Precautions and Contraindications
Carbamazepine may produce serious 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 epileptic patients may precipitate seizures or status epilepticus. Carbamazepine therapy should be withdrawn gradually to minimize the potential for increased seizure frequency.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.
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 clinician 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.
Pharmacogenetic testing is recommended in patients who may have a genetic predisposition to carbamazepine-induced cutaneous reactions.(See Pharmacogenetic Testing under Dosage and Administration: Administration.) If manifestations of multi-organ hypersensitivity occur during carbamazepine therapy, patients should be evaluated immediately; if an alternative cause cannot be identified, the drug should be discontinued. Because anaphylactic reactions and angioedema have occurred during carbamazepine therapy, patients should be advised to stop taking the drug and immediately report any signs or symptoms of hypersensitivity to their clinician. If anaphylaxis or angioedema develops during carbamazepine therapy, the drug should be discontinued and alternative therapy initiated; patients who experience severe hypersensitivity reactions should not be rechallenged with the drug. Because cross-hypersensitivity between carbamazepine and other anticonvulsants (e.g., phenytoin, phenobarbital, primidone) has been reported, a detailed drug history should be obtained from patients and their immediate family members. The benefits versus risks of carbamazepine therapy should be carefully considered in patients with a history of previous hypersensitivity to other anticonvulsants. Approximately one-third of patients with a history of carbamazepine hypersensitivity will develop hypersensitivity to oxcarbazepine.
Complete blood counts, including platelet and possibly reticulocyte counts and serum iron determinations, should be performed prior to initiating carbamazepine therapy; subsequent monitoring should 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. Patients with a history of bone marrow depression should 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. 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.(See Cautions: Hepatic Effects.) Liver function tests must be performed prior to carbamazepine therapy and periodically thereafter, particularly in patients with a history of liver disease. Discontinuance of the drug should be considered based on clinical judgment in patients with evidence of liver disease; some manufacturers recommend immediate discontinuance if worsening 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.
Because acute attacks of porphyria have been reported, carbamazepine should not be used in patients with a history of hepatic porphyria.
Because impairment of renal function has been observed in patients receiving carbamazepine, renal function (e.g., complete urinalysis and BUN determinations) should be performed prior to and periodically during therapy. Because of potential accumulation of the cyclodextrin excipient present in the IV formulation of carbamazepine, the manufacturer states that the drug generally should not be used in patients with moderate or several renal impairment. Such patients may be at greater risk of adverse renal effects and should be closely monitored if IV carbamazepine therapy is necessary.
Patients who are currently receiving or beginning therapy with any anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior.(See Cautions: Nervous System Effects.) Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy and advise them to 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. Clinicians who prescribe carbamazepine or any other anticonvulsant should 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 should consider whether these symptoms 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 a history of increased intraocular pressure should be assessed for such condition prior to and periodically 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 bone marrow depression or hypersensitivity to the drug or 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.)