Label Changes for:
Tegretol (carbamazepine) Tablets, Chewable Tablets, Oral Suspension, and Tegretol-XR (carbamazepine extended-release) Tablets
Changes have been made to the WARNINGS and PRECAUTIONS sections of the safety label.
Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
- Patients should be informed that about a third of patients who have had hypersensitivity reactions to carbamazepine also experience hypersensitivity reactions with oxcarbazepine (Trileptal®).
- Hyponatremia can occur as a result of treatment with Tegretol. In many cases, the hyponatremia appears to be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of developing SIADH with Tegretol treatment appears to be dose-related. Elderly patients and patients treated with diuretics are at greater risk of developing hyponatremia. Consider discontinuing Tegretol in patients with symptomatic 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 Tegretol in patients with symptomatic hyponatremia
- Tegretol suspension contains sorbitol and, therefore, should not be administered to patients with rare hereditary problems of fructose intolerance.
Agents That Increase Carbamazepine Levels
- CYP3A4 inhibitors inhibit Tegretol 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. Co-administration of inhibitors of human microsomal epoxide hydrolase may result in increased carbamazepine-10,11 epoxide plasma concentrations.
- Accordingly, the dosage of Tegretol should be adjusted and/or the plasma levels monitored when used concomitantly with loxapine, quetiapine, or valproic acid.
- In addition rare instances of vanishing bile duct syndrome have been reported. This syndrome consists of a cholestatic process .....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 and eosinophilia.”
Effect of Tegretol on Plasma Levels of Concomitant Agents
- Addition of three new agents: buprenorphone, mianserin, and sertraline
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 HLAA*3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine. These hypersensitivity reactions include SJS/TEN, maculopapul Systemic Symptoms.
- 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 Aamerican, 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 Tegretol therapy should be weighed before considering Tegretol 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 Tegretol 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 hyper sensitivity reactions, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring, have not been studied.
Agents That May Affect Tegretol Plasma Levels
- …. Drugs that have been shown, or would be expected, to increase plasma carbamazepine levels include:
Effect of Tegretol on Plasma Levels of Concomitant
- Cyclophosphamide is an inactive prodrug and is converted to its active metabolite in part by CYP3A. The rate of metabolism and the leukopenic activity of cyclophosphamide reportedly are increased by chronic administration of high doses of another CYP3A4 inducer. There is a potential for increased cyclophosphamide toxicity when coadministered with carbamazepine.
- When carbamazepine is added to aripiprazole therapy, the aripiprazole dose should be doubled. Additional dose increases should be based on clinical evaluation. When carbamazepine is withdrawn from the combination therapy, the aripiprazole dose should be reduced When carbamazepine is used with tacrolimus, monitoring of tacrolimus blood concentrations and appropriate dosage adjustments are recommended.
- CYP3A4 inducers such as carbamazepine should be avoided with temsirolimus.
- The use of carbamazepine with lapatinib should generally be avoided. Dosage adjustment should be considered if lapatinib is coadministered with carbamazepine. 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.