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Equetro

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Equetro




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 occur. 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 carbamazepine 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 HLAB* 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 ( > 15%); Taiwan (10%), North China (4%); south Asians, including Indians (2 to 4%); and Japan and Korea ( < 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 rash, or to predict Drug Reaction with Eosinophilia and Systemic Symptoms hypersensitivity syndrome or non-serious rash (maculopapular eruption [MPE]) or to predict Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity].

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.

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 Drug Reaction with Eosinophilia and Systemic Symptoms/Multiorgan Hypersensitivity].

HLA-A*3101 is expected to be present in the following frequencies: greater than 15% in patients of Japanese and Native American ancestry; up to about 10% in patients of Han Chinese, Korean, European, and Latin American ancestry; and up to about 5% in African-Americans and patients of Indian, 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.

Hypersensitivity And Limitations Of HLA Genotyping

Application of HLA-B*1502 genotyping as a screening tool has important limitations and must never substitute for appropriate clinical vigilance and patient management. Many HLA-B*1502-positive Asian 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 occurred in patients treated with carbamazepine. Data from a populationbased 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 carbamazepine 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.

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, 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

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.

In patients who have exhibited hypersensitivity reactions to carbamazepine, approximately 25 to 30% may experience hypersensitivity reactions with oxcarbazepine.

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 (5-100 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

Indication Placebo Antiepileptic Drugs Relative Risk: Incidence of Reactions in AED Group/ Incidence of Reactions in Placebo Group Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Reactions Per 1000 Patients Reactions Per 1000 Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 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.

Embryofetal Toxicity

EQUETRO is a Category D drug [see Use in Specific Populations].

EQUETRO can cause fetal harm when administered to a pregnant woman. Apprise women of childbearing potential of this risk. Use in pregnancy only if the potential benefits of treatment outweigh the risks

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.

In humans, transplacental passage of carbamazepine is rapid (30–60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.

Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10–25 times a human daily dosage of 1200 mg on a mg/kg basis or 1.5–4 times the human daily dosage of 1200 mg on a mg/m² basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg, and 4 of 119 offspring showed other anomalies at 650 mg/kg (cleft palate, 1; talipes, 1; anophthalmos, 2).

Tests to detect defects using current accepted procedures should be considered a part of routine prenatal care in childbearing women receiving carbamazepine.

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 American 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 http://www.aedpregnancyregistry.org/

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.

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. 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. 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].

Decreased Antiviral Effect Of Non-nucleoside Reverse Transcriptase Inhibitors With Concomitant Use Of EQUETRO

Coadministration of EQUETRO with non-nucleoside reverse transcriptase inhibitors, including delavirdine, 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 and EQUETRO can decrease delavirdine concentrations by 90% [see CONTRAINDICATIONS, Decreased Antiviral Effect of Non-nucleoside Reverse
Transcriptase Inhibitors with Concomitant use of
EQUETRO
, and DRUG INTERACTIONS].

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. Carbamazepine administration has also been demonstrated to increase porphyrin precursors in rodents, a presumed mechanism for the induction of acute attacks of porphyria.

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.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Inform patients and caregivers that a Medication Guide is available. Instruct them to read the Medication Guide before taking EQUETRO.

  • Serious Dermatologic Reactions
    Inform patients and caregivers about the risk of potentially fatal, serious skin reactions and the signs and symptoms that may signal a serious skin reaction. Instruct patients to consult with their healthcare provider immediately if a skin reaction occurs during treatment with EQUETRO [see WARNINGS AND PRECAUTIONS].
  • Agranulocytosis and Aplastic Anemia
    Inform patients and caregivers about the risk of potentially fatal agranulocytosis and aplastic anemia and the signs and symptoms that may signal these reactions. Instruct them to contact their healthcare provider immediately if symptoms occur [see WARNINGS AND PRECAUTIONS].
  • Drug Reaction with Eosinophilia and Systemic Symptoms
    Inform patients of the early toxic signs and symptoms of a potential hematologic, dermatologic, hypersensitivity, or hepatic reactions. Advise patients that these signs and symptoms may signal a serious reaction and to report any occurrence immediately to their healthcare provider [see WARNINGS AND PRECAUTIONS].
  • Suicidal Ideation and Behavior
    Counsel patients, their caregivers, and families that AEDs, including EQUETRO, may increase the risk of suicidal thinking and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers and families to report behaviors of concern immediately to healthcare providers [see WARNINGS AND PRECAUTIONS].
  • Embryofetal Toxicity
    Advise women of childbearing potential that EQUETRO may cause fetal harm. Use in pregnancy only if the potential benefits of treatment outweigh the risks [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
    Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
  • Abrupt Discontinuation and Risk of Seizure
    Inform patients that abrupt discontinuation of EQUETRO can cause seizures or an increase in seizure frequency. Advise patients that the drug should be tapered when discontinued [see WARNINGS AND PRECAUTIONS].
  • Hyponatremia
    Advise patients that EQUETRO may reduce serum sodium concentrations especially if they are taking other medications that can lower sodium. Advise patients to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, seizures, or more frequent or more severe seizures [see WARNINGS AND PRECAUTIONS].
  • Potential for 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 their ability to drive or operate machinery. Advise patients to exercise caution if alcohol is taken in combination with EQUETRO therapy, due to a possible additive sedative effect [see WARNINGS AND PRECAUTIONS].
  • Decreased Antiviral Effect of Delavirdine or other Non-nucleoside Reverse Transcriptase Inhibitors Inform patients that EQUETRO can significantly decrease serum concentrations of these drugs. Concomitant use of the drugs and EQUETRO are contraindicated [see WARNINGS AND PRECAUTIONS].
  • Concomitant Use with other Carbamazepine Products
    Inform patients that Equetro contains carbamazepine and should not be used in combination with any other medications containing carbamazepine.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

Carcinogenicity

Administration of carbamazepine to Sprague-Dawley rats for 2 years in the diet at doses of 25, 75, and 250 mg/kg/day (low dose approximately 0.2 times the human daily dose of 1200 mg on a mg/m² basis) resulted in a dose-related increase in the incidence of hepatocellular tumors in females and of benign interstitial cell adenomas in the testes of males.

Mutagenicity

Bacterial and mammalian mutagenicity studies using carbamazepine produced negative results.

Impairment Of Fertility

The effects of carbamazepine on male and female fertility have not been studied. Testicular atrophy occurred in rats receiving carbamazepine orally from 4–52 weeks at dosage levels of 50–400 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.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Risk Summary

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. Adverse developmental effects were seen in animal reproduction studies with carbamazepine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus [see WARNINGS AND PRECAUTIONS].

Pregnancy Registry

Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1888-233-2334. Information about the North American Drug Pregnancy Registry can be found at http://www.massgeneral.org/aed/ [see WARNINGS AND PRECAUTIONS].

Clinical Considerations

When treating a pregnant woman with EQUETRO, carefully consider both the potential risks and benefits of treatment and provide appropriate counseling. Tests to detect major congenital malformations using current accepted procedures should be considered a part of routine prenatal care in pregnant women receiving carbamazepine [see WARNINGS AND PRECAUTIONS].

Human Data

Epidemiological data suggest that there may be an association between the use of carbamazepine during pregnancy and congenital malformations, including spina bifida. Retrospective case reviews suggest that, compared with monotherapy, there may be a higher prevalence of teratogenic effects associated with the use of anticonvulsants in combination therapy.

Transplacental passage of carbamazepine is rapid (30–60 minutes), and the drug is accumulated in the fetal tissues, with higher levels found in liver and kidney than in brain and lung.

There have been a few cases of neonatal seizures and/or respiratory depression associated with maternal carbamazepine and other concomitant anticonvulsant drug use. A few cases of neonatal vomiting, diarrhea, and/or decreased feeding have also been reported in association with maternal carbamazepine use. These symptoms may represent a neonatal withdrawal syndrome.

Animal Data

Carbamazepine has been shown to have adverse effects in reproduction studies in rats when given orally in dosages 10–25 times a human daily dosage of 1200 mg on a mg/kg basis or 1.5–4 times the human daily dosage of 1200 mg on a mg/m² basis. In rat teratology studies, 2 of 135 offspring showed kinked ribs at 250 mg/kg, and 4 of 119 offspring showed other anomalies at 650 mg/kg (cleft palate, 1; talipes, 1; anophthalmos, 2).

Labor And Delivery

The effect of carbamazepine on human labor and delivery is unknown.Carbamazepine and its epoxide metabolite are transferred to breast milk during lactation. There is a potential for serious adverse reactions in nursing infants exposed to carbamazepine. Nursing mothers should consider the potential benefits and risks of treatment when deciding on whether to discontinue nursing or to discontinue treatment with EQUETRO, taking into account the importance of the drug to the mother.

Nursing Mothers

Carbamazepine and its epoxide metabolite are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants exposed to EQUETRO, a decision should be made whether to discontinue nursing or to discontinue treatment with EQUETRO, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of EQUETRO in pediatric and adolescent patients have not been established.

Geriatric Use

Clinical studies of EQUETRO did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This monograph has been modified to include the generic and brand name in many instances.

Last reviewed on RxList: 4/22/2016

Warnings
Precautions

Equetro - User Reviews

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