Instructions for Carbamazepine-FS tablets 200 mg No. 50
Composition
active ingredient: carbamazepine;
1 tablet contains 200 mg of carbamazepine;
Excipients: microcrystalline cellulose, gelatin, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Pills.
Main physicochemical properties: white or almost white tablets with a biconvex surface, round in shape, with a score on one side.
Pharmacotherapeutic group
Antiepileptic drugs. Carboxamide derivatives.
ATX code N03A F01.
Pharmacological properties
Pharmacodynamics.
As an anticonvulsant, carbamazepine is effective in partial seizures (simple and complex) with and without secondary generalization; generalized tonic-clonic seizures, as well as in a combination of these types of seizures.
In clinical studies, when carbamazepine was used as monotherapy in patients with epilepsy (especially in children and adolescents), the psychotropic effect of the drug was noted, which was partially manifested by a positive effect on symptoms of anxiety and depression, as well as a decrease in irritability and aggressiveness.
As a neurotropic agent, carbamazepine is effective in some neurological diseases: it prevents pain attacks in idiopathic and secondary trigeminal neuralgia. In addition, carbamazepine is used to relieve neurogenic pain in various conditions. In alcohol withdrawal syndrome, carbamazepine increases the threshold of seizure readiness (which is reduced in this condition) and reduces the severity of clinical manifestations of the syndrome, such as excitability, tremor, gait disturbance.
It has been confirmed that carbamazepine as a psychotropic agent is effective in affective disorders, namely: for the treatment of acute manic states, for the maintenance treatment of bipolar affective (manic-depressive) disorders (both monotherapy and in combination with neuroleptics, antidepressants or lithium preparations).
Pharmacokinetics.
Absorption: After oral administration, carbamazepine is absorbed almost completely, although relatively slowly. After a single dose, the maximum plasma concentration (Cmax) is reached after 12 hours.
The bioavailability of various oral dosage forms of carbamazepine has been shown to be in the range of 85–100%.
Food intake does not significantly affect the rate and extent of absorption of carbamazepine.
At doses up to 300 mg of carbamazepine, approximately 75% of the total amount reaches the systemic circulation within 6 hours. Accordingly, the maximum recommended daily dose for this dosage form is 250 mg four times a day.
Plasma concentrations. There are no clinically significant differences in the extent of absorption of the active substance after the use of different dosage forms of the drug for oral administration. After a single oral dose of a tablet containing 400 mg of carbamazepine, the average Cmax value of the unchanged active substance reaches about 4.5 μg/ml.
There is considerable interindividual variation in steady-state concentrations within the therapeutic range, with most patients in the range of 4 to 12 μg/ml (17–50 μmol/l). Concentrations of carbamazepine-10,11-epoxide (the pharmacologically active metabolite) are approximately 30% of those of carbamazepine.
The equilibrium concentration of the drug in the blood plasma is achieved within 1–2 weeks, which depends on the individual characteristics of metabolism (autoinduction of liver enzyme systems by carbamazepine, heteroinduction by other drugs used simultaneously), as well as on the patient's condition, the dose of the drug and the duration of treatment.
Distribution. The binding of carbamazepine to plasma proteins is 70-80%. The concentration of unchanged carbamazepine in cerebrospinal fluid and saliva is proportional to the proportion of the active substance not bound to blood proteins (20-30%). The concentration of carbamazepine in breast milk is 25-60% of its level in blood plasma. Carbamazepine penetrates the placental barrier. Provided that carbamazepine is completely absorbed, the conditional volume of distribution is 0.8-1.9 l/kg.
Metabolism. Carbamazepine is metabolized in the liver, mainly by the epoxide route, with the formation of several metabolites: the 10,11-transdiol derivative and its conjugates with glucuronic acid. At the first stage, oxidation to carbamazepine-10,11-epoxide occurs, mainly through the cytochrome P450 3A4 isoenzyme. It is believed that human microsomal epoxide hydrolase is responsible for the formation of pharmacologically active carbamazepine-10,11-epoxide, which is almost completely transformed into the 10,11-transdiol derivative and its glucuronides. As a result of these metabolic reactions, a “minor” metabolite is also formed - 9-hydroxy-methyl-10-carbamoylacridane. After a single oral dose of carbamazepine, approximately 30% of the active substance is detected in the urine as end products of epoxy metabolism. Other important pathways of carbamazepine biotransformation lead to the formation of various monohydroxylate derivatives, as well as carbamazepine N-glucuronide, which is formed with the participation of uridylyl diphosphate glucuronosyltransferase (UGT2B7).
Elimination. After a single dose of the drug, the elimination half-life of unchanged carbamazepine (T1/2) is on average approximately 36 hours, and after repeated use of the drug - on average 16-24 hours (due to autoinduction of metabolic enzymes) depending on the duration of treatment. In patients who are simultaneously taking other drugs that induce the same liver enzyme system (for example, phenytoin, phenobarbital), T1/2 of carbamazepine is on average 9-10 hours.
The mean T1/2 of the 10,11-epoxide metabolite from plasma is approximately 6 hours after a single oral dose of the epoxide. After a single oral dose of 400 mg of carbamazepine, 72% of the dose is excreted in the urine and 28% in the feces. Approximately 2% of the dose is excreted in the urine as unchanged carbamazepine, approximately 1% as the pharmacologically active 10,11-epoxide metabolite, approximately 30% as carbamazepine-10,11-transdiol and other inactive metabolites.
Features of pharmacokinetics in certain groups of patients.
Elderly patients: There is no evidence to suggest that the pharmacokinetics of carbamazepine are altered in elderly patients (compared to young adults).
Patients with renal or hepatic impairment: There are no data on the pharmacokinetics of carbamazepine in patients with renal or hepatic impairment.
Indication
Epilepsy:
complex or simple partial seizures (with or without loss of consciousness) with or without secondary generalization;
generalized tonic-clonic seizures;
mixed forms of convulsive seizures.
The drug Carbamazepine-FS can be used both as monotherapy and as part of combination therapy.
The drug Carbamazepine-FS is usually not effective in absence seizures (a mild form of epileptic seizure) and myoclonic seizures (see the section "Special instructions").
Acute manic states; maintenance therapy in bipolar affective disorders to prevent exacerbations or to reduce the clinical manifestations of exacerbations.
Alcohol withdrawal syndrome.
Idiopathic trigeminal neuralgia and trigeminal neuralgia in multiple sclerosis (typical and atypical).
Idiopathic glossopharyngeal neuralgia.
Contraindication
Hypersensitivity to carbamazepine and oxcarbazepine or to chemically similar drugs (e.g. tricyclic antidepressants) or to any other component of the drug;
atrioventricular block;
history of episodes of bone marrow suppression;
history of hepatic porphyria (e.g. acute intermittent porphyria, mixed porphyria, porphyria cutanea tarda);
in combination with monoamine oxidase inhibitors (MAOIs).
Interaction with other medicinal products and other types of interactions
Cytochrome P450 3A4 (CYP3A4) is the main enzyme responsible for the formation of the active metabolite carbamazepine-10,11-epoxide. Concomitant use of CYP3A4 inhibitors or epoxide hydrolase inhibitors with carbamazepine may lead to increased plasma concentrations of carbamazepine, which in turn may lead to adverse reactions. Accordingly, the dose of carbamazepine should be adjusted and plasma levels monitored.
Concomitant use of CYP3A4 inducers may lead to an acceleration of the metabolism of carbamazepine and, thus, to a possible decrease in the concentration of carbamazepine in the blood plasma and a decrease in the therapeutic effect. Similarly, discontinuation of the CYP3A4 inducer may reduce the rate of metabolism of carbamazepine, leading to an increase in the level of carbamazepine in the blood plasma. Accordingly, it may be necessary to adjust the dose of carbamazepine.
Carbamazepine is a potent inducer of CYP3A4 and other phase I and phase II enzyme systems in the liver, and therefore may reduce plasma concentrations of other drugs that are predominantly metabolized by CYP3A4 by inducing their metabolism.
Human microsomal epoxide hydrolase is the enzyme responsible for the formation of 10,11-transdiol derivatives from carbamazepine-10,11-epoxide. Concomitant use of inhibitors of human microsomal epoxide hydrolase (e.g. valproic acid) may lead to an increase in the plasma concentration of carbamazepine-10,11-epoxide.
Concomitant use of carbamazepine with direct-acting oral anticoagulants (rivaroxaban, dabigatran, apixaban, edoxaban) may lead to a decrease in the plasma concentration of direct-acting oral anticoagulants and thus an increase in the risk of thrombosis. Therefore, if concomitant use is necessary, patients should be closely monitored for signs and symptoms of thrombosis.
Drugs that may increase the level of carbamazepine in the blood plasma.
Since an increase in carbamazepine plasma levels may lead to adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dose of carbamazepine should be adjusted and/or the plasma levels of carbamazepine should be monitored when co-administered with the following drugs.
Analgesics, anti-inflammatory drugs: dextropropoxyphene, ibuprofen.
Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin), ciprofloxacin.
Antidepressants: desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.
Antiepileptics: stiripentol, vigabatrin.
Antifungals: azoles (e.g., itraconazole, ketoconazole, fluconazole, voriconazole).
Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.
Antihistamines: loratadine, terfenadine.
Antipsychotic drugs: olanzapine, loxapine, quetiapine.
Anti-tuberculosis drugs: isoniazid.
Antiviral drugs: protease inhibitors for HIV (ritonavir).
Carbonic anhydrase inhibitors: acetazolamide.
Cardiovascular drugs: diltiazem, verapamil.
Drugs for the treatment of gastrointestinal diseases: cimetidine, omeprazole.
Muscle relaxants: oxybutynin, dantrolene.
Antiplatelet drugs: ticlopidine.
Other substances: grapefruit juice, nicotinamide (in adults, only in high doses).
Drugs that may increase the level of the active metabolite carbamazepine-10,11-epoxide in blood plasma.
Since increased plasma levels of the active metabolite carbamazepine-10,11-epoxide may lead to adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of carbamazepine should be adjusted accordingly and/or the plasma levels of the drug monitored if carbamazepine is taken concomitantly with the following drugs: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide, brivaracetam.
Drugs that may reduce the level of carbamazepine in the blood plasma.
Dose adjustment of carbamazepine may be necessary when used concomitantly with the following drugs.
Antiepileptic drugs: felbamate, methsuximide, oxcarbazepine, phenobarbital, phensuximide, phenytoin (to avoid phenytoin intoxication and subtherapeutic carbamazepine concentrations, it is recommended to adjust the phenytoin plasma concentration to 13 μg/mL before starting carbamazepine treatment), fosphenytoin, primidone, clonazepam (although data on it are conflicting).
Anticancer drugs: cisplatin or doxorubicin.
Anti-tuberculosis drugs: rifampicin.
Bronchodilators or anti-asthma drugs: theophylline, aminophylline.
Dermatological drugs: isotretinoin.
Interaction with other medicines: herbal preparations containing St. John's wort (Hypericum perforatum).
Mefloquine may antagonize the antiepileptic effect of carbamazepine. The dose of carbamazepine should be adjusted accordingly.
Isotretinoin alters the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; in this case, monitoring of carbamazepine plasma concentrations is required.
The effect of the drug Carbamazepine-FS on the blood plasma levels of concomitantly prescribed drugs.
Carbamazepine can reduce the plasma concentration or reduce and even completely eliminate the effects of some drugs.
Dose adjustments of the following drugs may be necessary as clinically indicated.
Analgesics, anti-inflammatory drugs: buprenorphine, methadone, paracetamol (long-term use of carbamazepine with paracetamol (acetaminophen) may be associated with the development of hepatotoxicity), phenazone (antipyrine), tramadol.
Antibiotics: doxycycline, rifabutin.
Anticoagulants: oral anticoagulants (e.g. warfarin, phenprocoumon, dicumarol, acenocoumarol, rivaroxaban, dabigatran, apixaban, edoxaban).
Antidepressants: bupropion (carbamazepine may reduce the plasma levels of bupropion and increase the levels of its metabolite hydroxybupropion, thereby reducing the clinical efficacy and safety of bupropion), citalopram, mianserin, nefazodone, sertraline, trazodone, tricyclic antidepressants (e.g. imipramine, amitriptyline, nortriptyline, clomipramine).
The use of carbamazepine in combination with MAO inhibitors is contraindicated. The use of MAO inhibitors should be discontinued at least 2 weeks before the administration of carbamazepine (and if the clinical situation allows, even earlier).
Antiemetics: aprepitant.
Antiepileptic drugs: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid; zonisamide.
Against the background of the use of carbamazepine, the level of phenytoin in the blood plasma may either increase or decrease, and the level of mephenytoin may increase (in some cases).
To avoid phenytoin intoxication and subtherapeutic carbamazepine concentrations, it is recommended that the plasma concentration of phenytoin should not exceed 13 μg/mL before initiating carbamazepine therapy. There have been isolated reports of increased plasma concentrations of mephenytoin during carbamazepine administration, which in rare cases may result in confusion and even coma.
Antifungals: itraconazole, voriconazole, ketoconazole. Alternative antiepileptic agents may be recommended for patients receiving treatment with voriconazole or itraconazole.
Anthelmintic drugs: praziquantel, albendazole.
Neuroleptic drugs: clozapine, haloperidol, bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone.
Antiviral drugs: protease inhibitors for the treatment of HIV (indinavir, ritonavir, saquinavir).
Anxiolytics: alprazolam, midazolam.
Bronchodilators or anti-asthma drugs: theophylline.
Contraceptive drugs: hormonal contraceptives (alternative methods of contraception should be considered).
Cardiovascular drugs: calcium channel blockers (dihydropyridine group – felodipine, isradipine, digoxin, quinidine, propranolol, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.
Corticosteroids: (e.g., prednisolone, dexamethasone).
Drugs used to treat erectile dysfunction: tadalafil.
Immunosuppressants: cyclosporine, everolimus; tacrolimus, sirolimus.
Thyroid drugs: levothyroxine. Carbamazepine is thought to increase thyroid hormone excretion and the need for it in patients with hypothyroidism. Therefore, thyroid function should be monitored in patients receiving replacement therapy, both at the beginning and at the end of carbamazepine treatment.
If necessary, the dose of thyroid hormones should be adjusted. Thyroid function may be altered, particularly when carbamazepine is used concomitantly with other anticonvulsants (e.g. phenobarbital).
Interaction with other drugs: drugs containing estrogens and/or progesterones (alternative methods of contraception should be considered); buprenorphine, gestrinone, tibolone, toremifene, mianserin, sertraline.
Drug combinations that require separate consideration.
Concomitant use of carbamazepine and levetiracetam may lead to increased toxicity of carbamazepine.
Concomitant use of carbamazepine and isoniazid may lead to increased hepatotoxicity of isoniazid.
The combined use of carbamazepine and lithium or metoclopramide, as well as carbamazepine and neuroleptics (haloperidol, thioridazine) may lead to an increase in the frequency of undesirable neurological reactions (in the case of the latter combination, even at therapeutic concentrations of active substances in the blood plasma).
Therefore, clinical symptoms should be closely monitored. Carbamazepine should not be used earlier than 8 weeks after the end of previous treatment with neuroleptics. Simultaneous treatment should also be avoided. Patients should be closely monitored because the following neurotoxic symptoms may occur: unsteady gait, ataxia, horizontal nystagmus, increased proprioceptive muscle reflexes, muscle spasms (fasciculations).
According to literature data, the addition of carbamazepine to current neuroleptic therapy may increase the risk of neuroleptic malignant syndrome or Stevens-Johnson syndrome.
Concomitant use of carbamazepine with some diuretics (e.g. hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.
Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g. pancuronium). The dosage of these drugs may need to be increased and patients should be closely monitored because of the possibility of a more rapid than expected recovery from neuromuscular blockade. Carbamazepine, like other psychotropic drugs, may reduce alcohol tolerance. Therefore, patients are advised to abstain from alcohol.
Concomitant use of carbamazepine with direct-acting oral anticoagulants (rivaroxaban, dabigatran, apixaban, edoxaban) may lead to a decrease in the plasma concentration of direct-acting oral anticoagulants and thus an increase in the risk of thrombosis. Therefore, if concomitant use is necessary, patients should be closely monitored for symptoms of thrombosis.
Contraindicated interaction.
Because carbamazepine is structurally similar to tricyclic antidepressants, its use in combination with MAO inhibitors is contraindicated; MAO inhibitors should be discontinued for at least 2 weeks before starting carbamazepine, or even longer if the clinical situation permits.
Impact on serological studies.
Carbamazepine may give a false-positive result in HPLC analysis for determining perphenazine concentration.
Carbamazepine and 10,11-epoxide may give a false-positive result in the polarized fluorescence immunoassay for tricyclic antidepressant concentrations.
Application features
General.
Carbamazepine should be used only under medical supervision and only after a careful analysis of the benefit/risk ratio, as well as with careful and regular monitoring of patients with a history of heart, liver, kidney disease, sodium metabolism disorders, adverse hematological reactions to other drugs or withdrawal of previous carbamazepine treatment.
Carbamazepine exhibits mild anticholinergic activity, therefore patients with elevated intraocular pressure should be warned and counseled about possible risk factors.
One should be aware of the possible activation of latent psychoses, and in elderly patients, the possible activation of confusion and anxiety.
Carbamazepine is generally ineffective in absence seizures and myoclonic seizures. Anecdotal evidence suggests that it may increase seizures in patients with atypical absences.
Hematological effects. The use of carbamazepine has been associated with the development of agranulocytosis and aplastic anemia. However, due to the fact that such conditions occur very rarely, it is difficult to assess the significance of the risk. It is known that the total risk of developing agranulocytosis in the general population not treated with carbamazepine reached 4.7 cases per 1 million population per year, and aplastic anemia - 2 cases per 1 million population per year.
Patients should be informed about the early signs of toxicity, characteristic of possible hematological disorders, as well as about skin and liver symptoms and warned about the need to immediately consult a doctor in case of adverse reactions such as fever, sore throat, groin infection, rash, mouth ulcers, unexplained bruising, hemorrhages in the form of petechiae or purpura.
If the number of leukocytes or platelets decreases significantly during therapy, the patient's condition should be closely monitored, and complete blood counts should be performed regularly. Carbamazepine treatment should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical manifestations such as fever or sore throat. If signs of significant bone marrow depression are detected, carbamazepine should be discontinued.
During the use of carbamazepine, transient or persistent decreases in platelet or leukocyte counts have been reported with varying frequency. However, in most cases, these adverse events are transient and usually do not herald the onset of aplastic anemia or agranulocytosis. However, before starting treatment, as well as periodically during treatment, a clinical blood test should be performed, including a platelet count and, possibly, a reticulocyte count, and serum iron levels should be determined.
Serious dermatological reactions.
Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) or Lyell's syndrome, or toxic epidermal necrolysis (TEN), have occurred very rarely with carbamazepine. Patients with serious dermatological reactions may require hospitalization, as these conditions can be life-threatening and fatal. Most cases of Stevens-Johnson syndrome or Lyell's syndrome occur within the first few months of carbamazepine treatment. It has been reported that these dermatological reactions occur in an estimated 1 to 6 out of 10,000 new patients in countries with a predominantly Caucasian population. However, in some Asian countries the risk may be approximately 10-fold higher. If signs and symptoms suggestive of serious dermatological reactions (e.g. Stevens-Johnson syndrome or Lyell's syndrome) develop, carbamazepine should be discontinued immediately and alternative therapy should be instituted.
Pharmacogenomics.
There is increasing evidence that different HLA alleles influence a patient's susceptibility to immune-related adverse reactions.
Linkage with (HLA)-B*1502.
Retrospective studies in Han Chinese patients have shown a strong correlation between carbamazepine-associated skin reactions such as Stevens-Johnson syndrome or Lyell's syndrome and the presence of the human leukocyte antigen (HLA) allele (HLA)-B*1502 in these patients. The prevalence of this HLA-B*1502 allele varies from 2% to 12% in Han Chinese patients and is approximately 8% in Thailand. A higher incidence of SS (rare rather than very rare) has been reported in some Asian countries (e.g. Taiwan, Malaysia, and the Philippines) where the (HLA)-B*1502 allele is prevalent in the population.
Carrier rates of this allele in the Asian population are over 15% in the Philippines and some Malaysian populations. Prevalences of up to 2% and 6% have been reported in Korea and India, respectively.
The prevalence of the (HLA)-B*1502 allele is insignificant among European, African, Native American, and Hispanic populations (< 1%).
The allele prevalence reported in this document is the percentage of chromosomes in a given population that carry the allele. Thus, the percentage of patients who carry a copy of the allele on at least one of its two chromosomes (i.e., the “carrier frequency”) is almost twice the prevalence of the allele. Therefore, the percentage of patients who may be at risk is almost twice the prevalence of the allele.
In patients who are genetically at risk, testing for the presence of the (HLA)-B*1502 allele should be performed before starting treatment with carbamazepine.
Patients who have been tested and received a negative result for (HLA)-B*1502 have a low rate of developing Stevens-Johnson syndrome, although very rarely such reactions may still occur.
It has been found that identifying patients with the HLA-B*1502 allele and avoiding carbamazepine in such Han ethnic patients reduces the incidence of carbamazepine-related events.
At this time, due to a lack of data, it is not known for sure whether all individuals of Southeast Asian descent are at this risk.
The (HLA)-B*1502 allele may be a risk factor for Stevens-Johnson syndrome or Lyell syndrome in Chinese patients receiving other antiepileptic drugs that may be associated with the development of these syndromes. Therefore, other drugs that may be associated with Stevens-Johnson syndrome or Lyell syndrome should be avoided in patients with the (HLA)-B*1502 allele if other, alternative therapies are available. Genetic screening of patients from ethnic groups with a low incidence of the (HLA)-B*1502 allele or in those already receiving Carbamazepine-FS is generally not recommended, as the risk of Stevens-Johnson syndrome or Lyell syndrome is largely limited to the first few months, regardless of the presence of the (HLA)-B*1502 allele in the patient's genes.
Genetic screening results should not replace appropriate clinical surveillance, as many carriers of (HLA)-B*1502 do not develop SS/TEN, while other patients without genetic risk factors may develop SS/TEN for other reasons. The situation is similar for carriers of the (HLA)-A*3101 allele who are treated with carbamazepine. These patients do not necessarily develop SS/TEN, DRESS, AGEP or maculopapular rashes. However, patients without the HLA-A*3101 allele may develop serious skin reactions for other reasons. To date, there have been no studies investigating the extent to which other factors (such as dose, 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 occurrence of Stevens-Johnson syndrome.
Linkage with (HLA)-A*3101.
Human leukocyte antigen (HLA)-A*3101 may be a risk factor for the development of skin adverse reactions such as Stevens-Johnson syndrome, Lyell syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis, maculopapular eruptions. Therefore, if the presence of the (HLA)-A*3101 allele is detected, the drug should be discontinued.
It is known that retrospective analysis data in patients of Japanese nationality and residents of Northern Europe demonstrated an association between severe skin lesions (Stevens-Johnson syndrome, Lyell syndrome, drug eruptions with eosinophilia and systemic manifestations, acute generalized exanthematous pustulosis and maculopapular rashes) in carriers of the (HLA)-A*3101 allele of the human leukocyte antigen (HLA) gene and the use of carbamazepine.
The prevalence of this allele may vary in different ethnic groups: approximately 2-5% in the European population, approximately 10% in the Japanese. The prevalence of the allele is less than 5% in the population of Australia, Asia, Africa and North America. For the population of Western Europe, the prevalence of the allele (HLA)-A*3101 is estimated to be approximately 6.7% depending on the geographical region. Exceptions range from 5% to 12%. Prevalences of more than 15% have been established in some ethnic groups of South America (Argentina and Brazil), indigenous people of North America (Navajo and Sioux tribes, in Mexico – Sonora Seri), and South India (Tamil Nadu).
The allele prevalence reported in this document is the percentage of chromosomes in a defined population that carry the corresponding allele. Thus, the percentage of patients who carry a copy of the allele on at least one of its two chromosomes (i.e., the “carrier frequency”) is almost twice the prevalence of the allele. Therefore, the percentage of patients who may be at risk is almost twice the prevalence of the allele.
Before starting treatment with carbamazepine, it is recommended to screen for the (HLA)-A*3101 allele in possible carriers of the (HLA)-A*3101 allele (e.g. patients of Japanese ethnicity, Caucasians, Native Americans, Hispanics, South Indians and Arabs). The drug should be used in carriers of this allele only if the benefit of therapy outweighs the possible risk. Screening for the (HLA)-A*3101 allele is generally not required in patients who have already received carbamazepine for a long time, since SSRI/TEN, AGEP, DRESS and maculopapular rashes are usually observed only during the first few months of therapy.
Limitations of genetic screening.
Genetic screening results should not replace appropriate clinical supervision and management of patient treatment.
Other dermatological reactions. Transient and non-life-threatening mild dermatological reactions, such as isolated macular or maculopapular exanthema, may occur. These reactions usually resolve within a few days or weeks, even with continued treatment or after dose reduction. Since early signs of more serious dermatological reactions may be difficult to distinguish from mild transient reactions, the patient should be closely monitored by a physician during this time to ensure that the drug is discontinued immediately if the reaction worsens with continued use.
The presence of the (HLA)-A*3101 allele in a patient has been associated with the occurrence of less serious skin adverse reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or minor rashes (maculopapular rashes). However, it has not been established that the presence of the (HLA)-B*1502 allele in a patient may be a risk factor for the aforementioned skin reactions.
Hypersensitivity: Carbamazepine can provoke the development of 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, abnormal liver function tests and disappearing bile duct syndrome (including destruction and disappearance of the intrabiliary ducts), which may occur in various combinations.
Other organs may also be affected (lungs, kidneys, pancreas, myocardium, colon). The presence of the (HLA)-A*3101 allele in a patient is associated with the occurrence of less serious adverse skin reactions to carbamazepine, such as anticonvulsant hypersensitivity syndrome or minor rashes (maculopapular rashes).
Patients with hypersensitivity reactions to carbamazepine should be informed that approximately 25-30% of such patients may also have hypersensitivity reactions to oxcarbazepine.
When using carbamazepine and aromatic antiepileptic drugs (e.g. phenytoin, primidone and phenobarbital), cross-hypersensitivity may develop.
In general, if signs and symptoms suggestive of hypersensitivity appear, carbamazepine should be discontinued immediately.
Seizures: Since carbamazepine may induce or exacerbate absence seizures, carbamazepine should be used with caution in patients with mixed seizures that include absences (typical or atypical). In such circumstances, the drug may precipitate seizures. If seizures are precipitated, carbamazepine should be discontinued immediately.
An increase in the frequency of attacks is possible when switching from oral forms of the drug to suppositories.
Liver function. During therapy with the drug, it is necessary to assess liver function at baseline and periodically assess this function during therapy, especially in patients with a history of liver disease and in elderly patients. In case of exacerbation of liver function disorders or manifestations of an active phase of liver disease, carbamazepine should be discontinued immediately.
Renal function: Before starting treatment with carbamazepine and periodically during therapy, it is recommended to assess renal function and determine the level of blood urea nitrogen.
Hyponatremia: Hyponatremia has been reported with carbamazepine. In patients with pre-existing renal impairment or in patients receiving concomitant sodium-lowering drugs (e.g. diuretics, drugs associated with inappropriate antidiuretic hormone secretion), prior to initiation of carbamazepine therapy,
