United States - English - NLM (National Library of Medicine)
CARBAMAZEPINE- carbamazepine tablet
SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE
SERIOUS AND SOMETIMES FATAL DERMATOLOGIC REACTIONS, INCLUDING TOXIC
EPIDERMAL NECROLYSIS (TEN) AND STEVENS-JOHNSON SYNDROME (SJS), HAVE
BEEN REPORTED DURING TREATMENT WITH CARBAMAZEPINE. THESE
REACTIONS ARE ESTIMATED TO OCCUR IN 1 TO 6 PER 10,000 NEW USERS IN
COUNTRIES WITH MAINLY CAUCASIAN POPULATIONS, BUT THE RISK IN SOME
ASIAN COUNTRIES IS ESTIMATED TO BE ABOUT 10 TIMES HIGHER. STUDIES IN
PATIENTS OF CHINESE ANCESTRY HAVE FOUND A STRONG ASSOCIATION
BETWEEN THE RISK OF DEVELOPING SJS/TEN AND THE PRESENCE OF HLA-B*1502,
AN INHERITED ALLELIC VARIANT OF THE HLA-B GENE. HLA-B*1502 IS FOUND
ALMOST EXCLUSIVELY IN PATIENTS WITH ANCESTRY ACROSS BROAD AREAS OF
ASIA. PATIENTS WITH ANCESTRY IN GENETICALLY AT-RISK POPULATIONS
SHOULD BE SCREENED FOR THE PRESENCE OF HLA-B*1502 PRIOR TO INITIATING
TREATMENT WITH CARBAMAZEPINE. PATIENTS TESTING POSITIVE FOR THE
ALLELE SHOULD NOT BE TREATED WITH CARBAMAZEPINE UNLESS THE BENEFIT
CLEARLY OUTWEIGHS THE RISK (SEE WARNINGSAND PRECAUTIONS,
APLASTIC ANEMIA AND AGRANULOCYTOSIS
APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED IN
ASSOCIATION WITH THE USE OF CARBAMAZEPINE. DATA FROM A POPULATION-
BASED CASE CONTROL STUDY DEMONSTRATE THAT THE RISK OF DEVELOPING
THESE REACTIONS IS 5 TO 8 TIMES GREATER THAN IN THE GENERAL
POPULATION. HOWEVER, THE OVERALL RISK OF THESE REACTIONS IN THE
UNTREATED GENERAL POPULATION IS LOW, APPROXIMATELY SIX PATIENTS PER
ONE MILLION POPULATION PER YEAR FOR AGRANULOCYTOSIS AND TWO
PATIENTS PER ONE MILLION POPULATION PER YEAR FOR APLASTIC ANEMIA.
ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR
WHITE BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE
USE OF CARBAMAZEPINE, DATA ARE NOT AVAILABLE TO ESTIMATE
ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY
OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS
CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS.
BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC
ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN
MONITORING OF PATIENTS ON CARBAMAZEPINE ARE UNLIKELY TO SIGNAL THE
OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE
PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A
BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR
DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD
BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE
CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION
Before prescribing carbamazepine, the physician should be thoroughly familiar with the details of this
prescribing information, particularly regarding use with other drugs, especially those which accentuate
Carbamazepine Tablets, carbamazepine USP, is an anticonvulsant and specific analgesic for trigeminal
neuralgia, available for oral administration as tablets of 100 mg and 200 mg. Its chemical name is 5H-
dibenz[b,f ]azepine-5-carboxamide, and its structural formula is:
Carbamazepine USP is a white to off-white powder, practically insoluble in water and soluble in
alcohol and in acetone. Its molecular weight is 236.27.
Inactive IngredientsTablets: pregelatinized maize starch, FD & C red 40, croscarmellose sodium,
colloidal silicon dioxide and magnesium stearate.
"Meets USP Dissolution Test 2"
In controlled clinical trials, carbamazepine has been shown to be effective in the treatment of
psychomotor and grand mal seizures, as well as trigeminal neuralgia.
Mechanism of Action
Carbamazepine has demonstrated anticonvulsant properties in rats and mice with electrically and
chemically induced seizures. It appears to act by reducing polysynaptic responses and blocking the
post-tetanic potentiation. Carbamazepine greatly reduces or abolishes pain induced by stimulation of the
infraorbital nerve in cats and rats. It depresses thalamic potential and bulbar and polysynaptic reflexes,
including the linguomandibular reflex in cats. Carbamazepine is chemically unrelated to other
anticonvulsants or other drugs used to control the pain of trigeminal neuralgia. The mechanism of action
The principal metabolite of carbamazepine, carbamazepine-10, 11-epoxide, has anticonvulsant activity
as demonstrated in several in vivo animal models of seizures. Though clinical activity for the epoxide
has been postulated, the significance of its activity with respect to the safety and efficacy of
carbamazepine has not been established.
In clinical studies, Carbamazepine suspension, conventional tablets, and XR tablets delivered equivalent
amounts of drug to the systemic circulation. However, the suspension was absorbed somewhat faster,
and the XR tablet slightly slower, than the conventional tablet. The bioavailability of the XR tablet was
89% compared to suspension. Following a twice a day dosage regimen, the suspension provides higher
peak levels and lower trough levels than those obtained from the conventional tablet for the same
dosage regimen. On the other hand, following a three times a day dosage regimen, Carbamazepine
suspension affords steady-state plasma levels comparable to Carbamazepine tablets given twice a day
when administered at the same total mg daily dose. Following a twice a day dosage regimen,
Carbamazepine-XR tablets afford steady-state plasma levels comparable to conventional Carbamazepine
tablets given four times a day, when administered at the same total mg daily dose.Carbamazepine in
blood is 76% bound to plasma proteins. Plasma levels of Carbamazepine are variable and may range
from 0.5 to 25 mcg/mL, with no apparent relationship to the daily intake of the drug. Usual adult
therapeutic levels are between 4 and 12 mcg/mL. In polytherapy, the concentration of Carbamazepine
and concomitant drugs may be increased or decreased during therapy, and drug effects may be altered
(see PRECAUTIONS, DRUG INTERACTIONS). Following chronic oral administration of suspension,
plasma levels peak at approximately 1.5 hours compared to 4 to 5 hours after administration of
conventional Carbamazepine tablets, and 3 to 12 hours after administration of Carbamazepine-XR tablets.
The CSF/serum ratio is 0.22, similar to the 24% unbound Carbamazepine in serum. Because
Carbamazepine induces its own metabolism, the half-life is also variable. Autoinduction is completed
after 3 to 5 weeks of a fixed dosing regimen. Initial half-life values range from 25 to 65 hours,
decreasing to 12 to 17 hours on repeated doses. Carbamazepine is metabolized in the liver.
Cytochrome P450 3A4 was identified as the major isoform responsible for the formation of
carbamazepine-10,11-epoxide from Carbamazepine. Human microsomal epoxide hydrolase has been
identified as the enzyme responsible for the formation of the 10,11-transdiol derivative from
carbamazepine10,11 epoxide. After oral administration of 14 C-carbamazepine, 72% of the administered
radioactivity was found in the urine and 28% in the feces. This urinary radioactivity was composed
largely of hydroxylated and conjugated metabolites, with only 3% of unchanged Carbamazepine.
The pharmacokinetic parameters of carbamazepine disposition are similar in children and in adults.
However, there is a poor correlation between plasma concentrations of carbamazepine and
Carbamazepine Tablets dose in children. Carbamazepine is more rapidly metabolized to carbamazepine-
10, 11-epoxide (a metabolite shown to be equipotent to carbamazepine as an anticonvulsant in animal
screens) in the younger age groups than in adults. In children below the age of 15, there is an inverse
relationship between CBZ-E/CBZ ratio and increasing age (in one report from 0.44 in children below
the age of 1 year to 0.18 in children between 10 to 15 years of age).
The effects of race and gender on carbamazepine pharmacokinetics have not been systematically
Carbamazepine is indicated for use as an anticonvulsant drug. Evidence supporting efficacy of
carbamazepine as an anticonvulsant was derived from active drug-controlled studies that enrolled
patients with the following seizure types:
1. Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these
seizures appear to show greater improvement than those with other types.
2. Generalized tonic-clonic seizures (grand mal).
3. Mixed seizure patterns which include the above, or other partial or generalized seizures. Absence
seizures (petit mal) do not appear to be controlled by carbamazepine (see PRECAUTIONS, General).
Carbamazepine is indicated in the treatment of the pain associated with true trigeminal neuralgia.
Beneficial results have also been reported in glossopharyngeal neuralgia.
This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains.
Carbamazepine should not be used in patients with a history of previous bone marrow depression,
hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds, such as
amitriptyline, desipramine, imipramine, protriptyline, nortriptyline, etc. Likewise, on theoretical grounds
its use with monoamine oxidase (MAO) inhibitors is not recommended. Before administration of
carbamazepine, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the
clinical situation permits.
Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of
nefazodone and its active metabolite to achieve a therapeutic effect. Coadministration of carbamazepine
with nefazodone is contraindicated.
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.
Carbamazepine 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 less than 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 carbamazepine 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. Carbamazepine 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 BOXED
WARNING and PRECAUTIONS, 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 carbamazepine.
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 antiepileptic 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.
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 hypersensitivity below).
HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American,
Southern Indian (for example, Tamil Nadu) and some Arabic ancestry; up to about 10% in patients of Han
Chinese, Korean, European, Latin American, and other Indian ancestry; and up to about 5% in African-
Americans and patients of 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.
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 antiepileptic drug (AED)
dose, compliance, concomitant medications, comorbidities, 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 BOXED 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 Hypersensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan
hypersensitivity, has occurred with carbamazepine. Some of these events have been fatal or life-
threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or
lymphadenopathy, and/or facial swelling 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. Carbamazepine 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. 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 monitored.
Patients should be informed that about a third of patients who have had hypersensitivity reactions to
carbamazepine also experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
Anaphylaxis and Angioedema
Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelid have been
reported in patients after taking the first or subsequent doses of Carbamazepine. Angioedema associated
with laryngeal edema can be fatal. If a patient develops any of these reactions with Carbamazepine, the
drug should be discontinued and an alternative treatment started. These patients should not be
rechallenged with the drugs.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including carbamazepine, 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 to 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
Placebo Patients with Events Per 1,000 Patients
Drug Patients with Events Per 1,000 Patients
Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients
Risk Difference: Additional Drug Patients with Events Per 1,000 Patients
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 carbamazepine 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 and 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.
Carbamazepine has shown mild anticholinergic activity that may be associated with increased
intraocular pressure; therefore, patients with increased intraocular pressure should be closely observed
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 borne in mind.
The use of carbamazepine 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 carbamazepine therapy. Carbamazepine administration has also been
demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of
acute attacks of porphyria.
As with all antiepileptic drugs, carbamazepine should be withdrawn gradually to minimize the potential
of increased seizure frequency.
Hyponatremia can occur as a result of treatment with carbamazepine. In many cases, the hyponatremia
appears to be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The
risk of developing SIADH with carbamazepine treatment appears to be dose-related. Elderly patients
and patients treated with diuretics are at greater risk of developing hyponatremia. Signs and symptoms of
hyponatremia include headache, new or increased seizure frequency, difficulty concentrating, memory
impairment, confusion, weakness, and unsteadiness, which can lead to falls. Consider discontinuing
carbamazepine in patients with symptomatic hyponatremia.
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. There have also been reports that
associate carbamazepine with developmental disorders and congenital anomalies (e.g., craniofacial
defects, cardiovascular malformations, and anomalies involving various body systems). Developmental
delays based on neurobehavioral assessments have been reported. When treating or counseling women
of childbearing potential, the prescribing physician will wish to weigh the benefits of therapy against
the risks. 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.
Therefore, if therapy is to be continued, monotherapy may be preferable for pregnant women.
In humans, transplacental passage of carbamazepine is rapid (30 to 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 to 25 times the maximum human daily dosage (MHDD) of 1200 mg on a mg/kg
basis or 1.5 to 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 mg/kg.
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 currently 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 associated 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 withdrawal syndrome.
To provide information regarding the effects of in utero exposure to carbamazepine, physicians are
advised to recommend that pregnant patients taking carbamazepine 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/.
Before initiating therapy, a detailed history and physical examination should be made.
Carbamazepine should be used with caution in patients with a mixed seizure disorder that includes
atypical absence seizures, since in these patients carbamazepine has been associated with increased
frequency of generalized convulsions (see INDICATIONS AND USAGE).
Therapy should be prescribed only after critical benefit-to-risk appraisal in patients with a history of
cardiac conduction disturbance, including second-and third-degree AV heart block; cardiac, hepatic, or
renal damage; adverse hematologic or hypersensitivity reaction to other drugs, including reactions to
other anticonvulsants; or interrupted courses of therapy with carbamazepine.
AV heart block, including second-and third-degree block, have been reported following carbamazepine
treatment. This occurred generally, but not solely, in patients with underlying EKG abnormalities or risk
factors for conduction disturbances.
Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have
been reported (see ADVERSE REACTIONS and PRECAUTIONS, LABORATORY TESTS). In some
cases, hepatic effects may progress despite discontinuation of the drug. In addition rare instances of
vanishing bile duct syndrome have been reported. This syndrome consists of a cholestatic process with
a variable clinical course ranging from fulminant to indolent, involving the destruction and
disappearance of the intrahepatic bile ducts. Some, but not all, cases are associated with features that
overlap with other immunoallergenic syndromes such as multiorgan hypersensitivity (DRESS
syndrome) and serious dermatologic reactions. As an example there has been a report of vanishing bile
duct syndrome associated with Stevens-Johnson syndrome and in another case an association with fever
Since a given dose of carbamazepine suspension will produce higher peak levels than the same dose
given as the tablet, it is recommended that patients given the suspension be started on lower doses and
increased slowly to avoid unwanted side effects (see DOSAGE AND ADMINISTRATION).
Carbamazepine suspension contains sorbitol and, therefore, should not be administered to patients with
rare hereditary problems of fructose intolerance.
Information for Patients
Patients should be informed of the availability of a Medication Guide and they should be instructed to
read the Medication Guide before taking carbamazepine.
Patients should be made aware of the early toxic signs and symptoms of a potential hematologic
problem, as well as dermatologic, hypersensitivity or hepatic reactions. These symptoms may include,
but are not limited to, fever, sore throat, rash, ulcers in the mouth, easy bruising, lymphadenopathy and
petechial or purpuric hemorrhage, and in the case of liver reactions, anorexia, nausea/vomiting, or
jaundice. The patient should be advised that, because these signs and symptoms may signal a serious
reaction, that they must report any occurrence immediately to a physician. In addition, the patient should
be advised that these signs and symptoms should be reported even if mild or when occurring after
Patients should be advised that serious skin reactions have been reported in association with
carbamazepine. In the event a skin reaction should occur while taking carbamazepine, patients should
consult with their physician immediately (see WARNINGS).
Patients should be advised that anaphylactic and angioedema may occur during treatment with
Carbamazepine (see WARNINGS). Advise patients to immediately report signs and symptoms
suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in swallowing or
breathing) and to stop taking the drug until they have consulted with their healthcare provider.
Patients, their caregivers, and families should be counseled that AEDs, including carbamazepine, may
increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the
emergence or worsening of 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.
Carbamazepine may interact with some drugs. Therefore, patients should be advised to report to their
doctors the use of any other prescription or nonprescription medications or herbal products.
Caution should be exercised if alcohol is taken in combination with carbamazepine therapy, due to a
possible additive sedative effect.
Since dizziness and drowsiness may occur, patients should be cautioned about the hazards of operating
machinery or automobiles or engaging in other potentially dangerous tasks.
Patients should be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant.
This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To
enroll, patients can call the toll free number 1-888-233-2334 (see WARNINGS, Usage in Pregnancy
For genetically at-risk patients (see WARNINGS), high-resolution ‘HLA-B*1502 typing’ 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.
Complete pretreatment blood counts, including platelets and possibly reticulocytes and serum iron,
should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white
blood cell or platelet counts, the patient should be monitored closely. Discontinuation of the drug
should be considered if any evidence of significant bone marrow depression develops.
Baseline and periodic evaluations of liver function, particularly in patients with a history of liver
disease, must be performed during treatment with this drug since liver damage may occur (see
PRECAUTIONS, General and ADVERSE REACTIONS). Carbamazepine should be discontinued,
based on clinical judgment, if indicated by newly occurring or worsening clinical or laboratory
evidence of liver dysfunction or hepatic damage, or in the case of active liver disease.
Baseline and periodic eye examinations, including slit-lamp, funduscopy, and tonometry, are
recommended since many phenothiazines and related drugs have been shown to cause eye changes.
Baseline and periodic complete urinalysis and BUN determinations are recommended for patients
treated with this agent because of observed renal dysfunction.
Monitoring of blood levels (see CLINICAL PHARMACOLOGY) has increased the efficacy and safety
of anticonvulsants. This monitoring may be particularly useful in cases of dramatic increase in seizure
frequency and for verification of compliance. In addition, measurement of drug serum levels may aid in
determining the cause of toxicity when more than one medication is being used.
Thyroid function tests have been reported to show decreased values with carbamazepine administered
Interference with some pregnancy tests has been reported.
There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after
ingesting carbamazepine suspension immediately followed by Thorazine solution. Subsequent testing
has shown that mixing carbamazepine suspension and chlorpromazine solution (both generic and brand
name) as well as carbamazepine suspension and liquid Mellaril, resulted in the occurrence of this
precipitate. Because the extent to which this occurs with other liquid medications is not known,
carbamazepine suspension should not be administered simultaneously with other liquid medicinal agents
or diluents (see DOSAGE AND ADMINISTRATION).
Clinically meaningful drug interactions have occurred with concomitant medications and include (but are
not limited to) the following:
Agents That May Affect Carbamazepine Plasma Levels
When carbamazepine is given with drugs that can increase or decrease carbamazepine levels, close
monitoring of carbamazepine levels is indicated and dosage adjustment may be required.
Agents That Increase Carbamazepine Levels
CYP3A4 inhibitors inhibit carbamazepine metabolism and can thus increase plasma carbamazepine
levels. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels
include aprepitant, cimetidine, ciprofloxacin, danazol, diltiazem, macrolides, erythromycin,
troleandomycin, clarithromycin, fluoxetine, fluvoxamine, trazodone, olanzapine, loratadine, terfenadine,
omeprazole, oxybutynin, dantrolene, isoniazid, niacinamide, nicotinamide, ibuprofen, propoxyphene,
azoles (e.g., ketaconazole, itraconazole, fluconazole, voriconazole), acetazolamide, verapamil,
ticlopidine, grapefruit juice, and protease inhibitors.
Human microsomal epoxide hydrolase has been identified as the enzyme responsible for the formation
of the 10, 11-transdiol derivative from carbamazepine-10,11 epoxide. Coadministration of inhibitors of
human microsomal epoxide hydrolase may result in increased carbamazepine-10, 11 epoxide plasma
concentrations. Accordingly, the dosage of carbamazepine should be adjusted and/or the plasma levels
monitored when used concomitantly with loxapine, quetiapine, or valproic acid.
Agents That Decrease Carbamazepine Levels
CYP3A4 inducers can increase the rate of carbamazepine metabolism. Drugs that have been shown, or
that would be expected, to decrease plasma carbamazepine levels include cisplatin, doxorubicin HCl,
felbamate, fosphenytoin, rifampin, phenobarbital, phenytoin, primidone, methsuximide, theophylline,
Effect of Carbamazepine on Plasma Levels of Concomitant Agents
Decreased Levels of Concomitant Medications
Carbamazepine is a potent inducer of hepatic 3A4 and is also known to be an inducer of CYP1A2, 2B6,
2C9/19 and may therefore reduce plasma concentrations of co-medications mainly metabolized by CYP
1A2, 2B6, 2C9/19 and 3A4, through induction of their metabolism. When used concomitantly with
carbamazepine, monitoring of concentrations or dosage adjustment of these agents may be necessary:
When carbamazepine is added to aripiprazole, the aripiprazole dose should be doubled. Additional dose
increases should be based on clinical evaluation. If carbamazepine is later withdrawn, the aripiprazole
dose should be reduced.
When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and
appropriate dosage adjustments are recommended.
The use of concomitant strong CYP3A4 inducers such as carbamazepine should be avoided with
temsirolimus. If patients must be coadministered carbamazepine with temsirolimus, an adjustment of
temsirolimus dosage should be considered.
The use of carbamazepine with lapatinib should generally be avoided. If carbamazepine is started in a
patient already taking lapatinib, the dose of lapatinib should be gradually titrated up. If carbamazepine is
discontinued, the lapatinib dose should be reduced.
Concomitant use of carbamazepine with nefazodone results in plasma concentrations of nefazodone and
its active metabolite insufficient to achieve a therapeutic effect. Coadministration of carbamazepine
with nefazodone is contraindicated (see CONTRAINDICATIONS).
Monitor concentrations of valproate when carbamazepine is introduced or withdrawn in patients using