Serious Dermatologic Reactions
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and
Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment. The risk of
these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly
Caucasian populations. However, the risk in some Asian countries is estimated to be about 10
times higher. Carbatrol® should be discontinued at the first sign of a rash, unless the rash is clearly
not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed
and alternative therapy should be considered.
SJS/TEN And HLA-B*1502 Allele
Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong
association between the risk of developing SJS/TEN with carbamazepine treatment and the
presence of an inherited variant of the HLA-B gene, HLA-B*1502. The occurrence of higher rates of
these reactions in countries with higher frequencies of this allele suggests that the risk may be
increased in allele-positive individuals of any ethnicity.
Across Asian populations, notable variation exists in the prevalence of HLA-B*1502. Greater than
15% of the population is reported positive in Hong Kong, Thailand, Malaysia, and parts of the
Philippines, compared to about 10% in Taiwan and 4% in North China. South Asians, including
Indians, appear to have intermediate prevalence of HLA-B*1502, averaging 2 to 4%, but higher in
some groups. HLA-B*1502 is present in <1% of the population in Japan and Korea.
HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-
Americans, Hispanics, and Native Americans).
Prior to initiating Carbatrol® therapy, testing for HLA-B*1502 should be performed in patients
with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients
to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide,
keeping in mind the limitations of these figures due to wide variability in rates even within ethnic
groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry.
Carbatrol® should not be used in patients positive for HLA-B*1502 unless the benefits clearly
outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a
low risk of SJS/TEN (see Laboratory Tests).
Over 90% of carbamazepine treated patients who will experience SJS/TEN have this reaction within
the first few months of treatment. This information may be taken into consideration in determining
the need for screening of genetically at-risk patients currently on Carbatrol®.
The HLA-B*1502 allele has not been found to predict risk of less severe adverse cutaneous
reactions from carbamazepine, such as maculopapular eruption [MPE] or to predict Drug Reaction
with Eosinophilia and Systemic Symptoms (DRESS).
Limited evidence suggests that HLA-B*1502 may be a risk factor for the development of SJS/TEN
in patients of Chinese ancestry taking other anti-epileptic drugs associated with SJS/TEN, including
phenytoin. Consideration should 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.
Patients should be made aware that Carbatrol® contains carbamazepine and should not be used in
combination with any other medications containing carbamazepine.
Hypersensitivity Reactions And HLA-A*3101 Allele
Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have
found a moderate association between the risk of developing hypersensitivity reactions and the
presence of HLA-A*3101, an inherited allelic variant of the HLA-A gene, in patients using
carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and
Drug Reaction with Eosinophilia and Systemic Symptoms (see DRESS/Multiorgan
HLA-A*3101 is expected to be present in the following approximate frequencies: greater than 15%
in patients of Japanese and Native American ancestry; up to about 10% in patients of Han Chinese,
Korean, European, and Latin American ancestry; and up to about 5% in African-Americans and
patients of Indian, Thai, Taiwanese, and Chinese (Hong Kong) ancestry.
The risks and benefits of carbamazepine therapy should be weighed before considering
carbamazepine in patients known to be positive for HLA-A*3101.
General Information On HLA Genotyping And Hypersensitivity
Application of HLA genotyping as a screening tool has important limitations and must never
substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive
and HLA-A*3101-positive patients treated with carbamazepine will not develop SJS/TEN or other
hypersensitivity reactions, and these reactions can still occur infrequently in HLA-B*1502-negative
and HLA-A*3101-negative patients of any ethnicity. The role of other possible factors in the
development of, and morbidity from, SJS/TEN and other hypersensitivity reactions, such as AED
dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic
monitoring have not been studied.
Aplastic Anemia And Agranulocytosis
Aplastic anemia and agranulocytosis have been reported in association with the use of
carbamazepine. (see BOX WARNING.) Patients with a history of adverse hematologic reaction
to any drug may be particularly at risk of bone marrow depression.
Drug Reaction With Eosinophilia And Systemic Symptoms (DRESS)/Multiorgan
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan
hypersensitivity, have occurred with carbamazepine. Some of these events have been fatal or lifethreatening.
DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis,
hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection.
Eosinophilia is often present. This disorder is variable in its expression, and other organ systems
not noted here may be involved. It is important to note that early manifestations of hypersensitivity
(e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or
symptoms are present, the patient should be evaluated immediately. Carbatrol® should be
discontinued if an alternative etiology for the signs or symptoms cannot be established.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously
experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. A
history of hypersensitivity reactions should be obtained for patients and their immediate family
members. If such history is present, benefits and risks should be carefully considered, and, if
carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully
In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to
30% may experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
Withdrawal Precipitated Seizure, Status Epilepticus
Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased
seizure frequency, including status epilepticus. When in the judgment of the clinician, the need for
dosage reduction, discontinuation, or substitution of alternative anticonvulsant medication arises,
this should be done gradually. However, in the event of an allergic or hypersensitivity reaction, more
rapid substitution of alternative therapy may be necessary.
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including Carbatrol®, increase the risk of suicidal thoughts or behavior in
patients taking these drugs for any indication. Patients treated with any AED for any indication
should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior,
and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11
different AEDs showed that patients randomized to one of the AEDs had approximately twice the
risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to
patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks,
the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients
was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase
of approximately one case of suicidal thinking or behavior for every 530 patients treated. There
were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the
number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week
after starting drug treatment with AEDs and persisted for the duration of treatment assessed.
Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal
thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data
analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a
range of indications suggests that the risk applies to all AEDs used for any indication. The risk did
not vary substantially by age (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
Table 1 – Risk by indication for antiepileptic drugs in the pooled analysis
with Events Per
Events in Drug
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in
clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the
epilepsy and psychiatric indications.
Anyone considering prescribing Carbatrol® or any other AED must balance the risk of suicidal
thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which
AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk
of suicidal thoughts or behavior. Should suicidal thoughts and behavior emerge during treatment,
the prescriber needs to consider whether the emergence of these symptoms in any given patient
may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal
thoughts and behavior and should be advised of the need to be alert for the emergence or
worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or
the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern
should be reported immediately to healthcare providers.
Usage In Pregnancy
Carbamazepine can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine
during pregnancy and congenital malformations, including spina bifida. The prescribing physician
will wish to weigh the benefits of therapy against the risks in treating or counseling women of
childbearing potential. If this drug is used during pregnancy, or if the patient becomes pregnant
while taking this drug, the patient should be apprised of the potential hazard to the fetus.
Retrospective case reviews suggest that, compared with monotherapy, there may be a higher
prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.
In humans, transplacental passage of carbamazepine is rapid (30-60 minutes), and the drug is
accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.
Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given
orally in dosages 10-25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg
basis or 1.5-4 times the MHDD on a mg/m2 basis. In rat teratology studies, 2 of 135 offspring
showed kinked ribs at 250 mg/kg and 4 of 119 offspring at 650 mg/kg showed other anomalies (cleft
palate, 1; talipes, 1; anophthalmos, 2). In reproduction studies in rats, nursing offspring
demonstrated a lack of weight gain and an unkempt appearance at a maternal dosage level of 200
Antiepileptic drugs should not be discontinued abruptly in patients in whom the drug is administered
to prevent major seizures because of the strong possibility of precipitating status epilepticus with
attendant hypoxia and threat to life. In individual cases where the severity and frequency of the
seizure disorder are such that removal of medication does not pose a serious threat to the patient,
discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be
said with any confidence that even minor seizures do not pose some hazard to the developing
embryo or fetus.
Tests to detect defects using current accepted procedures should be considered a part of routine
prenatal care in childbearing women receiving carbamazepine.
There have been a few cases of neonatal seizures and/or respiratory depression reported in
association with maternal carbamazepine and other concomitant anticonvulsant drug use. A few
cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in
association with maternal carbamazepine use. These symptoms may represent a neonatal
To provide information regarding the effects of in utero exposure to Carbatrol®, physicians are
advised to recommend that pregnant patients taking Carbatrol® enroll in the North American
Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-
888-233-2334, and must be done by patients themselves. Information on the registry can also be
found at the website http://www.aedpregnancyregistry.org/.
Carbamazepine has shown mild anticholinergic activity; therefore, patients with increased
intraocular pressure should be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of a
latent psychosis and, in elderly patients, of confusion or agitation should be considered.
The use of Carbatrol® should be avoided in patients with a history of hepatic porphyria (e.g., acute
intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been
reported in such patients receiving Carbatrol® therapy. Carbamazepine administration has also
been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the
induction of acute attacks of porphyria.