WARNING: SERIOUS DERMATOLOGIC ADVERSE REACTIONS and APLASTIC ANEMIA AND AGRANULOCYTOSIS
Serious Dermatologic Reactions and HLA-B*1502 Allelle
Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS), have occurred in patients treated with carbamazepine. These syndromes may be accompanied by mucous membrane ulcers, fever, or painful rash. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations, but the risk in patients of Asian descent is estimated to be about 10 times higher. There is a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene that is found almost exclusively in patients with Asian ancestry. Test for HLA-B*1502, prior to initiating EQUETRO in patients with an increased likelihood of carrying this allele. Avoid use of EQUETRO in patients testing positive for the allele unless the benefit clearly outweighs the risk. Discontinue EQUETRO if you suspect that the patient has a serious dermatologic reaction [see Warnings and Precautions, Laboratory Tests)].
Aplastic Anemia and Agranulocytosis
Aplastic anemia and agranulocytosis can occur during treatment with EQUETRO. The risk of developing these reactions with EQUETRO is 5-8 times greater than in the general population. However, the overall risk in the general population is low (6 cases in a population of one million per year for agranulocytosis and two cases in a population of one million per year for aplastic anemia). Obtain a complete blood count before beginning treatment with EQUETRO, and monitor CBC periodically.
Consider discontinuing if EQUETRO if significant bone marrow depression develops [see Warnings and Precautions)].
EQUETRO is contraindicated in patients with bone marrow depression, known hypersensitivity to carbamazepine, such as anaphylaxis or serious hypersensitivity reaction, or known hypersensitivity to any of the tricyclic compounds, such as amitriptyline, desipramine, imipramine, protriptyline, and nortriptyline. Hypersensitivity reactions include anaphalyxis and serious rash. Concomitant use of delaviridine or other non-nucleoside reverse transcriptase inhibitors is contraindicated. EQUETRO can substantially reduce the concentrations of these drugs through induction of CYP3A4. This can lead to loss of virologic response and possible resistance to these medications. Concomitant use of monoamine oxidase inhibitors is contraindicated. Before administration of EQUETRO, MAO inhibitors should be discontinued for a minimum of 14 days, or longer if the clinical situation permits. Concomitant use can cause serotonin syndrome.
Coadministration of EQUETRO with nefazodone is contraindicated. Coadministration of carbamazepine and nefazodone may result in insufficient plasma concentrations of nefazodone and its active metabolite to achieve a therapeutic effect.
Serious Dermatologic Reactions
Discontinue EQUETRO if you suspect that a patient has a serious dermatologic reaction. If signs or symptoms suggest SJS/TEN, do not resume treatment with EQUETRO.
Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Sensitivity
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has occurred with carbamazepine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Equetro should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. A history of hypersensitivity reactions should be obtained for patients and their immediate family members. If such history is present, benefits and risks should be carefully considered, and, if carbamazepine is initiated, the signs and symptoms of hypersensitivity should be carefully monitored.
Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including EQUETRO, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
Anyone considering prescribing EQUETRO or any other AED must balance the risk of suicidal thought or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behaviors and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute differences were similar for the epilepsy and psychiatric indications.
Abrupt Discontinuation and Risk of Seizure
Do not discontinue EQUETRO abruptly, because of the risk of seizure and other withdrawal signs/symptoms.
Usage in Pregnancy
EQUETRO can cause fetal harm when administered to a pregnant woman.
Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. The prescribing physician will wish to weigh the benefits of therapy against the risks in treating or counseling women of childbearing potential. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of potential harm to the fetus.
To provide additional information regarding the effects of in utero exposure to EQUETRO, physicians are advised to recommend that pregnant patients taking EQUETRO enroll in the North America Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website.
Hyponatremia can occur as a result of treatment with EQUETRO. In many cases, the hyponatremia appears to be caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The risk of developing SIADH with EQUETRO treatment appears to be dose-related. Elderly patients and patients treated with diuretics are at greater risk of developing hyponatremia. Consider discontinuing EQUETRO 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 EQUETRO in patients with symptomatic hyponatremia.
Potential for Cognitive and Motor Impairment
EQUETRO has the potential to cause impairment in judgment, cognition, and motor function. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain the EQUETRO does not affect them adversely.
The use of EQUETRO should be avoided in patients with a history of hepatic porphyria (e.g., acute intermittent porphyria, variegate porphyria, porphyria cutanea tarda). Acute attacks have been reported in such patients receiving carbamazepine therapy.
Patients with a history of adverse hematologic reaction to any drug may be particularly at risk of bone marrow depression.
In patients with seizure disorder, carbamazepine should not be discontinued abruptly because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.
Carbamazepine has shown mild anticholinergic activity; therefore, patients with increased intraocular pressure should be closely observed during therapy.
Because of the relationship of the drug to other tricyclic compounds, the possibility of activation of latent psychosis, and in elderly patients, of confusion or agitation, should be considered.
Co-administration of EQUETRO and delavirdine may lead to loss of virologic response and possible resistance to the class of non-nucleoside reverse transcriptase inhibitors.
Before initiating therapy, a detailed history and physical examination should be made.
Therapy should be prescribed only after critical risk-to-benefit appraisal in patients with a history of cardiac, hepatic, or renal damage; adverse hematologic reaction to other drugs; or interrupted courses of therapy with carbamazepine.
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.
Usage in Pregnancy: Pregnancy Category D (see WARNINGS).
Nursing Mothers: Carbamazepine and its epoxide metabolite are transferred to breast milk during lactation. Because of the potential for serious adverse reactions in nursing infants from carbamazepine, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
The most severe adverse reactions previously observed with carbamazepine were reported in the hemopoietic system and skin (see BOXED WARNING) and in 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.
Clinical Trials Experience
The most commonly reported adverse reactions (>5% in the EQUETRO group and at least twice placebo) in the pooled 3-week placebo-controlled trials in patients with acute mania associated with Bipolar I Disorder (Studies 1 and 2) (N=251) were dizziness (44%), somnolence (32%), nausea (29%), vomiting (18%), ataxia (15%), constipation (10%), pruritus (8%), dry mouth (8%), asthenia (8%), rash (7%), blurred vision (6%), and speech disorder (6%).