Precautions and Contraindications
Carbamazepine may produce dangerous and alarming adverse effects, principally consisting of hematopoietic, dermatologic, cardiovascular, hepatic, and renal disturbances. The drug also shares the toxic potentials of the hydantoin-derivative anticonvulsants, and the usual precautions of anticonvulsant administration should be observed. When serious adverse effects occur requiring discontinuance of the drug, it is important to remember that abrupt withdrawal of any anticonvulsant drug in a responsive epileptic patient may precipitate seizures or status epilepticus. Carbamazepine therapy should be withdrawn gradually, whenever possible, to minimize the potential for increased seizure frequency. Patients must be carefully examined prior to initiation of carbamazepine therapy and should remain under close medical supervision throughout therapy with the drug. Carbamazepine should be prescribed only after careful benefit-to-risk evaluation in patients with a history of cardiac conduction disturbances; cardiac, hepatic, or renal damage; or adverse hematologic or hypersensitivity reaction to other drugs (e.g., other anticonvulsants) or who have had interrupted therapy with carbamazepine.
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis and Stevens-Johnson syndrome, have been reported in patients receiving carbamazepine therapy. These reactions are estimated to occur in 1-6 per 10,000 new users of the drug 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 skin rash, unless the rash is clearly not drug-related. If signs or symptoms suggest Stevens-Johnson syndrome or toxic epidermal necrolysis, carbamazepine therapy should not be resumed and alternative therapy should be considered. Retrospective case-control studies in patients of Asian ancestry have demonstrated a strong association between the risk of developing Stevens-Johnson syndrome and toxic epidermal necrolysis and the presence of human leukocyte antigen (HLA)-B*1502, an inherited allelic variant of the HLA-B gene; this allele is found almost exclusively in patients with ancestry across broad areas of Asia. Therefore, the US Food and Drug Administration (FDA) and the manufacturers of carbamazepine recommend that patients with ancestry in genetically at-risk populations be screened for the presence of the HLA-B*1502 allele prior to initiating carbamazepine therapy. Patients testing positive for this allele should not receive carbamazepine therapy unless the benefit clearly outweighs the risk.(See Cautions: Dermatologic and Sensitivity Reactions.)
Multiple-organ hypersensitivity reactions occurring days to weeks or months following initiation of carbamazepine have been reported rarely.(See Cautions: Dermatologic and Sensitivity Reactions.) Discontinuance of carbamazepine should be considered if any evidence of hypersensitivity develops. Because hypersensitivity reactions to carbamazepine have been reported in patients with a history of hypersensitivity reactions to other anticonvulsants (e.g., phenytoin, phenobarbital), a detailed drug history should be obtained from patients and their immediate family members. Carbamazepine should be used with caution in patients with a history of hypersensitivity reactions to other anticonvulsants. Approximately 25-30% of patients who demonstrated hypersensitivity reactions to carbamazepine also may experience hypersensitivity reactions to oxcarbazepine.
Close attention by the patient and clinician to signs and symptoms of the possible development of adverse hematologic, dermatologic, or hypersensitivity reactions is important in patients receiving carbamazepine. Patients should be informed of the early signs and symptoms of these potential problems, such as fever, sore throat, infection, rash, mouth ulcers, easy bruising, lymphadenopathy, and petechial or purpuric hemorrhage, and should be instructed to report to their physician immediately if any such sign or symptom occurs. In addition, patients should be advised that these manifestations should be reported even if they are mild in severity or if they occur after extended use.
Although the manufacturers previously recommended initial frequent (possibly weekly during the first 3 months of therapy) and then less frequent, periodic (monthly for at least 2-3 years) testing of hematologic function in any patient receiving carbamazepine, they currently state that, because the frequency of minor hematologic changes progressing to aplastic anemia and agranulocytosis is very low, the vast majority of such changes observed during routine, periodic monitoring are unlikely to be signaling the impending development of either abnormality. Therefore, the manufacturers currently recommend that complete blood counts, including platelet and possibly reticulocyte counts and serum iron determinations, be performed prior to initiating carbamazepine therapy and that subsequent monitoring be individualized by the clinician. Guidelines for periodic monitoring of hematologic function have been suggested by some clinicians, and clinicians experienced in the use of carbamazepine and knowledgeable about the drug's potential toxicity can be consulted for more specific information. Patients exhibiting baseline abnormalities and those receiving other potentially myelotoxic drugs or with a history of adverse hematologic reactions to any drug should be considered at special risk, and carbamazepine therapy should be monitored closely or avoided in these patients. The manufacturers recommend that patients with a history of bone marrow depression not receive the drug. Patients who exhibit low or decreased leukocyte or platelet counts during the course of carbamazepine therapy should be monitored closely. Discontinuance of carbamazepine therapy should be considered if any evidence of significant bone marrow depression develops. In addition, if such evidence develops, particularly if it occurs as a result of overdosage, it has been suggested that complete blood counts, platelet counts, and reticulocyte counts be performed daily and bone marrow aspiration and trephine biopsy be done immediately and repeated as often as necessary to monitor recovery. Alternatively, one manufacturer suggests that the frequency of this monitoring in patients who develop evidence of significant bone marrow depression during the usual course of carbamazepine therapy (i.e., not resulting from overdosage) may be individualized by the clinician. Other special periodic hematologic studies may also be helpful in patients with evidence of significant bone marrow depression. Fully developed aplastic anemia requires appropriate, intensive monitoring and therapy for which specialized consultation should be sought. Some clinicians also advise hematologic consultation if neutropenia and depressed platelet and reticulocyte counts occur during therapy with the drug.
Adverse hepatic effects, ranging from slight elevations in hepatic enzymes to rare cases of hepatic failure, have been reported. In some cases, hepatic effects may progress despite discontinuance of the drug. Liver function tests should be performed prior to carbamazepine therapy, particularly in patients with a history of liver disease, and periodically thereafter. Carbamazepine should be immediately discontinued if evidence of liver dysfunction or active liver disease is observed. In addition, patients should be advised of the early manifestations of adverse hepatic effects (e.g., anorexia, nausea/vomiting, jaundice) and instructed to report such symptoms to their clinician immediately, even if the symptoms are mild or occur after extended use. Complete urinalysis and BUN determinations also should be performed prior to and periodically during carbamazepine therapy.
FDA has informed healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants compared with placebo.(See Cautions: Nervous System Effects.) FDA recommends that all patients who are currently receiving or beginning therapy with any anticonvulsant for any indication be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. Symptoms such as anxiety, agitation, hostility, mania, and hypomania may be precursors to emerging suicidality. Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality so that they are aware and able to notify their clinician of any unusual behavioral changes. Patients, family members, and caregivers also should be advised not to make any changes to the medication regimen without first consulting with the responsible clinician. They should pay close attention to any day-to-day changes in mood, behavior, and actions; since changes can happen very quickly, it is important to be alert to any sudden differences. In addition, patients, family members, and caregivers should be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end one's life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions). If these or any new and worrisome behaviors occur, the responsible clinician should be contacted immediately. FDA also recommends that clinicians who prescribe carbamazepine or any other anticonvulsant balance the risk of suicidality with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician must consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Carbamazepine may exacerbate seizures in some children with mixed seizure disorders. Some clinicians recommend that prolonged video-EEG monitoring be performed prior to initiating carbamazepine therapy in children with mixed seizure disorders in an attempt to identify those children who may be at risk for carbamazepine-induced exacerbation of seizures.(See Cautions: Nervous System Effects.)
Persons who perform hazardous tasks requiring mental alertness or physical coordination should be warned about the possible adverse neurologic and sensory effects of carbamazepine. Patients receiving carbamazepine also should be advised that there is a potential for additive CNS effects if alcohol is used concomitantly with carbamazepine. Because of the relationship of carbamazepine to other tricyclic compounds, the possibility of activation of a latent psychosis or, in geriatric patients, confusion or agitation should be kept in mind.
Baseline and periodic eye examinations including slit-lamp, funduscopy, and tonometry are recommended in patients receiving carbamazepine. Carbamazepine has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during carbamazepine therapy.
Because of similarity in spelling between Tegretol or Tegretol-XR (trade names for carbamazepine) and Toprol-XL (metoprolol succinate, a β-adrenergic blocking agent), the potential exists for dispensing errors involving these drugs. These medication errors have been associated with serious adverse events sometimes requiring hospitalization as a result of either lack of the intended medication (e.g., seizure recurrence, return of hallucinations, suicide attempt, hypertension recurrence) or exposure to the wrong drug (e.g., bradycardia in a patient erroneously receiving metoprolol). Therefore, extra care should be exercised to ensure the accuracy of both oral and written prescriptions for these drugs.(See Dispensing and Administration Precautions under Dosage and Administration: Administration.) Dispensing errors involving Tegretol or Tegretol-XR (carbamazepine) and Toprol-XL (metoprolol succinate) should be reported to the manufacturers, the USP/ISMP (Institute for Safe Medication Practices) Medication Errors Reporting Program by phone (800-233-7767), or directly to the FDA MedWatch program by phone (800-FDA-1088), fax (800-FDA-0178), or internet (http://www.fda.gov/Safety/MedWatch).
Carbamazepine is contraindicated in patients with a history of previous bone marrow depression, acute intermittent porphyria, and/or hypersensitivity to the drug or in patients who have demonstrated sensitivity to any of the tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, nortriptyline, protriptyline). The drug also is contraindicated in patients currently receiving, or having recently received (i.e., within 2 weeks), monoamine oxidase (MAO) inhibitor therapy.(See Drug Interactions: Monoamine Oxidase Inhibitors.) Concomitant use of carbamazepine and nefazodone is contraindicated.(See Drug Interactions: Nefazodone.) In addition, the manufacturer of voriconazole states that concomitant use of carbamazepine and voriconazole is contraindicated. (See Drug Interactions: Azole Antifungal Agents.)