times daily (corresponding to 800–1200 mg/day). Some patients may require a Tegretol® dose up to 1600 mg or even 2000 mg daily, although such high doses should be avoided due to the increased frequency of adverse effects.

Elderly patients: due to the potential for drug interactions, Tegretol® dosage should be carefully titrated in elderly patients. The recommended initial dose is 100 mg twice daily.

Children: treatment may be initiated with a dose of 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 (administered in multiple doses).

Child's age	Daily dose
6–10 years	400–600 mg (in 2–3 doses)
11–15 years	600–1000 mg (in 3 doses)

For children aged 15 years and older, the dosage is the same as for adults.

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

When Tegretol® is prescribed in addition to ongoing antiepileptic therapy, the dose should be gradually increased without changing the dose of the currently used antiepileptic drug(s), or adjusting it if necessary.

Acute manic episodes and maintenance therapy in bipolar affective disorders

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

Alcohol withdrawal syndrome

Average dose – 200 mg three to four times daily. In severe cases, the dose may be increased during the first few days (e.g., up to 400 mg three times daily (1200 mg/day)). The dose should then be gradually reduced and therapy tapered off gradually. In severe cases of alcohol withdrawal, treatment should be initiated with a combination of Tegretol® and sedative-hypnotic agents (e.g., with clomethiazole, chlordiazepoxide), following the dosage recommendations outlined above. After completion of the acute phase, treatment with Tegretol® may continue as monotherapy.

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

Initial dose of Tegretol® is 200–400 mg daily (100 mg twice daily for elderly patients). The dose should be slowly increased until pain relief is achieved (usually to a dose of 200 mg three to four times daily). For most patients, a dose of 200 mg three or four times daily is sufficient to maintain a pain-free state. In some cases, a daily dose of Tegretol® up to 1600 mg may be required. After pain relief is achieved, the dose should be gradually reduced to the lowest effective maintenance dose. The maximum recommended dose is 1200 mg daily. The dose should then be gradually reduced and therapy tapered off gradually.

Children

Due to a faster elimination of carbamazepine, children may require higher doses of the drug (on a mg/kg basis) compared to adults. Tegretol® tablets may be administered to children aged 6 years and older.

Overdose

Symptoms. Symptoms and complaints occurring in overdose typically reflect involvement of the central nervous, cardiovascular, and respiratory systems, as well as adverse reactions to the drug listed in the section "Adverse Reactions."

Central nervous system: CNS depression; confusion, 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, occasionally arterial hypertension, conduction disturbances with widening of the QRS complex; syncope associated with cardiac arrest, accompanied by loss of consciousness.

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

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

Urinary system: Urinary retention, oliguria or anuria; fluid retention; water intoxication due to an 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 with this agent and to assess the degree 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, with continuous cardiac monitoring and careful correction of electrolyte disturbances.

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

Hemosorption using charcoal adsorbents is recommended. Hemodialysis is an effective treatment method for carbamazepine overdose. Forced diuresis and peritoneal dialysis have been reported as ineffective.

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

Adverse reactions.

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

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

Adverse effects observed during clinical trials and those identified based on spontaneous post-marketing reports are listed below.

The frequency of adverse reactions was determined according to the following criteria: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10,000, < 1/1000); very rare (< 1/10,000); unknown (frequency cannot be estimated from available data).

Infections and parasitic diseases: unknown – reactivation of human herpesvirus type 6.

Blood and lymphatic system disorders: very common – leukopenia (11%), persistent in 2% of cases; common – thrombocytopenia, eosinophilia; rare – lymphadenopathy, folic acid deficiency; very rare – leukocytosis, agranulocytosis, aplastic anemia, pancytopenia, erythroblastopenia, anemia, megaloblastic anemia, acute intermittent porphyria, mixed porphyria, late cutaneous porphyria, reticulocytosis, hemolytic anemia; unknown – bone marrow failure.

Immune system disorders: rare – multiorgan hypersensitivity reaction of delayed type with fever, skin rash, vasculitis, lymphadenopathy, lymphoma-like symptoms, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, and altered liver function tests, as well as duct disappearance 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); very rare – aseptic meningitis with myoclonus and peripheral eosinophilia; anaphylactic reaction, angioneurotic edema, hypogammaglobulinemia; unknown – drug reaction with eosinophilia and systemic symptoms (DRESS).

Endocrine system disorders: common – edema, fluid retention, weight gain, hyponatremia, and decreased plasma osmolality due to an antidiuretic hormone-like effect, which in isolated cases may lead to hyperhydration accompanied by lethargy, vomiting, headache, confusion, neurological disturbances, seizures, disorientation, impaired cognition, visual disturbances, or encephalopathy (syndrome of inappropriate antidiuretic hormone secretion, SIADH); very rare – increased blood prolactin levels, with or without associated symptoms such as galactorrhea, gynecomastia; changes in thyroid function tests: decreased levels of L-thyroxine (free thyroxine (FT4), thyroxine (T4), triiodothyronine (T3)) and increased levels of thyroid-stimulating hormone (TSH), which usually do not manifest clinically; disturbances in bone metabolism (decreased plasma calcium and 25-hydroxycholecalciferol levels), leading to osteomalacia/osteoporosis; in individual cases – increased cholesterol concentration, including high-density lipoprotein cholesterol and triglycerides.

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

Nervous system disorders: very common – dizziness (10–50%), ataxia (children – 10.4%, adults – 50%), somnolence, general weakness; common – headache, diplopia, visual accommodation disorders (e.g., blurred vision); uncommon – abnormal involuntary movements (e.g., tremor, "fluttering" tremor, dystonia, tic), nystagmus; rare – orofacial dyskinesia, eye movement disorders, speech disorders (e.g., dysarthria or slurred speech), choreoathetosis, peripheral neuropathy, paresthesia, muscle weakness, and paresis; very rare – taste disturbances, malignant neuroleptic syndrome (NMS), aseptic meningitis with myoclonus and peripheral eosinophilia, dysgeusia; unknown – sedative effect, memory impairment.

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

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

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

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

Gastrointestinal disorders: very common – nausea, vomiting (both 8%); common – dry mouth; uncommon – diarrhea or constipation; rare – abdominal pain; very rare – glossitis, stomatitis, pancreatitis; unknown – colitis.

Hepatobiliary disorders: very common – increased levels of gamma-glutamyltransferase (due to induction of liver enzymes), which is usually not clinically significant; common – increased levels of alkaline phosphatase in blood; uncommon – increased transaminase levels; rare – hepatitis of cholestatic, parenchymal (hepatocellular), or mixed type, bile duct disappearance syndrome, jaundice; very rare – granulomatous hepatitis, liver failure.

Skin and subcutaneous tissue disorders: very common – allergic dermatitis, pruritus, urticaria, sometimes in severe form; uncommon – exfoliative dermatitis, erythroderma; rare – systemic lupus erythematosus, pruritus; very rare – Stevens-Johnson syndrome (in some Asian countries this adverse event has also been reported with a frequency of "rare"), toxic epidermal necrolysis, photosensitivity, erythema multiforme and nodular erythema, skin pigmentation disorders, purpura, acne, increased sweating, excessive hair loss, hirsutism; unknown – acute generalized exanthematous pustulosis, lichenoid keratosis, onycho-madesis.

Musculoskeletal and connective tissue disorders: rare – muscle weakness; very rare – arthralgia, myalgia, muscle spasms, disturbances in bone metabolism (decreased plasma calcium and 25-hydroxycholecalciferol levels, which may lead to osteomalacia or osteoporosis); unknown – decreased bone mineral density, fractures.

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

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

Very rare reports of impaired male fertility and/or impaired spermatogenesis have been documented.

General disorders: very common – general weakness.

Laboratory and instrumental findings: very common – increased gamma-glutamyltransferase levels (due to induction of liver enzymes), which is usually not clinically significant; common – increased blood alkaline phosphatase levels; uncommon – increased transaminase levels; very rare – increased intraocular pressure, hypogammaglobulinemia.

Adverse reactions based on spontaneous reports (frequency unknown).

Information on the above-mentioned adverse reactions was obtained from post-marketing use of the drug via spontaneous reports and publications. Since these reports are spontaneous, it is not possible to determine the exact number of affected patients or reliably estimate the frequency of adverse reactions; therefore, their frequency is classified as "unknown."

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Packaging. 10 tablets in a blister pack, 5 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Novartis Farma S.p.A., Italy / Novartis Farma S.p.A. Italy.

Address. Via Provinciale Schito 131, 80058 Torre Annunziata (NA), Italy.