Apo-Carbamazepine

Apo-Carbamazepine Mechanism of Action

carbamazepine

Manufacturer:

Apotex

Distributor:

Pharmaforte
Full Prescribing Info
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Pharmacology: Carbamazepine has anticonvulsant properties which are useful in the treatment of psychomotor and other partial epilepsies when administered in conjunction with other anticonvulsant drugs to prevent the possible generalization of the epileptic discharge. A mild psychotropic effect has been observed in some patients. It seems related to the effect of carbamazepine in psychomotor or temporal lobe epilepsy.
Carbamazepine relieves or diminishes the pain associated with trigeminal neuralgia, often within 24 or 48 hours.
Like other tricyclic compounds, carbamazepine has a moderate anticholinergic action responsible for some of its side effects.
Watch for a tolerance to the action of carbamazepine which may develop after a few months of treatment.
A number of investigators have reported a deterioration of EEG abnormalities with regard to local alteration and higher incidence of records with nil beta activity during carbamazepine-combined treatment.
Ventricular automaticity may be suppressed by carbamazepine because of its membrane depressant effect associated with suppression of phase 4 depolarization of the heart muscle fibre.
The absorption and elimination of carbamazepine in humans in relatively slow. After a single-dose, oral administration of 400mg carbamazepine, peak plasma levels of 35 to 55 kg/ml were obtained in about 6 hours. Plasma levels were virtually unchanged for a further 6 hours (12 hours after administration). The acute biological half of carbamazepine is 37 hours.
Pharmacogenomics: There is growing evidence of the role of different HLA alleles in predisposing patients to immune-mediated adverse reactions.
Association with HLA-B*1502: Retrospective studies in patients of Han Chinese ancestry and Thai origin found a strong correlation between Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) skin reactions associated with carbamazepine and the presence in these patients of the Human Leukocyte Antigen (HLA)-B*1502 allele. The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations and is about 8% in Thai populations. Higher reporting rates of SJS (rare rather than very rare) are reported in some countries in Asia (e.g. Taiwan, Malaysia and the Philippines) in which there is a higher frequency of the HLA-B*1502 allele in the population (e.g. above 15% in the Philippines and some Malaysian populations). Allele frequencies up to about 2%, 6% and 12% have been reported in Korea, India and Singapore, respectively. The frequency of the HLA-B*1502 allele is negligible in persons of European descent, several African populations, indigenous peoples of the Americas, Hispanic populations sampled and in Japanese (<1%).
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e., the "carrier frequency") is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Testing for the presence of HLA-B*1502 allele is highly recommended prior to the initiation of carbamazepine therapy in new patients of Asian ancestry (see Information for the healthcare professionals as follows). The use of carbamazepine should be avoided in tested patients who are found to be positive for HLA-B*1502 unless the benefits clearly outweigh the risks. HLA-B*1502 may be a risk factor for the development of SJS/TEN in Chinese patients taking other anti-epileptic drugs (AED) associated with SJS/TEN. Consideration should therefore be given to avoiding use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low, e.g. in Caucasian. Screening is generally not recommended for any current carbamazepine users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLAB* 1502 status.
The identification of subjects carrying the HLA-B*1502 allele and the avoidance of carbamazepine therapy in these subjects has been shown to decrease the incidence of carbamazepine-induced SJS/TEN.
Association with HLA-A*3101: Human Leukocyte Antigen (HLA)-A*3101 may be a risk factor for the development of cutaneous adverse drug reactions such as SJS, TEN, DRESS, AGEP and maculopapular rash. Retrospective genome-wide studies in Japanese and Northern European populations reported association between severe skin reactions (SJS, TEN, DRESS, AGEP and maculopapular rash) associated with carbamazepine use and the presence of the HLA-A*3101 allele in these patients.
The frequency of the HLA-A*3101 allele varies widely between ethnic populations and its frequency is about 2 to 5% in European populations and about 10% in the Japanese population. The frequency of this allele is estimated to be less than 5% in the majority of Australian, Asian, African and North American populations with some exceptions within 5-12%. Prevalence above 15% has been estimated in some ethnic groups in South America (Argentina and Brazil), North America (US Navajo and Sioux, and Mexico Sonora Seri) and Southern India (Tamil Nadu) and between 10%-15% in other native ethnicities in these same regions.
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least one of their two chromosomes (i.e., the "carrier frequency") is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Testing for the presence of HLA-A*3101 allele should be considered in patients with ancestry in genetically at-risk populations (for example, patients of the Japanese and Caucasian populations, patients who belong to the indigenous populations of the Americas, Hispanic populations, people of southern India, and people of Arabic descent), prior to initiating treatment with carbamazepine (see Information for the healthcare professionals as follows). The use of carbamazepine should be avoided in patients who are found to be positive for HLA-A*3101, unless the benefits clearly outweigh the risks. Screening is generally not recommended for any current carbamazepine users, as the risk of SJS/TEN, AGEP, DRESS and maculopapular rash is largely confined to the first few months of therapy, regardless of HLA-A*3101 status.
Limitation of genetic screening: Genetic screening results must never substitute for appropriate clinical vigilance and patient management. Many patients positive for HLA-B*1502 and treated with carbamazepine will not develop SJS/TEN. In populations in which HLA-B*1502 is common, these reactions rarely occur in HLA-B*1502-negative patients. Many patients positive for HLA-A*3101 and treated with carbamazepine will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA-A*3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of, and morbidity from, these severe cutaneous adverse reactions, such as AED dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been studied.
Information for the healthcare professionals: If testing for the presence of the HLA-B*1502 allele is performed, high-resolution "HLA-B*1502 genotyping" is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected. Similarly if testing for the presence of the HLA-A*3101 allele is performed, high-resolution "HLA-A*3101 genotyping" respectively is recommended. The test is positive if either one or two HLA-A*3101 alleles are detected and negative if no HLA-A*3101 alleles are detected.
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