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Carbamazepine-Induced Severe Cutaneous Adverse Drug Reactions: A 21-Year Comparison Between Children and Adults in Malaysia

Hariraj V, Wo WK, Lee SC, Ramli A

J Clin Pharmacol, 2023 Oct;63(10):1126-1132.
PMID: 37291071 DOI: 10.1002/jcph.2289

Severe cutaneous adverse drug reactions (SCARs) are a life-threatening condition. We aimed to identify all carbamazepine-induced SCARs voluntarily reported to the Malaysian pharmacovigilance database and to compare between children and adults. Adverse drug reaction reports for carbamazepine were extracted from 2000 to 2020, and divided into 2 groups, that is, children (aged 0-17 years) and adults (aged 18 years and above). Age, sex, race, and carbamazepine dose were analyzed using multiple logistic regression. Of 1102 carbamazepine adverse drug reaction reports, 416 reports were SCARs (99 children, 317 adults). Stevens-Johnson syndrome and toxic epidermal necrolysis were the main SCAR types for both age groups. Median time-to-onset for any type of SCAR was 13 days, regardless of age. In children, Malay individuals were 3.6 times more likely to report SCARs (95% confidence interval, 1.356-9.546; P = .010) compared to the Chinese population. In adults, carbamazepine-induced SCARs were reported as 3.6 times higher in those with a daily dose of 200 mg or less as compared to a daily dose of 400 mg or more. (95% confidence interval, 2.257-5.758; P

Matched MeSH terms: Carbamazepine/adverse effects
Fulltext Recommendations for HLA-B*15:02 and HLA-A*31:01 genetic testing to reduce the risk of carbamazepine-induced hypersensitivity reactions

Amstutz U, Shear NH, Rieder MJ, Hwang S, Fung V, Nakamura H, et al.

Epilepsia, 2014 Apr;55(4):496-506.
PMID: 24597466 DOI: 10.1111/epi.12564

To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B*15:02 and HLA-A*31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B*15:02 or HLA-A*31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results?

Matched MeSH terms: Carbamazepine/adverse effects*
Fulltext Lamotrigine for trigeminal neuralgia: efficacy and safety in comparison with carbamazepine

Shaikh S, Yaacob HB, Abd Rahman RB

J Chin Med Assoc, 2011 Jun;74(6):243-9.
PMID: 21621166 DOI: 10.1016/j.jcma.2011.04.002

BACKGROUND: Anticonvulsants are regarded as useful for the treatment of neuropathic pain. In this study, we evaluated the efficacy and occurrence of side effects of lamotrigine (LTG) in comparison with carbamazepine (CBZ), in trigeminal neuralgia (TN) patients.
METHODS: The study was an interventional and crossover comparison. Twenty-one patients with TN were administered with LTG in comparison to CBZ. The clinical trials comprised two phases of 40 days each, with an intervening three-day washout period. The final titration in dose for LTG was 400 mg and 1,200 mg for CBZ. Efficacy of the medications involved was determined by visual analog scale (VAS) and verbal rating scale (VRS). Side effects were recorded through marking of the profiles of side effects encountered on administration of LTG and CBZ, together with baseline haematological, hepatic and renal investigations.
RESULTS: Both on VAS and VRS assessments, in terms of proportion of patients, CBZ benefitted 90.5% (19/21) of the patients with pain relief (p 0.05). Meanwhile, LTG inflicted 14% (3/21) of the patients with haematological, hepatic and renal derangements, as compared with 48% (10/21) on CBZ.
CONCLUSION: LTG is generally an effective and safe treatment for management of TN, compared to CBZ.

Matched MeSH terms: Carbamazepine/adverse effects
Pharmacogenetic screening of carbamazepine-induced severe cutaneous allergic reactions

Locharernkul C, Shotelersuk V, Hirankarn N

J Clin Neurosci, 2011 Oct;18(10):1289-94.
PMID: 21802305 DOI: 10.1016/j.jocn.2010.12.054

Recent studies associated the HLA-B 1502 allele with carbamazepine (CBZ)-induced Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in patients from China, Thailand and Malaysia. No association has been found in patients from Europe or Japan. Linkage summary reports from East and South-east Asia predict a highly significant odds ratio (OR) of 84.75 (95% confidence interval [CI]=42.53-168.91; p=8.96×10[-15]) with sensitivity and negative predictive values of 92% and 98%, respectively. The higher prevalence of HLA-B 1502 allele among certain Asian populations (10-15%) compared to Caucasians (1-2%) may explain a 10-fold to 25-fold higher incidence of CBZ-SJS/TEN in patients from Asia. Screening for HLA-B 1502 before using CBZ can prevent SJS/TEN in certain populations, but screening may be less beneficial in populations with low HLA-B 1502 allele frequency and in patients exposed to CBZ for more than 2 months. A retrospective study demonstrated that the costs of HLA-B 1502 screening were less than those of SJS treatment. This article reviews possible benefits and concerns of HLA-B 1502 screening in clinical practice.

Matched MeSH terms: Carbamazepine/adverse effects*
Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population

Chang CC, Too CL, Murad S, Hussein SH

Int J Dermatol, 2011 Feb;50(2):221-4.
PMID: 21244392 DOI: 10.1111/j.1365-4632.2010.04745.x

BACKGROUND: Carbamazepine (CBZ), a frequently used anticonvulsant drug, is one of the most common causes of life-threatening cutaneous adverse drug reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). Recent studies have revealed a strong association between HLA-B*1502 and CBZ-induced TEN/SJS in the Taiwan Han Chinese population.
OBJECTIVES: This study is aimed to investigate the association between human leucocyte antigens (HLA) and CBZ-induced TEN/SJS in the multi-ethnic Malaysian population.
METHODS: A sample of 21 unrelated patients with CBZ-induced TEN/SJS and 300 race-matched, healthy controls were genotyped for HLA-A, -B and -DR using polymerase chain reaction (PCR). Allele frequencies were compared.
RESULTS: HLA-B*1502 was present in 75.0% (12/16) of Malay patients with CBZ-induced TEN/SJS but in only 15.7% (47/300) of normal controls (odds ratio 16.15, 95% confidence interval 4.57-62.4; corrected P-value = 7.87 × 10(-6) ), which suggests a strong association between HLA and CBZ-induced TEN/SJS. Additionally, HLA-B*1502 was found in all three Chinese and two Indian patients. Existing data show that frequencies of the HLA-B*1502 allele are generally much higher in Asian populations than in White European populations, which explains the higher incidences of SJS and TEN in Asian countries.
CONCLUSIONS: HLA-B*1502 is strongly associated with CBZ-induced TEN/SJS in the Malay population in Malaysia, as has been seen in Han Chinese in Taiwan. This indicates that the genetic association apparent in the incidence of CBZ-induced TEN/SJS is linked with the presence of HLA-B*1502, irrespective of racial origin. Screening of patients for this genetic marker can help to prevent the occurrence of TEN/SJS.

Matched MeSH terms: Carbamazepine/adverse effects*
Fulltext High-flux haemodialysis treatment as treatment for carbamazepine intoxication

Koh KH, Tan HH

Med J Malaysia, 2006 Mar;61(1):109-11.
PMID: 16708747 MyJurnal

Acute severe intoxication with carbamazepine is associated with seizures, coma and respiratory depression. Traditionally, charcoal haemoperfusion is used to remove the drug. We present a case of carbamazepine intoxication, successfully treated with three hours of high-flux haemodialysis. Thus, haemodialysis using high-flux membranes is a feasible and effective therapeutic option for carbamazepine intoxication.

Matched MeSH terms: Carbamazepine/adverse effects*
Fulltext Coupling Genotyping and Computational Modeling in Prediction of Anti-epileptic Drugs that cause Stevens Johnson Syndrome and Toxic Epidermal Necrolysis for Carrier of HLA-B*15:02

Teh LK, Selvaraj M, Bannur Z, Ismail MI, Rafia H, Law WC, et al.

J Pharm Pharm Sci, 2016;19(1):147-60.
PMID: 27096699 DOI: 10.18433/J38G7X

PURPOSE: The importance of HLA-B*15:02 genotyping to avoid carbamazepine induced SJS/TEN and molecular modeling to predict the role of HLA-B*15:0 and AEDs induced SJS/TEN are investigated.
METHODS: DNA was extracted from eighty-six patients. The patients were genotyped by AS-PCR. Computational modeling of the HLA-B*15:02 followed by docking studies were performed to screen 26 AEDs that may induce ADR among HLA-B*15:02 carriers.
RESULTS: Odd ratio for CBZ induced SJS/TEN and HLA-B*15:02 was 609.0 (95% CI: 23-15873; p=0.0002). Molecular modeling studies showed that acetazolamide, ethosuxiamide, lamotrigine, oxcarbazepine, phenobarbital, phenytoin, primidone and sodium-valproate may induce ADR in HLA-B*15:02 carriers alike CBZ. Conclusion. We confirmed HLA-B*15:02 as a predictor of SJS/TEN and recommend pre-screening. Computational prediction of DIHR is useful in personalized medicine.

Matched MeSH terms: Carbamazepine/adverse effects*
Frequency of the HLA-B*1502 allele contributing to carbamazepine-induced hypersensitivity reactions in a cohort of Malaysian epilepsy patients

Then SM, Rani ZZ, Raymond AA, Ratnaningrum S, Jamal R

Asian Pac J Allergy Immunol, 2011 Sep;29(3):290-3.
PMID: 22053601

We describe the association of the HLA-B*1502 allele in 27 epilepsy patients (19 Malays, 8 Chinese) treated with carbamazepine (CBZ) at the UKM Medical Center (UKMMC), 6 with CBZ-Steven Johnson Syndrome (CBZ-SJS), 11 with CBZ-induced rash, 2 with suspected phenytoin-induced rash and 8 negative controls. Our study showed that 10 (6 Malay, 4 Chinese) patients were positive for HLA-B*1502. Out of the 10 patients, six were confirmed to have CBZ-SJS (p = 0.0006), while four patients developed a skin rash. However there were 6 Malay patients and 1 Chinese patient that developed a skin rash after CBZ administration who were not positive for the allele, indicating that there might be more that one allele associated with CBZ-induced hypersensitivity. Another 2 patients were suspected of having phenytoin-induced rash, instead of CBZ, and these patients did not have HLA-B*1502. In conclusion, this study confirmed the association of HLA-B*1502 with CBZ-SJS among Malaysian epilepsy patients, however there might be other genes that could be responsible for the CBZ-induced rash.

Matched MeSH terms: Carbamazepine/adverse effects*
HLA-A*31: 01 and HLA-B*15:02 association with Stevens-Johnson syndrome and toxic epidermal necrolysis to carbamazepine in a multiethnic Malaysian population

Khor AH, Lim KS, Tan CT, Kwan Z, Tan WC, Wu DB, et al.

Pharmacogenet Genomics, 2017 07;27(7):275-278.
PMID: 28570299 DOI: 10.1097/FPC.0000000000000287

The majority of the carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis CBZ-SJS/TEN are associated with HLA-B*15:02 in Asian populations where this allele is common. In contrast, the association with HLA-A*31:01 is only reported in Japanese and Europeans. This study aimed to further investigate the association with HLA-A*31:01 besides HLA-B*15:02 in a multiethnic Malaysian population. Twenty-eight CBZ-SJS/TEN cases and 227 CBZ-tolerant controls were recruited. Association was tested by comparing carrier frequencies of the alleles between cases and controls. Significant associations were detected between HLA-B*15:02 and CBZ-SJS/TEN in independent ethnic groups: Malays [P=2.00×10; odds ratio (OR): 49.0; 95% confidence interval (CI): 9.36-256.81], Chinese (P=0.0047; OR: 14.3; 95% CI: 2.38-86.03) and Indians (P=0.04; OR: 13.8; 95% CI: 1.51-124.99). Combined analysis of all ethnic groups showed a significant association with OR Cochran-Mantel-Haenszel (ORCMH) of 26.6 (95% CI: 12.80-55.25; PCMH=2.31×10). In Indians, HLA-A*31:01 was found to be associated significantly with CBZ-SJS/TEN (P=0.023; OR: 10.4; 95% CI: 1.64-65.79) and combined analyses of both variants, HLA-A*31:01 and HLA-B*15:02, increased the strength of the association (P=0.0068; OR: 14.3; 95% CI: 2.20-92.9). Besides HLA-B*15:02, our study found a new association between HLA-A*31:01 and CBZ-SJS/TEN in Indians.

Matched MeSH terms: Carbamazepine/adverse effects*
Fulltext Is universal HLA-B*15:02 screening a cost-effective option in an ethnically diverse population? A case study of Malaysia

Chong HY, Mohamed Z, Tan LL, Wu DBC, Shabaruddin FH, Dahlui M, et al.

Br J Dermatol, 2017 Oct;177(4):1102-1112.
PMID: 28346659 DOI: 10.1111/bjd.15498

BACKGROUND: A strong association has been documented between HLA-B*15:02 and carbamazepine-induced severe cutaneous adverse reactions (SCARs) in Asians. Human leucocyte antigen testing is potentially valuable in many countries to facilitate early recognition of patient susceptibility to SCARs.
OBJECTIVES: To determine the cost-effectiveness of universal HLA-B*15:02 screening in preventing carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in an ethnically diverse Malaysian population.
METHODS: A hybrid model of a decision tree and Markov model was developed to evaluate three strategies for treating newly diagnosed epilepsy among adults: (i) carbamazepine initiation without HLA-B*15:02 screening (current practice); (ii) universal HLA-B*15:02 screening prior to carbamazepine initiation; and (iii) alternative treatment [sodium valproate (VPA)] prescribing without HLA-B*15:02 screening. Base-case analysis and sensitivity analyses were performed over a lifetime time horizon. Incremental cost-effectiveness ratios were calculated.
RESULTS: Both universal HLA-B*15:02 screening and VPA prescribing were dominated by current practice. Compared with current practice, universal HLA-B*15:02 screening resulted in a loss of 0·0255 quality-adjusted life years (QALYs) at an additional cost of 707 U.S. dollars (USD); VPA prescribing resulted in a loss of 0·2622 QALYs at an additional cost of USD 4127, owing to estimated differences in antiepileptic treatment efficacy.
CONCLUSIONS: Universal HLA-B*15:02 screening is unlikely to be a cost-effective intervention in Malaysia. However, with the emergence of an ethnically diverse population in many other countries, this may render HLA-B*15:02 screening a viable intervention when an increasing proportion of the population is at risk and an equally effective yet safer antiepileptic drug is available.

Matched MeSH terms: Carbamazepine/adverse effects*