Carbamazepine 400 mg Tablet, Extended Release, 100-count — NDC 13668-286-01 (Billing 13668-0286-01)

WARNINGS 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.

Fixed drug eruption (FDE), which presents with single or multiple, circumscribed patches that occur in the same location with each exposure to an offending drug, has been reported with carbamazepine. With repeated exposure to carbamazepine, the skin lesions may progress to generalized bullous fixed drug eruption (GBFDE), a serious skin reaction which may resemble SJS/TEN. 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, FDE, or GBFDE, 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 hypersensiti… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS 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 epileptic patient may lead to seizures or even status epilepticus with its life-threatening hazards. The most severe adverse reactions have been observed in the hemopoietic system and skin (see BOXED WARNING), the liver, 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. The following additional adverse reactions have been reported: Hemopoietic System: Aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda. Skin: TEN and SJS (see BOXED WARNING), Acute Generalized Exanthematous Pustulosis (AGEP), pruritic and erythematous rashes, urticaria, photosensitivity reactions, fixed drug eruption, generalized bullous fixed drug eruption, alterations in skin pigmentation, exfoliative dermatitis, erythema multiforme and nodosum, purpura, aggravation of disseminated lupus erythematosus, alopecia, diaphoresis, onychomadesis and hirsutism.

In certain cases, discontinuation of therapy may be necessary. Cardiovascular System: Congestive heart failure, edema, aggravation of hypertension, hypotension, syncope and collapse, aggravation of coronary artery disease, arrhythmias and AV block, thrombophlebitis, thromboembolism (e.g., pulmonary embolism), and adenopathy or lymphadenopathy. Some of these cardiovascular complications have resulted in fatalities.

Myocardial infarction has been associated with other tricyclic compounds. L iver: Abnormalities in liver function tests, cholestatic and hepatocellular jaundice, hepatitis, very rare cases of hepatic failure. Pancreatic: Pancreatitis.

Respiratory System: Pulmonary hypersensitivity characterized by fever, dyspnea, pneumonitis, or pneumonia. Ge nitourinary System: Urinary frequency, acute urinary retention, oliguria with elevated blood pressure, azotemia, renal failure, and impotence. Albuminuria, glycosuria, elevated BUN, and microscopic deposits in the urine have also been reported.

There have been rare reports of impaired male fertility and/or abnormal spermatogenesis. Testicular atrophy occurred in rats receiving carbamazepine orally from 4 to 52 weeks at dosage levels of 50 to 400 mg/kg/day. Additionally, rats receiving carbamazepine in the diet for 2 years at dosage levels of 25, 75, and 250 mg/kg/day had a dose-related incidence of testicular atrophy and aspermatogenesis.

In dogs, it produced a brownish discoloration, presumably a metabolite, in the urinary bladder at dosage levels of 50 mg/kg and higher. Relevance of these findings to humans is unknown. Ne rvous System: Dizziness, drowsiness, disturbances of coordination, confusion, headache, fatigue, blurred vision, visual hallucinations, transient diplopia, oculomotor disturbances, nystagmus, speech disturbances, abnormal involuntary movements, peripheral neuritis and paresthesias, depression with agitation, talkativeness, tinnitus, hyperacusis, neuroleptic malignant syndrome.

There have been reports of associated paralysis and other symptoms of cerebral arterial insufficiency, but the exact relationship of these reactions to the drug has not been established. Isolated cases of neuroleptic malignant syndrome have been reported both with and without concomitant use of psychotropic drugs. D igestive System: Nausea, vomiting, gastric distress and abdominal pain, diarrhea, constipation, anorexia, and dryness of the mouth and pharynx, including glossitis and stomatitis.

Eyes: Scattered punctate cortical lens opacities, increased intraocular pressure (see WARN… [Excerpted — this section continues on DailyMed.]

Drug Interactions There has been a report of a patient who passed an orange rubbery precipitate in his stool the day after ingesting carbamazepine oral suspension immediately followed by Thorazine ®* solution. Subsequent testing has shown that mixing carbamazepine oral suspension and chlorpromazine solution (both generic and brand name) as well as carbamazepine oral 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 oral 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:

PRECAUTIONS General 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 SJS and in another case an association with fever and eosinophilia. Since a given dose of carbamazepine oral 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).

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 extended-release tablets. 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 extended use. 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 reactions and angioedema may occur during treatment with carbamazepine (see WARNINGS). Advise patients to immediately report signs and symptoms suggesting angioedema (swelling of the 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 unu… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE No evidence of abuse potential has been associated with carbamazepine, nor is there evidence of psychological or physical dependence in humans.