Tegretol CR, 200 mg, extended-release film-coated tablets, 50 pcs., Novartis Pharma buy in Moscow at a low price

Tegretol CR, 50 pcs., 200 mg, extended-release, film-coated tablets

The drug should be taken only under medical supervision.

Patients with mixed forms of epileptic seizures, including absence and myoclonic seizures

The drug is usually ineffective for absence seizures (petit mal) and myoclonic seizures. In patients with mixed forms of epileptic seizures, the drug should be used with caution and only with regular medical supervision (due to a possible increase in seizures). If attacks intensify, Tegretol® CR should be discontinued.

Decreased platelet and white blood cell counts

During use of the drug with varying frequency, a transient or persistent decrease in the number of platelets or leukocytes is observed. However, in most cases these phenomena are transient and usually do not predict the onset of aplastic anemia or agranulocytosis.

Before starting treatment, as well as periodically during treatment, clinical blood tests should be performed, including counting the number of platelets and, possibly, reticulocytes, as well as determining the concentration of iron in the blood serum.

Patients should be informed of early signs of toxicity associated with possible hematological disorders, as well as skin and liver symptoms. The patient is informed of the need to immediately consult a doctor in case of adverse reactions such as fever, sore throat, rash, mouth ulcers, unexplained hemorrhages, hemorrhages in the form of petechiae or purpura.

In cases where a low white blood cell or platelet count (or a trend towards a decrease) is noted during treatment, the patient's condition and complete clinical blood count should be closely monitored. If signs of significant bone marrow suppression are detected, Tegretol® CR should be discontinued.

Dermatological reactions

When using the drug Tegretol® CR, severe dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), were very rarely observed.

The drug Tegretol® CR should be immediately discontinued and alternative therapy should be selected if signs and symptoms are observed that presumably indicate the development of severe dermatological reactions - for example, Stevens-Johnson syndrome or Lyell's syndrome. If severe (in some cases life-threatening) skin reactions develop, the patient should be hospitalized in a hospital. In most cases, Stevens-Johnson syndrome and Lyell's syndrome developed in the first months of drug therapy. These reactions occurred in approximately 1-6 cases per 10,000 people taking the drug for the first time in countries with a predominantly Caucasian population.

Data from a retrospective analysis of Japanese and Northern European patients demonstrated an association between severe skin lesions (Stevens-Johnson syndrome, Lyell's syndrome, drug rash with eosinophilia and systemic manifestations, acute generalized exanthematous pustulosis and macular nodular rash) in carriers of the HLA-A allele *3101 human leukocyte antigen (HLA) gene and the use of carbamazepine.

The frequency of the HLA-A*3101 allele of the human leukocyte antigen (E1LA) gene may differ among different ethnic groups: about 2-5% in the European population, about 10% in the Japanese. The allele frequency is less than 5% in the populations of Australia, Asia, Africa and North America, with exceptions ranging from 5% to 12%. A frequency of more than 15% has been found in some ethnic groups of South America (Argentina and Brazil), indigenous people of North America (Navajo and Sioux tribes, Sanora Seri in Mexico), South India (Tamil Nadu), and 10-15% among other indigenous people these regions.

When using carbamazepine in possible carriers of the HLA-A*3101 allele (for example, patients of Japanese nationality, Caucasians, Native Americans, Latin Americans, people of southern India and Arabs), it is recommended to carry out genotyping for this allele. The drug should be used in carriers of this allele only if the benefits of therapy outweigh the possible risks.

For patients already receiving therapy with Tegretol® CR, genotyping for this allele is not recommended, since severe skin reactions in most cases were observed in the first months of drug use (regardless of the presence of HLA-A*3101).

According to a retrospective analysis of the use of the drug in patients of Chinese and Thai nationality, there is a correlation between the incidence of Stevens-Johnson syndrome and Lyell syndrome and the presence of the HLA-B*1502 allele of the human leukocyte antigen (HLA) gene in the patient’s genome. The frequency of occurrence of this allele in patients of Chinese nationality is 2-12%, in Thai patients it is about 8%.

When carbamazepine was used in patients in the countries of the Asian region (Taiwan, Malaysia, the Philippines), where there is a high prevalence of the HLA-B* 1502 allele, an increase in the incidence of Stevens-Johnson syndrome was detected (from “very rare” to “rare”). The frequency of distribution of the HLA-B* 1502 allele is: in the Philippines and among some groups of the population of Malaysia - more than 15%. The prevalence of the HLA-BM502 allele in Korea and India is 2% and 6%, respectively.

The prevalence of this allele in people of Caucasian, Negroid races, Latin Americans, Indians and Japanese is insignificant (<1%). These allele frequencies represent the percentage of chromosomes in specific populations that carry the allele. This means that the percentage of patients carrying a copy of the allele on at least one of their two chromosomes is almost twice the frequency of the allele. Thus, the percentage of patients who may be at risk is almost twice the allele frequency.

When using carbamazepine in possible carriers of the HLA-B*1502 allele, it is recommended to carry out genotyping for this allele.

The drug should be used in carriers of this allele only if the benefits of therapy outweigh the possible risks. It is not recommended to carry out genotyping in representatives of nationalities in whose population the frequency of occurrence of the specified allele is low.

Identification of patients with the presence of the HLA-B* 1502 allele and avoidance of carbamazepine use in such patients has been shown to reduce the incidence of carbamazepine-induced Stevens-Johnson syndrome or Lyell's syndrome.

However, the results of genotyping should not affect the degree of monitoring of the patient's condition and the doctor's alertness regarding severe skin reactions. The development of severe skin lesions is possible in patients negative for these alleles. Also, in many cases, in patients positive for the HLA-B* 1502 or HLA-A*3101 alleles, the development of severe skin syndromes was not observed when using the drug Tegretol® CR.

The influence of other factors, such as the dose of anticonvulsants, patient compliance, concomitant therapy with other drugs, concomitant diseases, or the level of control of dermatological reactions, on the incidence and prevalence of severe skin reactions has not been established.

Mild skin reactions, for example, isolated macular or maculopapular exanthema, are in most cases transient and mild, usually disappearing within a few days or weeks with continued treatment or after reducing the dose of the drug. However, since differential diagnosis between early manifestations of severe skin reactions and mild, transient skin rashes can be difficult, if any skin reactions develop, the patient should be under medical supervision (with a view to timely discontinuation of drug therapy if the patient's condition worsens).

There is a relationship between the presence of the HLA-A*3101 allele in the genome and the development of less severe skin reactions (such as hypersensitivity syndrome to anticonvulsants or mild maculopapular exanthema); such a relationship has not been established for the HLA-B*1502 allele.

Hypersensitivity reactions

With the development of hypersensitivity to the drug Tegretol® CR, patients may experience various reactions, including drug rash with eosinophilia and systemic manifestations, delayed multiorgan manifestations of hypersensitivity with the development of fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, changes in parameters liver function and bile duct destruction syndrome with a decrease in their number, which can occur in any combination. Damage to other internal organs (including lungs, kidneys, pancreas, myocardium, colon) is also possible.

In case of development of manifestations and symptoms of hypersensitivity to the drug Tegretol® CR, the drug should be discontinued immediately.

Patients with known hypersensitivity to carbamazepine should be informed of the possibility of developing hypersensitivity reactions to oxcarbazepine in 25-30% of cases. Cross-hypersensitivity reactions also occur between carbamazepine and phenytoin.

Hyponatremia

The development of hyponatremia is associated with the use of carbamazepine. In patients with pre-existing renal impairment associated with low serum sodium or in patients receiving concomitant drugs that reduce sodium (eg, diuretics, drugs that affect antidiuretic hormone secretion), serum sodium should be determined before initiation of carbamazepine therapy. Thereafter, sodium levels should be determined approximately two weeks later and then monthly for the first three months of therapy, or as clinically necessary. These risk factors are especially common in older patients. If hyponatremia occurs, water restriction is an important criterion to determine the condition when clinically indicated.

Hypothyroidism

Carbamazepine may reduce serum concentrations of thyroid hormones through enzyme induction, requiring an increase in the dose of drugs used for replacement therapy in patients with hypothyroidism. In this category of patients, monitoring of thyroid function is necessary to select the dose of replacement therapy drugs.

Liver dysfunction

Before using the drug Tegretol® CR and during treatment, it is necessary to conduct a liver function test, especially in patients with a history of liver disease, as well as in elderly patients. If pre-existing liver dysfunction worsens or active liver disease develops, Tegretol® should be discontinued immediately.

Renal dysfunction

Before starting treatment with the drug and periodically during therapy, it is recommended to conduct a general urine test and determine the concentration of urea in the blood.

M-anticholinergic activity

The drug has weak m-anticholinergic activity. Therefore, when using the drug in patients with increased intraocular pressure and urinary retention, constant monitoring of this indicator is necessary.

Mental disorders

Since the use of the drug may exacerbate latent mental disorders, elderly patients should be monitored to identify symptoms such as confusion and psychomotor agitation.

Suicidal behavior or intentions

Cases of suicidal behavior or intent have been reported in patients receiving anticonvulsants for a number of indications. The results of a meta-analysis of randomized placebo-controlled trials showed a small increase in the risk of developing suicidal behavior in patients receiving anticonvulsants. The mechanism of increased suicidal behavior in this category of patients has not been established. Therefore, careful monitoring of symptoms of suicidal behavior and intentions and decisions on appropriate treatment are necessary. Patients (and their caregivers) should be strongly advised to seek help from a physician if they experience symptoms of suicidal behavior or intentions.

Endocrinological disorders

The drug may reduce the effectiveness of medications containing estrogens and/or progesterone, so women of childbearing age should use alternative methods of birth control during treatment with the drug.

To date, there have been very rare reports of disturbances in male fertility and/or disturbances in spermatogenesis.

Determination of carbamazepine concentration in blood plasma

Although the relationship between drug dose, carbamazepine plasma concentration, clinical efficacy or tolerability is very small, regular determination of carbamazepine concentration may be advisable in the following situations: when there is a sharp increase in the frequency of attacks, in order to check whether the patient is taking the drug properly; during pregnancy; when treating children or adolescents; if there is a suspicion of impaired absorption of carbamazepine; if toxic reactions are suspected if the patient is taking several medications.

Tegretol®

While taking Tegretol, agranulocytosis and aplastic anemia may develop. However, because these conditions occur so rarely, it is difficult to calculate specific risk values for them. It is known that the total risk of developing agranulocytosis in the general untreated population is 4.7 cases per 1 million population per year, and aplastic anemia is 2.0 cases per 1 million population per year.

During the use of Tegretol with varying frequency, a transient or persistent decrease in the number of platelets or leukocytes is observed. However, in most cases, these side effects are transient and usually do not predict the onset of aplastic anemia or agranulocytosis. However, before starting treatment, and periodically during treatment, clinical blood tests should be performed, including platelet counts and possibly reticulocyte counts, and serum iron levels should be determined.

In cases where a low level of white blood cell or platelet count (or a tendency to decrease) is noted during treatment, the patient's condition and complete clinical blood count should be closely monitored. If signs of significant bone marrow suppression are detected, Tegretol should be discontinued.

Tegretol should be discontinued immediately if signs and symptoms suggestive of severe dermatological reactions, such as Stevens-Johnson syndrome or Lyell's syndrome, are observed.

Tegretol should only be used under medical supervision.

Caution should be exercised when using Tegretol in patients with mixed forms of epileptic seizures, including absence seizures (typical and atypical). In all these cases, Tegretol can cause increased attacks. If this happens, Tegretol should be discontinued.

Before prescribing Tegretol and during treatment, liver function testing is necessary, especially in patients with a history of liver disease, as well as in elderly patients. If pre-existing liver dysfunction worsens or if active liver disease develops, Tegretol should be discontinued immediately.

Patients should be informed of early signs of toxicity associated with possible hematological disorders, as well as skin and liver symptoms. The patient is informed of the need to immediately consult a doctor in case of adverse reactions such as fever, sore throat, rash, mouth ulcers, causeless hematomas, hemorrhages in the form of petechiae or purpura.

For patients with a history of heart, liver, kidney disease, adverse hematological reactions to other drugs, or discontinuation of previous treatment with Tegretol, the drug should be prescribed only after a thorough analysis of the relationship between the expected effect of treatment and the possible risk of therapy and with careful and regular monitoring.

Before starting treatment with Tegretol and periodically during therapy, it is recommended to study a general urine test and the level of urea in the blood.

Mild skin reactions, for example, isolated macular or maculopapular exanthema, are in most cases transient and mild, usually disappearing within a few days or weeks even with continued treatment or after a dose reduction. However, the patient should be under close medical supervision at this time.

Tegretol has weak anticholinergic activity. Therefore, when using the drug in patients with increased intraocular pressure, constant monitoring of this indicator is necessary.

The possibility of activation of latent psychoses should be taken into account, and in elderly patients, the possibility of developing disorientation or agitation.

To date, there have been isolated reports of disturbances in male fertility and/or disturbances in spermatogenesis. However, the causal relationship of these disorders with the use of Tegretol has not yet been established.

There are reports of bleeding in women between menstruation in cases where oral contraceptives were used simultaneously. Tegretol can significantly reduce the therapeutic effect of oral contraceptives due to the induction of microsomal enzymes, therefore women of childbearing age should use alternative methods of birth control during treatment with Tegretol.

Although the relationship between the dose of the drug and the level of carbamazepine in the blood plasma, as well as between the level of carbamazepine in the blood plasma and its clinical effectiveness or tolerability, is very insignificant, nevertheless, regular determination of carbamazepine levels may be useful in the following situations: with a sharp increase in the frequency of attacks; to check whether the patient is taking the drug properly; during pregnancy; when treating children or adolescents; if there is a suspicion of impaired absorption of the drug; if toxic reactions are suspected if the patient is taking several medications.

Sudden cessation of Tegretol may provoke epileptic seizures. If it is necessary to abruptly interrupt treatment with Tegretol for a patient with epilepsy, in this case it is necessary to switch to another antiepileptic drug under the cover of the drug indicated in such cases (for example, diazepam administered intravenously or rectally, or phenytoin administered intravenously).

It is possible to develop cross-reactions of hypersensitivity to carbamazepine and oxcarbazepine.

Hypersensitivity cross-reactions may also occur between carbamazepine and phenytoin.

Tegretol, like other psychotropic drugs, can reduce alcohol tolerance. In this regard, the patient is advised to stop drinking alcohol.

Several cases of epileptic seizures and/or respiratory depression have been described in newborns whose mothers took Tegretol simultaneously with other anticonvulsants. In addition, several cases of vomiting, diarrhea and/or poor nutrition in newborns have also been reported in association with maternal use of Tegretol. It is possible that these reactions represent neonatal manifestations of withdrawal syndrome.

Impact on the ability to drive vehicles and operate machinery

The ability of a patient taking Tegretol to respond quickly, especially at the beginning of therapy or during dose titration, may be impaired due to dizziness and drowsiness. Therefore, the patient should exercise caution when driving a car or operating machinery.

Tegretol

When assessing the frequency of occurrence of various adverse reactions, the following gradations were used: very often - 10% and more often; often - 1-10%; sometimes - 0.1-1%; rarely - 0.01-0.1%; very rare - less than 0.01%.

Dose-dependent adverse reactions usually resolve within a few days, either spontaneously or after a temporary dose reduction. The development of adverse reactions from the central nervous system may be a consequence of a relative overdose of the drug or significant fluctuations in the concentrations of the active substance in plasma. In such cases, it is recommended to monitor the concentration of drugs in plasma.

From the side of the central nervous system: very often - dizziness, ataxia, drowsiness, asthenia; often - headache, accommodation paresis; sometimes - abnormal involuntary movements (for example, tremor, “fluttering” tremor - asterixis, dystonia, tics); nystagmus; rarely - orofacial dyskinesia, oculomotor disorders, speech disorders (eg dysarthria), choreoathetoid disorders, peripheral neuritis, paresthesia, myasthenia gravis and symptoms of paresis. The role of carbamazepine as a drug that causes or contributes to the development of neuroleptic malignant syndrome, especially when it is prescribed together with antipsychotics, remains unclear.

From the mental sphere: rarely - hallucinations (visual or auditory), depression, loss of appetite, anxiety, aggressive behavior, agitation, disorientation; very rarely - activation of psychosis.

Allergic reactions to the components of the drug: often - urticaria; sometimes - erythroderma; rarely - lupus-like syndrome, skin itching; very rarely - exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), photosensitivity.

Rarely - multiorgan delayed-type hypersensitivity reactions with fever, skin rash, vasculitis (including erythema nodosum as a manifestation of cutaneous vasculitis), lymphadenopathy, signs resembling lymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly and altered liver function tests (these manifestations found in various combinations). Other organs (eg, lungs, kidneys, pancreas, myocardium, colon) may also be involved. Very rarely - aseptic meningitis with myoclonus and peripheral eosinophilia, anaphylactoid reaction, angioedema, allergic pneumonitis or eosinophilic pneumonia. If the above allergic reactions occur, use of the drug should be discontinued.

From the hematopoietic organs: very often - leukopenia; often - thrombocytopenia, eosinophilia; rarely - leukocytosis, lymphadenopathy, folic acid deficiency; very rarely - agranulocytosis, aplastic anemia, true erythrocyte aplasia, megaloblastic anemia, acute intermittent porphyria, reticulocytosis, hemolytic anemia.

From the digestive system: very often - nausea, vomiting; often - dry mouth; sometimes - diarrhea or constipation, abdominal pain; very rarely - glossitis, stomatitis, pancreatitis.

From the liver: very often - increased GGT activity (due to the induction of this enzyme in the liver), which usually does not matter; often - increased alkaline phosphatase activity; sometimes - increased activity of “liver” transaminases; rarely - hepatitis of cholestatic, parenchymal (hepatocellular) or mixed type, jaundice; very rarely - granulomatous hepatitis, liver failure.

From the cardiovascular system: rarely - intracardiac conduction disorders; decrease or increase in blood pressure; very rarely - bradycardia, arrhythmias, AV block with fainting, collapse, worsening or development of CHF, exacerbation of coronary heart disease (including the appearance or increase in angina attacks), thrombophlebitis, thromboembolic syndrome.

From the endocrine system and metabolism: often - edema, fluid retention, weight gain, hyponatremia (decrease in plasma osmolarity due to an effect similar to the effect of ADH, which in rare cases leads to dilution hyponatremia, accompanied by lethargy, vomiting, headache, disorientation and neurological disorders); very rarely - hyperprolactinemia (may be accompanied by galactorrhea and gynecomastia); a decrease in the concentration of L-thyroxine (free T4, T4, T3) and an increase in the concentration of TSH (usually not accompanied by clinical manifestations); disorders of calcium-phosphorus metabolism in bone tissue (decreased concentrations of Ca2+ and 25-OH-colecalciferol in plasma): osteomalacia; hypercholesterolemia (including HDL cholesterol) and hypertriglyceridemia.

From the genitourinary system: very rarely - interstitial nephritis, renal failure, impaired renal function (for example, albuminuria, hematuria, oliguria, increased urea/azotemia), frequent urination, urinary retention, decreased potency.

From the musculoskeletal system: very rarely - arthralgia, myalgia or convulsions.

From the senses: very rarely - disturbances in taste, clouding of the lens, conjunctivitis; hearing impairment, incl. tinnitus, hyperacusis, hypoacusia, changes in the perception of pitch.

Other: skin pigmentation disorders, purpura, acne, increased sweating, alopecia. Rare cases of hirsutism have been reported, but the causal relationship of this complication with carbamazepine remains unclear. Overdose. Symptoms: usually reflect disorders of the central nervous system, cardiovascular system and respiratory system.

From the side of the central nervous system and sensory organs - depression of central nervous system functions, disorientation, drowsiness, agitation, hallucinations, fainting, coma; visual disturbances (“fog” before the eyes), dysarthria, nystagmus, ataxia, dyskinesia, hyperreflexia (initially), hyporeflexia (later); convulsions, psychomotor disorders, myoclonus, hypothermia, mydriasis).

From the cardiovascular system: tachycardia, decreased blood pressure, sometimes increased blood pressure, intraventricular conduction disturbances with widening of the QRS complex; heart failure.

From the respiratory system: respiratory depression, pulmonary edema.

From the digestive system: nausea and vomiting, delayed evacuation of food from the stomach, decreased motility of the colon.

From the urinary system: urinary retention, oliguria or anuria; fluid retention; dilution hyponatremia.

Laboratory indicators: leukocytosis or leukopenia, hyponatremia, metabolic acidosis, hyperglycemia and glycosuria, increased CPK muscle fraction.

Overdose.

Treatment: there is no specific antidote. Treatment is based on the patient's clinical condition; hospitalization, determination of the concentration of carbamazepine in plasma (to confirm poisoning with this drug and assess the degree of overdose), gastric lavage, administration of activated charcoal are indicated (late evacuation of gastric contents can lead to delayed absorption for 2 and 3 days and the reappearance of symptoms of intoxication during the recovery period) .

Forced diuresis, hemodialysis and peritoneal dialysis are ineffective (dialysis is indicated for a combination of severe poisoning and renal failure). Young children may require exchange transfusions. Symptomatic supportive treatment in the intensive care unit, monitoring of cardiac function, body temperature, corneal reflexes, renal and bladder function, correction of electrolyte disorders. When blood pressure decreases: position with the head end down, plasma expanders, if ineffective - intravenous dopamine or dobutamine; for heart rhythm disturbances, treatment is selected individually; for convulsions - administration of benzodiazepines (for example diazepam), with caution (due to a possible increase in respiratory depression) administration of other anticonvulsants (for example phenobarbital). With the development of dilution hyponatremia (water intoxication), limit the administration of fluids and slow intravenous infusion of a 0.9% NaCl solution (can help prevent the development of cerebral edema). It is recommended to carry out hemosorption on carbon sorbents.

Tegretol® CR

The drug should be taken only under medical supervision.

Patients with mixed forms of epileptic seizures, including absence and myoclonic seizures

Decreased platelet and white blood cell counts

Dermatological reactions

When using the drug Tegretol® CR, severe dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), were very rarely observed.

When using carbamazepine in possible carriers of the HLA-B*1502 allele, it is recommended to carry out genotyping for this allele.

Hypersensitivity reactions

In case of development of manifestations and symptoms of hypersensitivity to the drug Tegretol® CR, the drug should be discontinued immediately.

Hyponatremia

Hypothyroidism

Liver dysfunction

Renal dysfunction

Before starting treatment with the drug and periodically during therapy, it is recommended to conduct a general urine test and determine the concentration of urea in the blood.

M-anticholinergic activity

The drug has weak m-anticholinergic activity. Therefore, when using the drug in patients with increased intraocular pressure and urinary retention, constant monitoring of this indicator is necessary.

Mental disorders

Since the use of the drug may exacerbate latent mental disorders, elderly patients should be monitored to identify symptoms such as confusion and psychomotor agitation.

Suicidal behavior or intentions

Endocrinological disorders

To date, there have been very rare reports of disturbances in male fertility and/or disturbances in spermatogenesis.

Determination of carbamazepine concentration in blood plasma

Psychiatry Psychiatry and psychopharmacotherapy named after. P.B. Gannushkina No. 1 2004 Appendix

The effectiveness of treatment of epilepsy leaves much to be desired. Continuous population studies in different regions of Russia give the proportion of patients without seizures from the total number of those treated equal to 13–28%, while with proper treatment it should be 50–80% [1]. Treatment failure is largely due to errors in the diagnosis of the form of epilepsy and the choice of drug. The purpose of this report is to determine, based on the standards and recommendations developed by experts of the International League Against Epilepsy (IAL) and our own experience, an algorithm for the treatment of focal epilepsies, which make up more than half of all cases of epilepsy, taking into account also that it is focal epilepsies that account for the bulk of drug-resistant cases that create the largest problems in treatment. According to the proposal of the Commission on the Classification and Terminology of MPEL, all focal epilepsies and epileptic syndromes are divided into: 1) idiopathic focal infancy and childhood, 2) focal familial (autosomal dominant) and 3) symptomatic or probably symptomatic focal [2]. Comparison with the 1989 Classification of Epilepsies and Epileptic Syndromes shows changes in terminology and some features of rubrification. It is proposed to abandon the term “partial” in favor of “focal”. Incorrectness of the term “partial”, i.e. incomplete, partial, is obvious, since it presupposes some ideal “complete form” of a seizure, of which the partial would be part. The second innovation is the rubric of focal familial (autosomal dominant) epilepsies. These include those few of the idiopathic focal epilepsies of the previous classification for which the gene has been mapped. Finally, the term “cryptogenic” has been removed from the terminology as redundant and implicit, and “presumably symptomatic”, which previously served as a decoding of the term “cryptogenic,” is used instead. It should be said right away that the long-practiced approach of choosing a drug based on the type of epileptic seizure turned out to be insufficient and formal adherence to it is one of the most common reasons for the failure of therapy. International experience of recent decades has shown that the algorithm for pharmacological treatment of epilepsy should include the form of epilepsy, features of the electroencephalographic (EEG) picture, the dynamics of clinical symptoms and EEG during treatment. These provisions are especially important for the effective use of one of the most widely used drugs in the treatment of focal epilepsies - tegretol.

Pharmacological properties of tegretol and principles of clinical use

Tegretol is a pharmacoform of the chemical compound carbamazepine. Carbamazepine is an iminostilbene derivative with a carbamyl group in the 6th position, which mainly determines its anticonvulsant effect. Its structural formula - 5-carbamyl-5-H-dibenzazepine - is close to tricyclic antidepressants. When carbamazepine is metabolized, carbamazepine epoxide is produced, which has the same medicinal properties as the original product, providing a significant prolongation of the antiepileptic effect. In experiments, carbamazepine effectively suppresses convulsions in response to maximum electric shock, inhibits high-frequency discharge activity, enhances the inactivation of Na+ channels and delays the restoration of their activity. In addition, carbamazepine reduces the conductivity of Ca2+ channels, affects synaptic transmission, partially blocking the effect of aspartate and glutamate, inhibits the uptake of catecholamines in high concentrations, and enhances GABAergic inhibition [3]. Obviously, such a variety of neuropharmacodynamic effects determines the complex positive effect of carbamazepine, providing not only effective suppression of epileptic seizures, but also a good thymoleptic effect, elimination of behavioral and mental disorders accompanying epilepsy (Table 1) [4–7].

Carbamazepine is the first choice drug for simple focal seizures, focal seizures with loss of consciousness and secondary generalized tonic-clonic seizures and accounts for 16% (Japan) to 55% (Germany) of all prescribed anticonvulsants [1, 8]. The Swiss drug Tegretol was the first form for clinical use. Already in 1965, several studies showed the high effectiveness of tegretol in the treatment of focal seizures and its beneficial effect on mental functions in patients with epilepsy [6, 7, 9]. Tegretol currently occupies the main place among carbamazepine anticonvulsants. Thus, from a number of articles devoted to the use of different forms of carbamazepine for epilepsy, in the Internet database Highwire.stanford.edu. 90% of publications from three continents relate to Tegretol, and in studies devoted to the comparative assessment of the effectiveness of various drugs, Tegretol is used as a reference [10, 11]. Currently, it is produced in a prolongated form (Tegretol retard), Tegretol in the form of chewable tablets, Tegretol syrup. The last two forms differ in that they allow you to quickly obtain a high concentration in the blood plasma, and Tegretol syrup, in addition to the convenience of treating small children, if necessary, can be administered through a nasogastric tube or even rectally (in particular, with impaired swallowing function or in status epilepticus). Tegretol retard is the optimal form for long-term treatment of epilepsy, as it provides a controlled release of the active substance and, therefore, maintaining a stable concentration of the drug in the blood plasma, allowing you to limit yourself to two or even one dose per day [12].

Currently, clear indications for the use of Tegretol have been developed for various forms of focal epilepsy (Table 2). As can be seen from table. 1, Tegretol is the first choice drug for symptomatic and presumed symptomatic epilepsies

, making up the majority of all epilepsies, as well as some idiopathic focal epilepsies. An approximate estimate of the share of tegretol in the treatment of focal epilepsies in the population can be obtained from the distribution of different forms of focal epilepsies in the population. As is known, the largest number of cases of epilepsy occurs in children and elderly patients. At the age of 55–95 years, focal epilepsies account for 80% of all epilepsies in men and 65% in women, and all cases are symptomatic [13]. Thus, Tegretol is the main drug in the treatment of focal epilepsies in older people. At the age of up to 15 years, focal epilepsies account for 58%. The structure of focal epilepsies in childhood is as follows: idiopathic – 38%, symptomatic – 19% and presumably symptomatic – 43% [14].

Thus, if for symptomatic focal epilepsies in the pediatric subgroup the drug of choice is also tegretol, then for some idiopathic epilepsies carbamazepine is ineffective or can even cause worsening of symptoms, so its use in the pediatric subgroup must be carefully verified. The algorithm for treating focal epilepsy with Tegretol is presented in the figure. When considering an algorithm, it is useful to keep a few additional considerations in mind. Tegretol is effective for all types of focal seizures - simple, with impaired consciousness and secondary generalization. As for contraindications, they primarily relate to the precise determination of the form of epilepsy. The main contraindications are absence seizures, myoclonic and astatic seizures and epileptic spasms. In typical cases, diagnosing these forms is not difficult, since in most cases they relate to specific idiopathic primary generalized epilepsies or epileptic encephalopathies. Difficulties arise in atypical cases of myoclonic-astatic idiopathic epilepsy, juvenile myoclonic epilepsy and epilepsy with myoclonic absence seizures, occurring with asymmetrical convulsions resembling focal seizures. This may also correspond to the lateralization of epileptiform activity in the EEG. Nevertheless, a careful analysis of the entire picture of the disease in the vast majority of cases makes it possible to correctly diagnose these forms and avoid errors in drug selection [8, 12, 15–17]. You should also refrain from using Tegretol as a first-line drug for idiopathic epilepsy of childhood with centrotemporal spikes, in which it can cause worsening epileptiform activity and the appearance of behavioral, cognitive and psychiatric symptoms. For the same reason, the use of Tegretol in Landau–Kleffner epileptic aphasia is inappropriate [8, 12]. A predictor of failure of carbamazepine therapy is also the presence in the EEG of bilateral synchronous discharges of spike-wave complexes, as well as periods of slowing activity in the theta rhythm in the central-parietal regions of the brain [8, 18, 19]. Regarding general somatic contraindications, the main ones are atrioventricular block and increased sensitivity to tricyclic antidepressants. The main condition for avoiding side effects is to gradually increase the dose. It is advisable to start with 100–200 mg at night and then increase the dose in steps of 100 mg every 3 days until the dose is effective (as determined by the cessation of seizures) or to the maximum recommended, based on body weight and age (see Table 1). To prevent such unpleasant dose-dependent side effects as drowsiness, headache, double vision, tremor, the retard form of tegretol should be used from the very beginning [16, 17, 20, 21]. By entering the blood more slowly, this form of Tegretol avoids concentration peaks and, therefore, side effects. By maintaining the therapeutic concentration without failure until the next dose, the retard form prevents relapse of seizures [15–18, 20, 21]. The same feature of the prolonged form of Tegretol allows it to be taken 2 times: in the morning and in the evening, which significantly improves the patient’s compliance, freeing him from taking the drug during daytime activity. The Tegretol retard form, containing 400 mg of carbamazepine per tablet, is especially convenient for twice daily use. The effective initial dose may be high enough due to self-induction effects that, if there is a positive, sustained seizure-cessation effect, it can be further reduced by 25–30% while monitoring plasma drug levels. If seizure control is not achieved when the upper recommended limit of the therapeutic dose is reached, the drug level in the blood plasma should be measured and if seizures continue after adjusting the dose according to the drug level, a control EEG study should be performed. An increase in epileptiform activity in the EEG, especially in the form of bilateral synchronous discharges, indicates the patient’s resistance to carbamazepine and the advisability of switching to another drug. If the EEG does not show signs of worsening epileptiform activity, duotherapy should be tried, optimally in combination with a prolonged form of valproate [1, 8, 12, 15, 22, 23]. Idiosyncratic reactions during treatment with Tegretol, in our experience, are observed much less frequently than with other forms of carbamazepine, and are associated with a rapid increase in the dose or the absence of its corrective reduction after the initial autoinduction period. In 10% of patients, itching occurs, most often at the end of the 2nd - beginning of the 3rd week of use, which in the majority stops spontaneously or due to a slight decrease in the daily dose. Rarely, erythematous rashes occur, which require special attention, since they can be a harbinger of a very rare but dangerous complication - Stevens-Johnson syndrome. Mild reversible leukopenia is occasionally observed, which does not require discontinuation of therapy unless the leukocyte count falls below 2000. Even more rare are red blood disorders, hepatopathy and severe hyponatremia, when the sodium concentration drops below 125 mmol/l, manifested by confusion, peripheral edema and increased frequency of seizures [16]. With a slow dose increase, these complications are not observed. When treating with any anticonvulsant drugs, the ideal of monotherapy is feasible in 50–80% of cases; in other cases, it is necessary to try combinations of Tegretol with another drug. When used together, carbamazepine accelerates the metabolism of valproic acid, ethosuximide, phenobarbital, primidone, lamotrigine, and Topamax. The combination with phenytoin is not rational. Paradoxically, being an inducer of liver enzymes, carbamazepine, when interacting with another inducer, phenytoin, increases the concentration of the latter by approximately 1/3 [16]. Therefore, if it is necessary to replace phenytoin with Tegretol in order to avoid the toxic effects of phenytoin, increasing the dose of Tegretol should be parallel to reducing the dose of phenytoin. The combination of phenobarbital and carbamazepine, which is common in Russia, is inappropriate because, being enzyme inducers, these drugs reduce each other’s concentrations, and the summation of the sedative effect inherent, in particular, to phenobarbital, causes unfavorable pharmacodynamic symptoms from the central nervous system. On the other hand, the combination of the sodium channel blocker carbamazepine with the GABAergic effect of valproic acid makes, for example, the combination of Tegretol retard with Depakine Chrono one of the most effective, widely used and recommended forms of polytherapy for epilepsy [1, 8, 12, 15, 22, 23 ]. The combinations of Tegretol + topiramate, Tegretol + tiagabine, Tegretol + clonazepam are rational. It should be remembered that the prescription of clonazepam, like other benzodiazepines, in polytherapy is permissible only for a short period (up to 1.5 months), since their chronic use leads to tolerance with the subsequent development of withdrawal attacks. Their short-term use is most appropriate for a temporary increase in seizures, which is especially characteristic of frontal lobe epilepsy.

Efficacy of Tegretol

In monotherapy, Tegretol is equally effective as valproate, phenytoin, and phenobarbital in controlling seizures [24–26].
For symptomatic and presumably symptomatic focal epilepsies, which make up more than half of all epileptic disorders, Tegretol monotherapy is effective in 60–85% of cases, with complete cessation of seizures achieved in half. Tegretol produces significantly fewer side effects than phenytoin and phenobarbital and provides a better quality of life [12, 17, 24]. A comparison of carbamazepine with valproate showed no significant differences in the total number of patients with complete cessation of seizures and the effect on tonic-clonic seizures, but revealed a significant advantage of carbamazepine in reducing the overall frequency of seizures and reducing the number of complex partial seizures [11, 25, 26]. In monotherapy, carbamazepine at a standard dose of 600 mg/day is significantly more effective than vigabatrin and gabapentin [16, 17]. The effectiveness of carbamazepine and lamotrigine does not differ [17]. It should be recalled that the cost of treatment with the newest drugs is 2 times or more higher than the cost of treatment with Tegretol. When treated with carbamazepine, the prognosis is drug-free remission, i.e. practical cure is better, and the likelihood of withdrawal seizures is lower than with other anticonvulsants [27]. An analysis of our cases of treatment regarding the ineffectiveness of Tegretol treatment showed that in most cases it is explained by the initial irrational polytherapy and insufficient dosage (70% of cases) [1, 8]. In 80% of these cases, switching to Tegretol monotherapy and increasing the dose to the therapeutic dose, based on the recommended per 1 kg of body weight, allowed us to achieve significant improvement with remission of 1 year or more in 60%. Although Tegretol is considered the first choice drug for focal epilepsies, it is advisable to use it when the first choice drugs are ineffective for generalized epilepsy with tonic-clonic seizures, since in these cases underdiagnosis of the primary focal onset cannot be ruled out. In any case, in published studies its effectiveness in generalized tonic-clonic seizures is estimated at 50–65% and is not inferior to phenobarbital and valproate [17, 24]. The success of treating idiopathic autosomal dominant frontal lobar nocturnal epilepsy and late-onset childhood occipital lobar epilepsy (Gastaut form)
, often resistant to other drugs, when treated with a long-acting form of carbamazepine is explained by the stable therapeutic concentration of the drug during the night, which is mainly due to seizures are confined [8, 18].
Tegretol is the first choice drug for onset epilepsy
, where seizures (usually focal from the supplementary motor area or generalized tonic-clonic) are triggered by frightening unexpected stimuli [8, 12].
It is advisable to attempt treatment with carbamazepine in cases resistant to therapy with other drugs, diagnosed as Rolandic childhood epilepsy and early-onset occipitolobar childhood epilepsy
, since a presumably symptomatic etiology cannot be excluded. The benefits of Tegretol in some special situations should be noted. Tegretol, in addition to suppressing seizures, has a positive effect on mood, normalization of thinking and communication processes, and social functioning. The pronounced psychotropic effect of carbamazepine makes the transition to treatment with Tegretol retard especially indicated in patients with depression, psychotic hallucinatory and behavioral disorders, and ideational disorders [12]. In case of status epilepticus associated with unauthorized withdrawal of carbamazepine, emergency administration of 10–20 ml of a 2% solution of Tegretol syrup per rectally or through a nasogastric tube allows you to quickly restore the concentration of carbamazepine in the blood plasma and interrupt the status [12]. Tegretol retard is the drug of first choice when managing pregnancy in a patient with epilepsy, since it ranks last in terms of teratogenicity [12, 28]. The symptomatic use of Tegretol in patients with post-traumatic encephalopathy, considered as a non-convulsive manifestation of subclinical epileptic discharges in the brain, has a beneficial rehabilitative effect [5].