Instructions for Mezacar SR prolonged-release tablets 400 mg blister No. 50
Composition
active ingredient: carbamazepine;
1 tablet contains 400 mg of carbamazepine;
excipients: microcrystalline cellulose, hypromellose, sodium lauryl sulfate, povidone (PVP K 30), colloidal anhydrous silicon dioxide, magnesium stearate.
Dosage form
Extended-release tablets.
Main physicochemical properties: white or almost white round tablets with “C400” embossed on one side and a cross-shaped score on the other.
Pharmacotherapeutic group
Antiepileptic drugs. ATX code N03A F01.
Pharmacological properties
Pharmacodynamics
Carbamazepine, the active ingredient of Mezacar® SR, is an anticonvulsant effective in partial seizures (simple and complex) with and without secondary generalization; generalized tonic-clonic seizures, as well as in a combination of the above types of seizures. The mechanism of action of carbamazepine is only partially understood. Carbamazepine stabilizes the membranes of overexcited nerve fibers, inhibits the occurrence of repeated neuronal discharges and reduces synaptic conduction of excitatory impulses. It has been established that the main mechanism of action of the drug is to prevent the re-formation of sodium-dependent action potentials in depolarized neurons by blocking sodium channels. The anticonvulsant effect of the drug is mainly due to a decrease in the release of glutamate and stabilization of neuronal membranes, while the antimanic effect may be due to inhibition of dopamine and noradrenaline metabolism.
When carbamazepine was used as monotherapy in patients with epilepsy (especially in children and adolescents), a psychotropic effect 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. The effect of carbamazepine on cognitive function and psychomotor performance was shown to be dose-dependent and was either questionable or negative. A positive effect of carbamazepine on indicators characterizing attention, learning ability and memory was also noted.
As a neurotropic agent, carbamazepine is effective in some neurological diseases, as it prevents pain attacks in idiopathic and secondary trigeminal neuralgia. In addition, the drug should be used to relieve neurogenic pain in various conditions, including spinal cord tuberculosis, post-traumatic paresthesias and post-herpetic neuralgia. In alcohol withdrawal syndrome, the drug increases the threshold for convulsive readiness (which is reduced in this condition) and reduces the severity of clinical manifestations of the syndrome, such as excitability, tremor, gait disturbance. In patients with diabetes insipidus of central genesis, the drug reduces diuresis and thirst.
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 almost completely absorbed, but the rate of absorption from tablets is slow and may vary between different formulations in different patients. After a single dose of the prolonged-release preparation, the peak plasma concentration (Cmax) of the active substance is reached after 24 hours. The prolonged-release preparation shows approximately 15% lower bioavailability than conventional carbamazepine preparations due to a significant decrease in peak plasma levels due to the prolonged release of the same dose of carbamazepine. Plasma concentrations show less fluctuation, but auto-induction of carbamazepine occurs as with conventional carbamazepine tablets.
The bioavailability of various dosage forms of carbamazepine for oral administration was 85-100%. Food intake does not significantly affect the rate and extent of absorption of carbamazepine (regardless of the dosage form). Equilibrium concentrations of carbamazepine in blood plasma are 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, dose of the drug and duration of treatment.
The bioavailability of different dosage forms of carbamazepine may vary. To prevent a decrease in the effect of the drug or the risk of epileptic seizures while taking it, changing dosage forms of carbamazepine should be avoided.
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 proteins (20-30%). The concentration of carbamazepine in breast milk is 25-60% of its level in plasma. Carbamazepine penetrates the placental barrier. Under the condition of complete absorption of carbamazepine, the apparent volume of distribution is from 0.8 to 1.9 l/kg.
Carbamazepine is metabolized in the liver mainly by the epoxy pathway, resulting in the formation of the main metabolites - 10,11-transdiol derivative and its conjugate with glucuronic acid. The main isoenzyme that provides the biotransformation of carbamazepine to carbamazepine-10,11-epoxide is cytochrome P450 3A4. As a result of these metabolic reactions, a "minor" metabolite 9-hydroxy-methyl-10-carbamoyl acridane is also formed. After a single oral administration of carbamazepine, approximately 30% of the active substance is determined 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 glucuronosyl transferase (UGT2B7).
Breeding.
After a single oral dose, the elimination half-life of unchanged carbamazepine is on average 36 hours, and after repeated doses, it is on average 16-24 hours (due to autoinduction of the liver monooxygenase system), depending on the duration of treatment. In patients who are simultaneously taking other drugs that induce the same liver enzyme system (e.g. phenytoin, phenobarbital), the elimination half-life of carbamazepine is on average 9-10 hours.
The mean plasma half-life of the 10,11-epoxide metabolite is approximately 6 hours after a single oral dose of the epoxide.
After a single oral dose of 400 mg carbamazepine, 72% of the dose is excreted in the urine and 28% in the feces. Almost 2% of the dose is excreted in the urine as unchanged drug and approximately 1% as the pharmacologically active metabolite 10,11-epoxide.
Features of pharmacokinetics in certain groups of patients.
Children: Due to the more rapid elimination of carbamazepine, children may require higher doses of carbamazepine on a mg/kg body weight basis compared to adults to maintain therapeutic drug concentrations.
Elderly patients: There is no evidence to suggest that the pharmacokinetics of carbamazepine are altered in elderly patients (compared to young adults).
Patients with impaired renal or hepatic function. There are no data on the pharmacokinetics of carbamazepine in patients with impaired renal or hepatic function.
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 seizures.
Mezacar® SR can be used as monotherapy or as part of combination therapy.
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 related drugs (e.g. tricyclic antidepressants), or to any other component of the drug. Atrioventricular block. History of bone marrow depression. History of hepatic porphyria (e.g. acute intermittent porphyria, mixed porphyria, porphyria cutanea tarda). Concomitant use with monoamine oxidase inhibitors (MAO).
Interaction with other medicinal products and other types of interactions
Cytochrome P450 3A4 (CYP3A4) is the main enzyme that catalyzes the formation of the active metabolite of 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 the development of adverse reactions. Accordingly, the dose of Mezacar® SR should be adjusted and its plasma levels monitored. Concomitant use of CYP3A4 inducers may increase the metabolism of carbamazepine, which may lead to a potential decrease in carbamazepine serum concentrations and therapeutic effect. Similarly, discontinuation of a CYP3A4 inducer may reduce the rate of carbamazepine metabolism, leading to increased plasma levels of carbamazepine. Accordingly, a dose adjustment of Mezacar® SR may be necessary.
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 the 10,11-transdiol derivative of carbamazepine-10,11-epoxide. Concomitant administration of inhibitors of human microsomal epoxide hydrolase (e.g. valproic acid) may lead to increased plasma concentrations of carbamazepine-10,11-epoxide.
Since an increase in carbamazepine plasma levels may lead to undesirable reactions (such as dizziness, drowsiness, ataxia, diplopia), the dosage of Mezacar® SR should be adjusted accordingly and/or its plasma levels monitored when used simultaneously with the following drugs.
Analgesics, anti-inflammatory drugs: dextropropoxyphene, ibuprofen.
Androgens: danazol.
Antibiotics: macrolide antibiotics (e.g. erythromycin, troleandomycin, josamycin, clarithromycin, ciprofloxacin).
Antidepressants: desipramine, fluoxetine, fluvoxamine, nefazodone, paroxetine, trazodone, viloxazine.
Antiepileptics: stiripentol, vigabatrin.
Antifungals: azoles (e.g. itraconazole, ketoconazole, fluconazole, voriconazole). Alternative antiepileptic agents may be recommended for patients receiving voriconazole or itraconazole treatment.
Antihistamines: loratadine, terfenadine.
Antipsychotic drugs: olanzapine, loxapine, quetiapine.
Anti-tuberculosis drugs: isoniazid.
Antiviral drugs: protease inhibitors for HIV (e.g. ritonavir).
Carbonic anhydrase inhibitors: acetazolamide.
Cardiovascular drugs: diltiazem, verapamil.
Drugs for the treatment of gastrointestinal (GI) 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 levels of the active metabolite carbamazepine-10,11-epoxide in the blood plasma may lead to the development of adverse reactions (e.g. dizziness, drowsiness, ataxia, diplopia), the dosage of Mezacar® SR should be adjusted accordingly and/or the plasma levels of the drug monitored if Mezacar® SR is taken concomitantly with the following drugs: loxapine, quetiapine, primidone, progabide, valproic acid, valnoctamide and valpromide.
Drugs that may reduce the level of carbamazepine in the blood plasma.
Dose adjustment of Mezacar® SR 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) and fosphenytoin, primidone, and clonazepam (although data on this are conflicting).
Anticancer drugs: cisplatin or doxorubicin.
Anti-tuberculosis drugs: rifampicin.
Bronchodilators or anti-asthma drugs: theophylline, aminophylline.
Dermatological drugs: isotretinoin.
Interaction with other substances: herbal preparations containing St. John's wort (Hypericum perforatum).
Mefloquine may antagonize the antiepileptic effect of Mezacar® SR. The dose of Mezacar® SR may need to be adjusted accordingly.
Isotretinoin has been reported to alter the bioavailability and/or clearance of carbamazepine and carbamazepine-10,11-epoxide; plasma concentrations of carbamazepine should be monitored.
The effect of carbamazepine on the plasma levels of concomitantly administered drugs.
Carbamazepine may reduce the plasma levels of some drugs and reduce or eliminate their effects. Dosage 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, 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 Mezacar® SR in combination with monoamine oxidase inhibitors (MAO) is not recommended. The use of MAO inhibitors should be discontinued at least 2 weeks before the administration of Mezacar® (and if the clinical situation allows, even earlier).
Antiepileptic drugs: clobazam, clonazepam, ethosuximide, felbamate, lamotrigine, eslicarbazepine, oxcarbazepine, primidone, tiagabine, topiramate, valproic acid, zonisamide. Both increased and decreased phenytoin plasma levels have been reported with carbamazepine, and isolated cases of increased mephenytoin plasma levels have been reported. To avoid phenytoin intoxication and subtherapeutic carbamazepine concentrations, it is recommended that the phenytoin plasma concentration should not exceed 13 μg/ml before starting carbamazepine therapy. There have been isolated reports of increased mephenytoin plasma concentrations with carbamazepine, which in rare cases resulted in confusion and even coma.
Antifungals: itraconazole, voriconazole, ketoconazole. Alternative antiepileptic agents may be recommended for patients receiving voriconazole or itraconazole treatment.
Anthelmintic drugs: praziquantel, albendazole.
Anticancer drugs: imatinib, cyclophosphamide, lapatinib, temsirolimus.
Neuroleptic drugs: clozapine, haloperidol and bromperidol, olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, paliperidone.
Antiviral drugs: protease inhibitors for the treatment of HIV (e.g. indinavir, ritonavir, saquinavir).
Anxiolytics: alprazolam, midazolam.
Bronchodilators or anti-asthma drugs: theophylline.
Contraceptives: Hormonal contraceptives (alternative methods of contraception should be considered). There have been reports of reduced efficacy of hormonal contraceptives and breakthrough bleeding in women when oral contraceptives were used concomitantly with carbamazepine. Such patients should be advised to use a product containing at least 50 mcg of estrogen or alternative non-hormonal methods of contraception.
Cardiovascular drugs: calcium channel blockers (dihydropyridine group), e.g. felodipine, isradipine, digoxin, quinidine, propranolol, simvastatin, atorvastatin, lovastatin, cerivastatin, ivabradine.
Corticosteroids: prednisolone, dexamethasone.
Drugs used to treat erectile dysfunction: tadalafil.
Immunosuppressants: cyclosporine, everolimus, tacrolimus, sirolimus.
Thyroid medications: levothyroxine. Carbamazepine appears to promote thyroid hormone excretion and increase thyroid hormone requirements in patients with hypothyroidism. Therefore, thyroid function should be monitored in patients receiving replacement therapy, both at the beginning and 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 simultaneous use of carbamazepine and lithium or metoclopramide, as well as carbamazepine and neuroleptics (haloperidol, thioridazine) may lead to increased neurological side effects (in the case of the latter combination - even at therapeutic plasma levels). Therefore, clinical symptoms should be closely monitored. At least 8 weeks should elapse after the end of previous treatment with neuroleptics. Simultaneous treatment should also be avoided. Patients should be monitored for the following neurotoxic symptoms: unsteady gait, ataxia, horizontal nystagmus, increased proprioceptive muscle reflexes, muscle cramps (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.
Combination therapy with carbamazepine and some diuretics (hydrochlorothiazide, furosemide) may lead to symptomatic hyponatremia.
Carbamazepine may antagonize the effects of non-depolarizing muscle relaxants (e.g. pancuronium). Doses of these drugs may need to be increased and patients should be monitored closely because of the possibility of a more rapid than expected recovery from neuromuscular blockade.
Carbamazepine, like other psychotropic drugs, may reduce alcohol tolerance, so patients are advised to abstain from alcohol.
Concomitant use of carbamazepine with direct-acting oral anticoagulants (rivaroxaban, dabigatran, apixaban, edoxaban) may lead to decreased plasma concentrations of direct-acting oral anticoagulants and thus an increased risk of thrombosis. Therefore, if concomitant use is necessary, patients should be closely monitored for signs and symptoms of thrombosis.
Since carbamazepine is structurally similar to tricyclic antidepressants, Mezacar® SR is not recommended for use simultaneously with monoamine oxidase inhibitors (MAOIs); before starting the drug, it is necessary to stop taking the MAO inhibitor (at least two weeks or earlier if clinical circumstances allow).
Impact on serological studies.
Carbamazepine may give a false-positive result in HPLC (high-performance liquid chromatography) assays for 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 warnings.
Mezacar®SR should be prescribed only under medical supervision, only after assessing the benefit/risk ratio and subject to careful monitoring of patients with cardiac, hepatic or renal disorders, a history of adverse hematological reactions to other drugs, disorders of sodium metabolism, and patients with interrupted courses of carbamazepine therapy.
It is recommended to perform a complete urinalysis and determine the level of urea nitrogen in the blood at the beginning and at certain intervals during therapy.
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.
The drug is usually ineffective in absence (petit mal) and myoclonic seizures. Individual reports indicate that in patients with atypical absence seizures, seizures may be exacerbated.
Hematological effects.
Agranulocytosis and aplastic anemia have been associated with carbamazepine; however, the extremely low incidence of these conditions makes it difficult to estimate a significant risk with Mezacar® SR. The overall risk for patients not receiving carbamazepine therapy is 4.7 person/1,000,000 per year for agranulocytosis and 2 person/1,000,000 per year for aplastic anemia.
Patients should be informed about the early signs of toxicity and symptoms of possible haematological disorders, as well as symptoms of dermatological and hepatic reactions. The patient should be warned that in the event of reactions such as fever, sore throat, skin rash, mouth ulcers, easy bruising, petechial haemorrhages or haemorrhagic purpura, they should seek medical advice immediately.
If the number of leukocytes or platelets decreases significantly during therapy, the patient's condition should be closely monitored and a complete blood count should be performed regularly. Treatment with Mezacar® SR should be discontinued if the patient develops leukopenia that is severe, progressive, or accompanied by clinical manifestations such as fever or sore throat. The use of Mezacar® SR should be discontinued if signs of bone marrow suppression appear.
Periodically or frequently, a temporary or persistent decrease in the number of platelets or white blood cells has been reported in association with carbamazepine. However, most of these cases have been confirmed to be transient and do not indicate the development of aplastic anemia or agranulocytosis. Before starting therapy and periodically during it, a blood test should be performed, including determination of the platelet count (and possibly the reticulocyte count, hemoglobin level and serum iron level).
Serious dermatological reactions. Serious dermatological reactions, including toxic epidermal necrolysis (TEN), or Lyell's syndrome, and Stevens-Johnson syndrome (SJS), 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 SJS/TEN occur during the first few months of carbamazepine treatment. It is estimated that these dermatological reactions occur in 1-6 out of 10,000 new patients in countries with a predominantly white population. However, in some Asian countries the risk may be increased by approximately 10-fold. If signs and symptoms suggestive of serious dermatological reactions (e.g. SJS, Lyell's syndrome/TEN) develop, Mezacar® SR 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.
Retrospective studies in Han Chinese patients have shown a strong correlation between carbamazepine-associated cutaneous reactions of SS/TEN 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 frequency of reports of SS (rare rather than very rare) is characteristic of some Asian countries (e.g. Taiwan, Malaysia and the Philippines), where the (HLA)-B*1502 allele is prevalent in the population. The number of carriers of this allele in the Asian population is more than 15% (in the Philippines and in some Malaysian populations). In Korea and India, the prevalence of this allele in the population is up to 2% and 6%, 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 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.
Patients considered to be genetically at risk should be tested for the presence of the (HLA)-B*1502 allele before starting carbamazepine treatment. If the patient tests positive for the (HLA)-B*1502 allele, treatment with Mezacar® SR should not be initiated unless there are no other therapeutic options. When assessing risk, it should be remembered that the HLA-B*1502 allele is also a risk factor for other antiepileptic drugs. Patients who are tested and have a negative result for (HLA)-B*1502 are at low risk of developing SSRIs, 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 people of Southeast Asian descent are at risk.
The (HLA)-B*1502 allele may be a risk factor for the development of SCD/TEN in Chinese patients receiving other antiepileptic drugs that may be associated with the development of SCD/TEN. Therefore, the use of other drugs that may be associated with the development of SCD/TEN in patients with the (HLA)-B*1502 allele should be avoided if other, alternative therapies are available. Genetic screening of patients from ethnic groups with a low incidence of the (HLA)-B*1502 allele is generally not recommended. Screening of patients already receiving carbamazepine is generally not recommended because the risk of SCD/TEN 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 HLA-B*1502 carriers do not develop SS/TEN, while other patients without genetic risk factors may develop SS/TEN for other reasons. The situation is similar for HLA-A*3101 carriers treated with carbamazepine. These patients do not necessarily develop SS/TEN, DRESS, AGEP or maculopapular rash. 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 SSc.
Association with HLA-A*3101
Human leukocyte antigen may be a risk factor for the development of cutaneous adverse reactions such as SJS, TEN, drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), maculopapular rash. If the analysis reveals the presence of the HLA-A*3101 allele, the use of Mezacar® SR should be avoided.
Retrospective analysis of Japanese and Northern European patients has demonstrated an association between severe skin lesions (SSD/TEN, DRESS, AGEP, and maculopapular rash) in carriers of the HLA-A*3101 allele of the human leukocyte antigen (HLA) gene and the use of carbamazepine.
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 Mezacar® SR, possible carriers of the HLA-A*3101 allele (e.g. patients of Japanese ethnicity, Caucasians, Native Americans, Hispanics, South Indians and Arabs) are recommended to be screened for this allele (see section “Dosage and Administration”). Carbamazepine 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 period, since SSRI/TEN, AGEP, DRESS and maculopapular rash are usually observed only during the first few months of therapy.
Limitations of genetic screening
Genetic screening results should not replace appropriate clinical monitoring and treatment of patients. Other possible factors such as antiepileptic drug dosage, adherence to treatment regimen, concomitant medications play a role in the occurrence of these severe skin adverse reactions. The impact of other diseases and the level of monitoring of skin disorders have not been studied.
Other dermatological reactions.
Transient and non-life-threatening mild dermatological reactions, such as isolated macular or maculopapular exanthema, may also occur. They usually resolve within a few days or weeks, both with continued carbamazepine dosing and after dose reduction. Since early signs of more serious dermatological reactions can be very difficult to distinguish from mild transient reactions, the patient should be closely monitored 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, the presence of (HLA)-B*1502 has not been shown to be associated with the risk of these skin reactions.
Hypersensitivity: Carbamazepine may cause hypersensitivity reactions, including DRESS, delayed-type multiple hypersensitivity reactions with fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests, and vanishing bile duct syndrome (including destruction and disappearance of the intrabiliary ducts), which may occur in various combinations. Clinical manifestations from other organs (lungs, kidneys, pancreas, myocardium, colon) are also possible.
The presence of the HLA-A*3101 allele in a patient is associated with the occurrence of less serious adverse skin reactions when using 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 experience 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, Mezacar® SR should be discontinued immediately.
Seizures. Since carbamazepine may induce or exacerbate absence seizures, Mezacar® SR 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, Mezacar® SR should be discontinued immediately.
An increase in the frequency of seizures is possible when switching from oral forms of carbamazepine to suppositories.
Liver function. During carbamazepine therapy, liver function should be assessed at baseline and periodically during therapy, especially in patients with a history of liver disease and in elderly patients. In case of exacerbation of liver function disorders or in patients with active liver disease, Mezacar® SR should be discontinued immediately.
Some laboratory tests used to assess liver function may be abnormal in patients taking carbamazepine, particularly gamma-glutamyltransferase (GGT). This is likely due to induction of liver enzymes. Enzyme induction may also result in a modest increase in alkaline phosphatase.
