The drug should be taken only with medical supervision.
Patients with mixed forms of epileptic seizures, including absence and myoclonic seizures
The drug is usually ineffective in absences (petit mal) and myoclonic seizures. In patients with mixed forms of epileptic seizures, the drug should be used with caution and only on condition that regular medical supervision is provided (due to possible increased seizures). In case of increased seizures, Tegretol® should be discontinued.
Decrease in the number of platelets and leukocytes
During the application of the drug at different frequencies, there is a transient or persistent decrease in the number of platelets or leukocytes. However, in most cases, these phenomena are transient and usually do not precede the onset of aplastic anemia or agranulocytosis.
Before starting treatment, and also periodically during the 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.
It is necessary to inform patients about the early signs of toxicity inherent in probable hematologic disorders, as well as symptoms from the skin and liver. The patient is informed of the need to consult a doctor immediately if there are undesirable reactions such as fever, sore throat, rash, oral ulcers, an unreasonable occurrence of hemorrhages, haemorrhages in the form of petechiae or purpura.
In those cases when the low content of leukocytes or platelets (or the tendency to decrease them) during the treatment, it is necessary to closely monitor the patient's condition and the parameters of the developed clinical blood test. If signs of significant bone marrow depression are detected, Tegretol® should be withdrawn.
Dermatological reactions
With the use of Tegretol®, very rarely severe dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome). The drug Tegretol® should be immediately discontinued and alternative therapy should be selected if signs and symptoms are noted,presumably indicative of the development of severe dermatological reactions - for example, Stevens-Johnson syndrome or Lyell syndrome. With the development of severe (in some cases life-threatening patient) skin reactions, the patient should be hospitalized in a hospital. In most cases, Stevens-Johnson syndrome and Lyell's syndrome developed during the first months of therapy with the drug. These reactions developed in approximately 1-6 cases per 10,000 first-time drug users in countries with predominantly Caucasoid populations.
These retrospective analysis of the Japanese nationality patients and northern Europe have demonstrated the link between severe lesions of the skin (Stevens-Johnson syndrome, Lyell syndrome, drug rash with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis and mottled nodular rash) in carriers of allele HLA-A * 3101 of the human leukocyte antigen (HLA) gene and the use of carbamazepine.
Frequency of allele HLA-A * 3101 gene of human leukocyte antigen (E1LA) may differ among different ethnic groups: about 2-5% of the population of Europe, about 10% - in Japanese.The allele frequency is less than 5% in the population of Australia, Asia, Africa and North America, exceptions range from 5% to 12%. The frequency of more than 15% is found in some ethnic groups of South America (Argentina and Brazil), the indigenous peoples of North America (the Navajo and Siocs, Sanora Seri in Mexico), South India (Tamil Nadu), and 10-15% among other indigenous people these regions.
When carbamazepine is used, it is recommended to carry out genotyping with this allele in possible carriers of the HLA-A * 3101 allele (for example, patients of Japanese nationality, Caucasians, Native Americans, Hispanics, people of southern India and Arabs). Use the drug in carriers of this allele should be only if the benefit of therapy exceeds the possible risk.
Patients already receiving therapy with Tegretol® are not recommended to carry out genotyping for this allele, since severe skin reactions were mostly observed in the first months of application (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 nationalities, there isa correlation between the incidence of Stevens-Johnson syndrome and Lyell's syndrome and the presence of the HLA-B * 1502 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 - about 8%.
When carbamazepine was used in patients in the countries of the Asian region (Taiwan, Malaysia, Philippines), where there was a high prevalence of the HLA-B * 1502 allele, there was an increase in the frequency of development (from the "very rare" to "rarely") syndrome of Stevens-Johnson syndrome. The frequency of distribution of the HLA-B * 1502 allele is more than 15% in the Philippines and among some population groups in Malaysia. The frequency of distribution of the HLA-BM502 allele in Korea and India is 2% and 6%, respectively.
The prevalence of this allele in Caucasians, Negroid races, Latinos, Indians and Japanese is insignificant (<1%). The frequencies of these alleles represent the percentage of chromosomes in certain population populations that carry the allele. This means that the percentage of patients carrying a copy of the allele in at least one of their two chromosomes is almost twice as high as the frequency of the allele.Thus, the percentage of patients who may be at risk is almost twice as likely to be alleles.
When carbamazepine is used, it is recommended that the HLA-B * 1502 allele (eg Chinese people) be genotyped according to this allele.
Use the drug in carriers of this allele should be only if the benefit of therapy exceeds the possible risk. It is not recommended to carry out genotyping in representatives of nationalities in which the frequency of occurrence of this allele is low.
Patients who are already receiving therapy with Tegretol® are not recommended to carry out genotyping for this allele, since severe skin reactions were mostly observed in the first months of application (regardless of the presence of HLA-B * 1502.
It has been shown that the detection of patients with the presence of the HLA-B * 1502 allele and the absence of carbamazepine in such patients reduces the incidence of carbamazepine-induced Stevens-Johnson syndrome or Lyell syndrome.
However, the results of genotyping should not affect the degree of control over the patient's condition and the doctor's vigilance regarding severe skin reactions.The development of severe skin lesions is possible in patients who are negative for these alleles. Also in many cases, patients with positive HLA-B * 1502 or HLA-A * 3101 alleles did not develop severe skin syndromes when using Tegretol®.
The influence of other factors, such as the dose of anticonvulsant drugs, patient compliance, simultaneous therapy with other drugs, concomitant diseases or the level of control of dermatological reactions, the incidence and prevalence of severe skin reactions has not been established.
Slightly expressed skin reactions, for example, isolated macular or maculopapular exanthema, in most cases are transient and non-severe, usually occur for several days or weeks with continued treatment or after a reduction in the dose of the drug. Nevertheless, since differential diagnostics between early manifestations of severe skin reactions and mild transient skin rashes can be difficult, with the development of any skin reactions the patient should be under the supervision of a doctor (in order to timely stop therapy with the drug in case of deterioration of the patient's condition).
There is a correlation 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 anticonvulsant or mildly dense muculopapular exanthema), for the HLA-B * 1502 allele such a relationship is not established.
Hypersensitivity reactions
With the development of hypersensitivity to the drug Tegretol®, a variety of reactions can occur, including a rash with eosinophilia and systemic manifestations, delayed polyorganism hypersensitivity with the development of fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, changes in indices liver function and the syndrome of destruction of the bile ducts with a decrease in their number, which can occur in any combination. Also it may result in other internal organs (r. H. The lung, kidney, pancreas, myocardium, colon). In case of development of symptoms and symptoms of hypersensitivity to the drug Tegretol®, the drug should be immediately canceled.
Patients with known hypersensitivity to carbamazepine should be informed about the possibility of 25-30% of cases of development of hypersensitivity reactions to oxcarbazepine. Cross-reactivity hypersensitivity is also found between carbamazepine and phenytoin.
Hyponatremia
The development of hyponatremia is associated with the use of carbamazepine. Patients with pre-existing kidney lesions associated with low serum sodium levels, or in patients receiving concomitant sodium-reducing drugs (eg, diuretics, drugs that affect the secretion of antidiuretic hormone) should determine the serum sodium content before initiation of therapy with carbamazepine. After that, the sodium content should be determined after about two weeks, and then monthly during the first three months of therapy, or according to clinical need. These risk factors are especially common in elderly patients. If hyponatremia is observed, water restriction is an important criterion for determining the condition in the presence of clinical indications.
Hypothyroidism
Carbamazepine can reduce serum concentrations of thyroid hormones by inducing enzymes, which requires an increase in the dose of drugs used for substitution therapy in patients with hypothyroidism.This category of patients needs to monitor the function of the thyroid gland to select a dose of substitution therapy.
Dysfunction of the liver
Before the use of Tegretol® and during the treatment it is necessary to conduct a study of liver function, especially in patients whose history includes information on liver diseases, as well as in elderly patients. In case of strengthening of already existing violations of the liver function or when there is an active liver disease, Tegretol® should be immediately discontinued.
Renal impairment
Before starting treatment with the drug and periodically during the therapy, it is recommended to study the general urine test and determine the concentration of urea in the blood.
M-holinoblocking activity
The drug has a weak m-cholinoblocking activity. Therefore, in the case of using the drug in patients with increased intraocular pressure and urinary retention, continuous monitoring of this indicator is necessary.
Mental disorders
Since the use of the drug may exacerbate latent mental disorders,should be monitored for elderly patients in order to identify such symptoms as confusion and psychomotor agitation.
Suicidal behavior or intentions
In patients who received anticonvulsants for a number of indications, there were cases of suicidal behavior or intentions. The results of a meta-analysis of randomized placebo-controlled trials showed a slight increase in the risk of suicidal behavior in patients receiving anticonvulsant drugs. The mechanism of strengthening suicidal behavior in this category of patients is not established. Therefore, it is necessary to carefully monitor the symptoms of suicidal behavior and intentions and to decide on the appropriate treatment. Patients (caregivers) should be urged to seek help from a doctor in case of symptoms of suicidal behavior or intentions.
Endocrinological disorders
The drug may reduce the effectiveness of medications containing estrogens and / or progesterone, therefore women of childbearing age should be treated with alternative methods of protection from pregnancy during treatment with the drug.
To date, very rare reports of male fertility impairment and / or spermatogenesis disorders have been recorded.
Determination of the concentration of carbamazepine in the blood plasma
Although the relationship between the dose of the drug, the concentration of carbamazepine in the blood plasma, its clinical efficacy or tolerability is very low, nevertheless, a regular determination of the carbamazepine concentration may be appropriate in the following situations: with a sharp increase in the frequency of seizures, in order to check whether the patient the drug is properly administered; during pregnancy; when treating children or adolescents; with suspected carbamazepine absorption abnormalities; if there is a suspicion of the development of toxic reactions in the event that the patient takes several medicines.