Carbamazepine: uses, appearance and warnings

Epilepsy Carbamazepine extended-release capsules are 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: Partial seizures with complex symptomatology (psychomotor, temporal lobe). Patients with these seizures appear to show greater improvements than those with other types. Generalized tonic-clonic seizures (grand mal). 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 ). Trigeminal Neuralgia Carbamazepine extended-release capsules are 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 extended-release capsules 100 mg are hard gelatin capsules with white opaque body and blue-green opaque cap, imprinted “APO C100” in black ink with white to off-white granule fill. They are supplied as follows: Bottles of 30s (NDC 60505-2805-3) Bottles of 120s (NDC 60505-2805-7) Bottles of 1000s (NDC 60505-2805-8) Carbamazepine extended-release capsules 200 mg are hard gelatin capsules with white opaque body and blue-green opaque cap, imprinted “APO C200” in black ink with white to off-white granule fill. They are supplied as follows: Bottles of 30s (NDC 60505-2806-3) Bottles of 120s (NDC 60505-2806-7) Bottles of 1000s (NDC 60505-2806-8) Carbamazepine extended-release capsules 300 mg are hard gelatin capsules with white opaque body and blue-green opaque cap, imprinted “APO C300” in black ink with white to off-white granule fill. They are supplied as follows: Bottles of 30s (NDC 60505-2807-3) Bottles of 120s (NDC 60505-2807-7) Bottles of 500s (NDC 60505-2807-5) Store at 20˚C to 25°C (68˚F to 77°F); excursions permitted to 15˚C to 30°C (59˚F to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP]. Dispense with Medication Guide available at https://www.apotex.com/products/us/mg.asp APOTEX INC. CARBAMAZEPINE EXTENDED-RELEASE CAPSULES 100 mg, 200 mg and 300 mg Manufactured by: Apotex Inc. Toronto, Ontario Canada M9L 1T9 Manufactured for: Apotex Corp. Weston, Florida USA 33326 Rev. 11

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 and nortriptyline. Likewise, on theoretical grounds its use with monoamine oxidase 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. Coadministration of carbamazepine is contraindicated with delavirdine due to the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

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 extended-release capsules 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 carbamazepine extended-release capsules 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 extended-release capsules 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 WARNINGS 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 extended-release capsules. 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 carbamazepine extended-release capsules contain 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 hypersensitivity below). HLA-A*3101 is expected to be carried by more than 15% of patients of Japanese, Native American, Southern Indian (e.g., 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. 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 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, have occurred with carbamazepine. …

General : If adverse reactions are of such severity that the drug must be discontinued, the physician must be aware that abrupt discontinuation of any anticonvulsant drug in a responsive patient with epilepsy may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see BOXED WARNING ), and the cardiovascular system. The most frequently observed adverse reactions, particularly during the initial phases of therapy, are dizziness, drowsiness, unsteadiness, nausea, and vomiting. To minimize the possibility of such reactions, therapy should be initiated at the lowest dosage recommended. …

Clinically meaningful drug interactions have occurred with concomitant medications and include, but are not limited to the following: Agents Highly Bound to Plasma Protein: Carbamazepine is not highly bound to plasma proteins; therefore, administration of carbamazepine extended-release capsules to a patient taking another drug that is highly protein bound should not cause increased free concentrations of the other drug. Agents that Inhibit Cytochrome P450 Isoenzymes and/or Epoxide Hydrolase: Carbamazepine is metabolized mainly by cytochrome P450 (CYP) 3A4 to the active carbamazepine 10, 11-epoxide, which is further metabolized to the trans-diol by epoxide hydrolase. Therefore, the potential exists for interaction between carbamazepine and any agent that inhibits CYP3A4 and/or epoxide hydrolase. …