use of carbamazepine (Carbatrol; Equetro; Tegretol) is common for the treatment
of acute manic and mixed episodes associated with bipolar I disorder, epilepsy,
and trigeminal neuralgia.1,2 Unfortunately, carbamazepine is associated
with a number of problems and/or side effects one of which includes
hypersensitivity reactions that most commonly involves the skin, but is also
associated with other organs (liver, kidneys) as well.3 Many patients
will typically exhibit a triad of fever, rash, and lymphadenopathy, but are
also known to have eosinophilia and atypical lymphocytosis.3,4 As it
relates to the hypersensitivity reaction involving the skin, the condition can
range from a mild skin rash (generalized exanthematous eruptions) to the
development of life-threatening skin reactions that include Stevens-Johnson
syndrome (SJS) and/or toxic epidermal necrolysis (TEN).3-6 While the
incidence in the general population is low, the development of SJS and TEN can
lead to an increase in morbidity and mortality.5-7
there any risk factors that predispose patients to carbamazepine induced SJS
Yes. It appears that patients of Asian descent
(specifically Han Chinese) are at greatest risk for developing SJS and/or TEN
when treated with carbamazepine.8-14 Case-controlled studies have now
shown a high association of these patients to also be positive for the human
leukocyte antigen (HLA)-B*1502 allele.8,9 As a short review, HLA-B is
one type of the class I human major histocompatibility complexes that are used
to present antigens (short peptide fragments of self and non-self) to cytotoxic
CD8+ T-lymphocytes (or natural killer cells) of the immune system. When
circulating CD8+ T-lymphocytes come in proximity to nucleated cells with
antigen bound to HLA-B, the T-cell receptors on these CD8+ T-lymphocytes will
interact with the HLA-B proteins to "read" the antigen being
presented. If the CD8+ T-cells "see" or "read" the
antigen being presented as foreign or "non-self", it will then become
activated with the final result being death to that cell. Therefore, the
interaction between the antigen (peptide) and the HLA-B molecule can influence
how the CD8+ T-lymphocyte will respond. Certain genotypes (or variations)
for the HLA-B proteins may then cause the immune system to see combination of
the antigen bound HLA-B complex as something foreign enough to feel the need to
kill or clear that cell from the body. It is important to know that
patients of Asian descent with the HLA-B*1502 allele and who
are taking carbamazepine have an estimated odds ratio (OR) of 1357 (95%
confidence interval: 193.2 - 8838.3; p<1.6 x 10-21).9 Assuming a 0.25%
incidence of carbamazepine-induced SJS and/or TEN in newly prescribed patients
and a 3% false positive rate for HLA-B*1502, the estimated
performance of screening tests in this population of high risk patients would
be a 98.3% sensitivity, 97% specificity, 7.7% positive predictive value and a
100% negative predictive value.14 While additional studies are needed,
this adverse drug reaction appears to also put patients from India, Singapore,
Malaysia and possibly Thailand at increased risk due to their greater
likelihood of having the HLA-B*1502 allele.11-14
above information led the FDA to require all of the manufacturers add a black
box warning to their product package inserts that not only informed healthcare
providers about this adverse drug reaction but to also state that,
"patients with ancestry in genetically at-risk populations should be
screened for the presence of HLA-B*1502 allele prior to
initiating carbamazepine."8 The "at-risk populations"
referenced here refers to several Asian countries not just the Han Chinese from
is the FDA's recommendation limited to patients of Asian descent?
Interestingly, two studies of Caucasians of non-Asian ancestry who were
positive for the HLA-B*1502 allele failed to show a
correlation between the development of SJS and/or TEN while taking
carbamazepine.15,16 This suggests that something else in addition to
having HLA-B*1502 alleleis related to the increased risk for
developing carbamazepine-induced SJS and/or TEN. Until further evidence
becomes available it does not appear that the screening of patients with no
Asian ancestry is of significant value.
most cases this adverse reaction will start in the first 8 weeks of
carbamazepine therapy.6 If a patient develops this adverse drug reaction
(regardless of the type of HLA-B) while on carbamazepine, immediate
discontinuation of carbamazepine is essential.17,18 While no single
treatment intervention is most effective, many patients with SJS and/or TEN
will require admission to the intensive care unit (ICU) or burn unit where the
use of corticosteroids, cyclosporin and intravenous immunoglobulin are
sometimes used to modulate the immune system.18 This article, in addition to
several others at EBM Consult not only reveal the
growing complexity in drug therapy, but how among many patient specific
factors, the influence of a patient's genotype can also contribute to the
safety and efficacy of drug therapy.
- Carbamazepine extended release capsules (Carbatrol) product package insert. Schire US Inc. Wayne, PA. April 2009.
extended release capsules (Equetro) product package insert. Validus
Pharmaceuticals Inc. Parsippany, NJ. December 2007.
- Vittorio CC, Muglia JJ. Anticonvulsant hypersensitivity syndrome. Arch Intern Med 1995;155:2285-90.
NH, Spielberg SP. Anticonvulsant hypersensitivity syndrome. In vitro
assessment of risk. J Clin Invest 1988;82:1826-32.
P, Stern RS. Risk of serious cutaneous disorders after initiation of
use of phenytoin, carbamazepine, or sodium valproate: a record linkage
study. Neurology 1997;49:542-6.
B, Correia O, Kelly JP et al. Risk of Stevens-Johnson syndrome and
toxic epidermal necrolysis during first weeks of antiepileptic therapy: a
case-control study. Study group of the International Case Control
Study on Severe Cutaneous Adverse Reactions. Lancet 1999;353:2190-4.
- Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272-85.
States Food and Drug Administration. Carbamazepine (marketed as
Carbatrol, Equetro, Tegreto and generics). MedWatch The FDA Safety
Information and Adverse Event Reporting Program. December 12, 2007.
Last accessed on 08/06/2009.
- Chung WH, Hung SI, Hong HS et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486.
SI, Chung WH, Jee SH et al. Genetic susceptibility to
carbamazepine-induced cutaneous adverse drug reactions. Pharamcogenet
K, George S, Criton S et al. Carbamazepine-the commonest cause of
toxic epidermal necrolysis and Stevens-Johnson syndrome: a study of 7
years. Indian J Dermatol Venereol Leprol 2005;71:325-8.
VK, Sethuraman G, Kumar B et al. Cutaneous adverse drug reactions:
clinical pattern and causative agents-a 6 year series from Chandigarh,
India. J Postgrad Med 2001;47:95-9.
MD, Zainai D, Mokhtar N et al. Erythema multiforme, Stevens-Johnson
syndrome and toxic epidermal necrolysis in northeastern Malaysia. Int J
PB Jr., McLeod HL. Carbamazepine, HLA-B*1502 and risk of
Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA
recommendations. Pharmacogenomics 2008;9:1543-6.
A, Jorgensen AL, Williamson PR et al. HLA-B locus in Caucasian
patients with carbamazepine hypersensitivity. Pharmacogenomics
C, Thomas L, Borot N et al. A marker for Stevens-Johnson
syndrome...:ethnicity matters. Pharmacogenomics J 2006;6:265-8.
I, LeCleach L, Bocquet H et al. Toxic epidermal necrolysis and
Stevens-Johnson syndrome: does early withdrawal of causative drugs
decrease the risk of death? Arch Dermatol 2000;136:323-7.
B, Bahna SL. Pathogenesis and recent therapeutic trends in
Stevens-Johnson syndrome and toxic epidermal necrolysis. Ann Allergy
Asthma Immunol 2006;97:272-80.