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warnings and cautions
5 WARNINGS AND PRECAUTIONS Drug Reaction with Eosinophilia and Systemic Symptoms : Monitor for hypersensitivity. Discontinue if another cause can not be established ( 5.3 ) Suicidal Behavior and Ideation: Monitor for depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior ( 5.4 ) Embryofetal Toxicity : Advise women of child-bearing potential of possible risks to the fetus ( 5.5 , 8.1 , 8.3) Abrupt Discontinuation and Risk of Seizure : Taper the dose when discontinuing treatment ( 5.6 ). Hyponatremia: Consider discontinuing EQUETRO in patients with significant symptomatic hyponatremia ( 5.7 ). Cognitive and Motor Impairment: Advise patients not to drive or operate machinery until they have gained sufficient experience on EQUETRO to gauge whether it adversely affects these activities ( 5.8 ). Liver Damage: Monitor liver function. Discontinue EQUETRO with aggravated liver dysfunction or active liver disease ( 5.10 ). Hepatic Porphyria : Avoid EQUETRO use in patients with hepatic porphyria: can cause acute episodes of porphyria ( 5.12 ) 5.1 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. These syndromes may be accompanied by mucous membrane ulcers, fever, or painful rash. Over 90% of carbamazepine-treated patients who experienced SJS/TEN developed these reactions within the first few months of treatment. The risk of these reactions 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. Discontinue EQUETRO if you suspect that the patient has a serious dermatologic reaction. If signs or symptoms suggest SJS/TEN, do not resume treatment with EQUETRO. 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 EQUETRO treatment and the presence of the HLA-B*1502 allele (an inherited variant of the HLA-B gene). Prior to initiating EQUETRO therapy in patients at higher likelihood for this allele, perform testing for HLA-B*1502. The high resolution genotype test is positive if one or two HLA-B*1502 alleles are present. Avoid use of EQUETRO in patients positive for the HLA-B*1502 allele unless the benefits clearly outweighs the risks of serious dermatologic reactions. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN associated with carbamazepine treatment. The prevalence of the HLA-B*1502 allele may be higher in Asian populations: Hong Kong, Thailand, Malaysia, and parts of the Philippines (greater than 15%); Taiwan (10%), North China (4%); south Asians, including Indians (2 to 4%); and Japan and Korea (less than 1%). HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans). The accuracy of estimated rates of the HLA-B*1502 allele in these populations may be limited by wide variability in rates within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. 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) [ s ee Warnings and Precautions ( 5.3 )] . 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 [se e Dosage and Administration ( 2.1 )] . 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 [ s ee Warnings and Precautions ( 5.3 ) ] . HLA-A*3101 is expected to be present in the following frequencies: greater than 15% in 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 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 EQUETRO therapy should be weighed before considering EQUETRO in patients known to be positive for HLA-A*3101. Hypersensitivity and Limitations of HLA Genotyping 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 EQUETRO 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. 5.2 Aplastic Anemia and Agranulocytosis Aplastic anemia and agranulocytosis have occurred in patients treated with carbamazepine. Data from a population-based case-control study suggest that the risk of developing these reactions is 5-8 times greater than in the general population. However, the overall risk of these reactions in the untreated general population is low, approximately six patients per one million population per year for agranulocytosis and two patients per one million population per year for aplastic anemia. Although reports of transient or persistent decreased platelet or white blood cell counts are not uncommon in association with the use of carbamazepine, data are not available to estimate accurately their incidence or outcome. However, the vast majority of the cases of leukopenia have not progressed to the more serious conditions of aplastic anemia or agranulocytosis. Because of the very low incidence of agranulocytosis and aplastic anemia, the vast majority of minor hematologic changes observed in monitoring of patients on EQUETRO are unlikely to signal the occurrence of either abnormality. Nonetheless, complete pretreatment hematological testing should be obtained as a baseline. If a patient in the course of treatment exhibits low or decreased white blood cell or platelet counts, the patient should be monitored closely. Consider discontinuing EQUETRO if any evidence of significant bone marrow depression develops. Clinical features can include fever, dyspnea on exertion, fatigue, easy bruising, petechiae, epistaxis, gingival bleeding, and heavy menses. 5.3 Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, have occurred with carbamazepine. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, 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 Hypersensitivity reactions to carbamazepine have been reported in patients who previously experienced this reaction to anticonvulsants including phenytoin, primidone, and phenobarbital. If such history is present, benefits and risks should be carefully considered, and, if EQUETRO is initiated, the signs and symptoms of hypersensitivity should be carefully monitored. In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may experience hypersensitivity reactions with oxcarbazepine. 5.4 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. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. 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. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to100 years) in the clinical trials analyzed. Table 1 presents the absolute and relative risk by indication for all evaluated AEDs. Table 1. Risk of suicidal thoughts or behavior (reactions) for antiepileptic drugs by indication in the pooled analysis Pla cebo Antiepileptic Drugs Indication Reactions Per 1000 Patients Reactions Per 1000 Patients Relative Risk: Incidence of Reactions in AED Group/ Incidence of Reactions in Placebo Group Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy Psychiatric Other Total 1.0 5.7 1.0 2.4 3.4 8.5 1.8 4.3 3.5 1.5 1.9 1.8 2.4 2.9 0.9 1.9 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. 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. 5. 5 Embryofetal Toxicity EQUETRO can cause fetal harm when administered to a pregnantfemale. [see Use in Specific Populations ( 8.1 )] . Pregnancy registries and epidemiological data suggest a potential association between the use of carbamazepine during pregnancy and major congenital malformations, including neural tube defects and malformations involving other body systems (e.g., craniofacial defects and cardiovascular malformations). These available data suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy. In animal studies, administration of carbamazepine at clinically relevant doses during pregnancy resulted in developmental toxicity, including increased incidences of fetal malformations. Inform females who may become pregnant about the potential increased risk of major congenital malformations with EQUETRO use during pregnancy. Assess the risks and benefits of EQUETRO and discuss with the patient to determine if an alternative treatment should be considered. EQUETRO can reduce the effectiveness of hormonal contraceptives. Females of reproductive potential should be counseled on the consistent use of effective nonhormonal contraception or barrier methods during treatment with EQUETRO [see Drug Interactions ( 7.2 ) and Use in Specific Populations ( 8.1 , 8.3 )] . 5. 6 Abrupt Discontinuation and Risk of Seizure Do not discontinue EQUETRO abruptly, because of the risk of seizure and other withdrawal signs/symptoms. Patients with seizure disorder are at increased risk of developing seizure and status epilepticus with attendant hypoxia and threat to life. However, in the event of an allergic or hypersensitivity reaction, more rapid substitution of alternative therapy may be necessary. 5. 7 Hyponatremia 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. 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. 5. 8 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 . Adverse reactions in the clinical trials in bipolar disorder included (EQUETRO, N= 251 and Placebo, N= 248): somnolence (32% vs. 13%), ataxia (15% vs. 0.4%), dizziness (44% vs. 12%), vertigo (2% vs. 1%), thinking abnormal (2% vs. 0.4%), tremor (3% vs. 1%), and blurred vision (6% vs. 2%) [see Adverse Reactions ( 6.1 )]. 5. 9 Potential for Loss of Virologic Response to N on-nucleoside R everse T ranscriptase I nhibitors that are substrates for CYP3A4 with Concomitant U se of EQUETRO Coadministration of EQUETRO with non-nucleoside reverse transcriptase inhibitors, including delavirdine, is contraindicated because it may lead to loss of virologic response and possible resistance. Through induction of CYP3A4, EQUETRO can markedly decrease the concentrations of these drugs. Coadministration of delavirdine, an NNRTI and a substrate of CYP3A4, and EQUETRO can decrease delavirdine concentrations by 90% [ see Contraindications ( 4 ), Drug Interactions ( 7.2 )] . 5.10 Liver Damage Hepatic effects, ranging from slight elevations in liver enzymes to rare cases of hepatic failure have been reported. 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 serious dermatologic reactions and Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.1 , 5.2 )] . Baseline and periodic evaluations of liver function, particularly in patients with a history of liver disease, must be performed during treatment with this drug since liver damage may occur. The drug should be discontinued immediately in cases of aggravated liver dysfunction or active liver disease. 5.11 AV Heart Block 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. 5.12 Hepatic Porphyria 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. EQUETRO administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria. 5.1 3 Increased Intraocular Pressure Carbamazepine has mild anticholinergic activity. In patients with a history of increased intraocular pressure, consider assessing intraocular pressure before initiating treatment and periodically during therapy.