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according to authors of a recent review. And if putting higher-risk patients on drugs most associated with human leukocyte antigen (HLA)–related reaction risk before test results are available, authors advised starting at low doses and titrating slowly.
“When someone is having a seizure drug prescribed,” said senior author Ram Mani, MD, MSCE, chief of epilepsy at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, “it’s often a tense clinical situation because the patient has either had the first few seizures of their life, or they’ve had a worsening in their seizures.”
To help physicians optimize choices, Dr. Mani and colleagues reviewed literature regarding 31 ASMs. Their study was published in Current Treatment Options in Neurology.
Overall, said Dr. Mani, incidence of benign skin reactions such as morbilliform exanthematous eruptions, which account for 95% of cutaneous adverse drug reactions (CADRs), ranges from a few percent up to 15%. “It’s a somewhat common occurrence. Fortunately, the reactions that can lead to morbidity and mortality are fairly rare.”
Severe Cutaneous Adverse Reactions
Among the five ASMs approved by the Food and Drug Administration since 2018, cenobamate has sparked the greatest concern. In early clinical development for epilepsy, a fast titration schedule (starting at 50 mg/day and increasing by 50 mg every 2 weeks to at least 200 mg/day) resulted in three cases of drug reaction with eosinophilia and systemic symptoms (DRESS, also called drug-induced hypersensitivity reaction/DIHS), including one fatal case. Based on a phase 3 trial, the drug’s manufacturer now recommends starting at 12.5 mg and titrating more slowly.
DRESS/DIHS appears within 2-6 weeks of drug exposure. Along with malaise, fever, and conjunctivitis, symptoms can include skin eruptions ranging from morbilliform to hemorrhagic and bullous. “Facial edema and early facial rash are classic findings,” the authors added. DRESS also can involve painful lymphadenopathy and potentially life-threatening damage to the liver, heart, and other organs.
Stevens-Johnson syndrome (SJS), which is characterized by detached skin measuring less than 10% of the entire body surface area, typically happens within the first month of drug exposure. Flu-like symptoms can appear 1-3 days before erythematous to dusky macules, commonly on the chest, as well as cutaneous and mucosal erosions. Along with the skin and conjunctiva, SJS can affect the eyes, lungs, liver, bone marrow, and gastrointestinal tract.
When patients present with possible DRESS or SJS, the authors recommended inpatient multidisciplinary care. Having ready access to blood tests can help assess severity and prognosis, Dr. Mani explained. Inpatient evaluation and treatment also may allow faster access to other specialists as needed, and monitoring of potential seizure exacerbation in patients with uncontrolled seizures for whom the drug provided benefit but required abrupt discontinuation.
Often, he added, all hope is not lost for future use of the medication after a minor skin reaction. A case series and literature review of mild lamotrigine-associated CADRs showed that most patients could reintroduce and titrate lamotrigine by waiting at least 4 weeks, beginning at 5 mg/day, and gradually increasing to 25 mg/day.
Identifying Those at Risk
With millions of patients being newly prescribed ASMs annually, accurately screening out all people at risk of severe cutaneous adverse reactions based on available genetic information is impossible. The complexity of evolving recommendations for HLA testing makes them hard to remember, Dr. Mani said. “Development and better use of clinical decision support systems can help.”
Accordingly, he starts with a thorough history and physical examination, inquiring about prior skin reactions or hypersensitivity, which are risk factors for future reactions to drugs such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, rufinamide, and zonisamide. “Most of the medicines that the HLA tests are being done for are not the initial medicines I typically prescribe for a patient with newly diagnosed epilepsy,” said Dr. Mani. For ASM-naive patients with moderate or high risk of skin hypersensitivity reactions, he usually starts with lacosamide, levetiracetam, or brivaracetam. Additional low-risk drugs he considers in more complex cases include valproate, topiramate, and clobazam.
Only if a patient’s initial ASM causes problems will Dr. Mani consider higher-risk options and order HLA tests for patients belonging to indicated groups — such as testing for HLA-B*15:02 in Asian patients being considered for carbamazepine. About once weekly, he must put a patient on a potentially higher-risk drug before test results are available. If after a thorough risk-benefit discussion, he and the patient agree that the higher-risk drug is warranted, Dr. Mani starts at a lower-than-labeled dose, with a slower titration schedule that typically extends the ramp-up period by 1 week.
Fortunately, Dr. Mani said that, in 20 years of practice, he has seen more misdiagnoses — involving rashes from poison ivy, viral infections, or allergies — than actual ASM-induced reactions. “That’s why the patient, family, and practitioner need to be open-minded about what could be causing the rash.”
Dr. Mani reported no relevant conflicts. The study authors reported no funding sources.
according to authors of a recent review. And if putting higher-risk patients on drugs most associated with human leukocyte antigen (HLA)–related reaction risk before test results are available, authors advised starting at low doses and titrating slowly.
“When someone is having a seizure drug prescribed,” said senior author Ram Mani, MD, MSCE, chief of epilepsy at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, “it’s often a tense clinical situation because the patient has either had the first few seizures of their life, or they’ve had a worsening in their seizures.”
To help physicians optimize choices, Dr. Mani and colleagues reviewed literature regarding 31 ASMs. Their study was published in Current Treatment Options in Neurology.
Overall, said Dr. Mani, incidence of benign skin reactions such as morbilliform exanthematous eruptions, which account for 95% of cutaneous adverse drug reactions (CADRs), ranges from a few percent up to 15%. “It’s a somewhat common occurrence. Fortunately, the reactions that can lead to morbidity and mortality are fairly rare.”
Severe Cutaneous Adverse Reactions
Among the five ASMs approved by the Food and Drug Administration since 2018, cenobamate has sparked the greatest concern. In early clinical development for epilepsy, a fast titration schedule (starting at 50 mg/day and increasing by 50 mg every 2 weeks to at least 200 mg/day) resulted in three cases of drug reaction with eosinophilia and systemic symptoms (DRESS, also called drug-induced hypersensitivity reaction/DIHS), including one fatal case. Based on a phase 3 trial, the drug’s manufacturer now recommends starting at 12.5 mg and titrating more slowly.
DRESS/DIHS appears within 2-6 weeks of drug exposure. Along with malaise, fever, and conjunctivitis, symptoms can include skin eruptions ranging from morbilliform to hemorrhagic and bullous. “Facial edema and early facial rash are classic findings,” the authors added. DRESS also can involve painful lymphadenopathy and potentially life-threatening damage to the liver, heart, and other organs.
Stevens-Johnson syndrome (SJS), which is characterized by detached skin measuring less than 10% of the entire body surface area, typically happens within the first month of drug exposure. Flu-like symptoms can appear 1-3 days before erythematous to dusky macules, commonly on the chest, as well as cutaneous and mucosal erosions. Along with the skin and conjunctiva, SJS can affect the eyes, lungs, liver, bone marrow, and gastrointestinal tract.
When patients present with possible DRESS or SJS, the authors recommended inpatient multidisciplinary care. Having ready access to blood tests can help assess severity and prognosis, Dr. Mani explained. Inpatient evaluation and treatment also may allow faster access to other specialists as needed, and monitoring of potential seizure exacerbation in patients with uncontrolled seizures for whom the drug provided benefit but required abrupt discontinuation.
Often, he added, all hope is not lost for future use of the medication after a minor skin reaction. A case series and literature review of mild lamotrigine-associated CADRs showed that most patients could reintroduce and titrate lamotrigine by waiting at least 4 weeks, beginning at 5 mg/day, and gradually increasing to 25 mg/day.
Identifying Those at Risk
With millions of patients being newly prescribed ASMs annually, accurately screening out all people at risk of severe cutaneous adverse reactions based on available genetic information is impossible. The complexity of evolving recommendations for HLA testing makes them hard to remember, Dr. Mani said. “Development and better use of clinical decision support systems can help.”
Accordingly, he starts with a thorough history and physical examination, inquiring about prior skin reactions or hypersensitivity, which are risk factors for future reactions to drugs such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, rufinamide, and zonisamide. “Most of the medicines that the HLA tests are being done for are not the initial medicines I typically prescribe for a patient with newly diagnosed epilepsy,” said Dr. Mani. For ASM-naive patients with moderate or high risk of skin hypersensitivity reactions, he usually starts with lacosamide, levetiracetam, or brivaracetam. Additional low-risk drugs he considers in more complex cases include valproate, topiramate, and clobazam.
Only if a patient’s initial ASM causes problems will Dr. Mani consider higher-risk options and order HLA tests for patients belonging to indicated groups — such as testing for HLA-B*15:02 in Asian patients being considered for carbamazepine. About once weekly, he must put a patient on a potentially higher-risk drug before test results are available. If after a thorough risk-benefit discussion, he and the patient agree that the higher-risk drug is warranted, Dr. Mani starts at a lower-than-labeled dose, with a slower titration schedule that typically extends the ramp-up period by 1 week.
Fortunately, Dr. Mani said that, in 20 years of practice, he has seen more misdiagnoses — involving rashes from poison ivy, viral infections, or allergies — than actual ASM-induced reactions. “That’s why the patient, family, and practitioner need to be open-minded about what could be causing the rash.”
Dr. Mani reported no relevant conflicts. The study authors reported no funding sources.
according to authors of a recent review. And if putting higher-risk patients on drugs most associated with human leukocyte antigen (HLA)–related reaction risk before test results are available, authors advised starting at low doses and titrating slowly.
“When someone is having a seizure drug prescribed,” said senior author Ram Mani, MD, MSCE, chief of epilepsy at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, “it’s often a tense clinical situation because the patient has either had the first few seizures of their life, or they’ve had a worsening in their seizures.”
To help physicians optimize choices, Dr. Mani and colleagues reviewed literature regarding 31 ASMs. Their study was published in Current Treatment Options in Neurology.
Overall, said Dr. Mani, incidence of benign skin reactions such as morbilliform exanthematous eruptions, which account for 95% of cutaneous adverse drug reactions (CADRs), ranges from a few percent up to 15%. “It’s a somewhat common occurrence. Fortunately, the reactions that can lead to morbidity and mortality are fairly rare.”
Severe Cutaneous Adverse Reactions
Among the five ASMs approved by the Food and Drug Administration since 2018, cenobamate has sparked the greatest concern. In early clinical development for epilepsy, a fast titration schedule (starting at 50 mg/day and increasing by 50 mg every 2 weeks to at least 200 mg/day) resulted in three cases of drug reaction with eosinophilia and systemic symptoms (DRESS, also called drug-induced hypersensitivity reaction/DIHS), including one fatal case. Based on a phase 3 trial, the drug’s manufacturer now recommends starting at 12.5 mg and titrating more slowly.
DRESS/DIHS appears within 2-6 weeks of drug exposure. Along with malaise, fever, and conjunctivitis, symptoms can include skin eruptions ranging from morbilliform to hemorrhagic and bullous. “Facial edema and early facial rash are classic findings,” the authors added. DRESS also can involve painful lymphadenopathy and potentially life-threatening damage to the liver, heart, and other organs.
Stevens-Johnson syndrome (SJS), which is characterized by detached skin measuring less than 10% of the entire body surface area, typically happens within the first month of drug exposure. Flu-like symptoms can appear 1-3 days before erythematous to dusky macules, commonly on the chest, as well as cutaneous and mucosal erosions. Along with the skin and conjunctiva, SJS can affect the eyes, lungs, liver, bone marrow, and gastrointestinal tract.
When patients present with possible DRESS or SJS, the authors recommended inpatient multidisciplinary care. Having ready access to blood tests can help assess severity and prognosis, Dr. Mani explained. Inpatient evaluation and treatment also may allow faster access to other specialists as needed, and monitoring of potential seizure exacerbation in patients with uncontrolled seizures for whom the drug provided benefit but required abrupt discontinuation.
Often, he added, all hope is not lost for future use of the medication after a minor skin reaction. A case series and literature review of mild lamotrigine-associated CADRs showed that most patients could reintroduce and titrate lamotrigine by waiting at least 4 weeks, beginning at 5 mg/day, and gradually increasing to 25 mg/day.
Identifying Those at Risk
With millions of patients being newly prescribed ASMs annually, accurately screening out all people at risk of severe cutaneous adverse reactions based on available genetic information is impossible. The complexity of evolving recommendations for HLA testing makes them hard to remember, Dr. Mani said. “Development and better use of clinical decision support systems can help.”
Accordingly, he starts with a thorough history and physical examination, inquiring about prior skin reactions or hypersensitivity, which are risk factors for future reactions to drugs such as carbamazepine, phenytoin, phenobarbital, oxcarbazepine, lamotrigine, rufinamide, and zonisamide. “Most of the medicines that the HLA tests are being done for are not the initial medicines I typically prescribe for a patient with newly diagnosed epilepsy,” said Dr. Mani. For ASM-naive patients with moderate or high risk of skin hypersensitivity reactions, he usually starts with lacosamide, levetiracetam, or brivaracetam. Additional low-risk drugs he considers in more complex cases include valproate, topiramate, and clobazam.
Only if a patient’s initial ASM causes problems will Dr. Mani consider higher-risk options and order HLA tests for patients belonging to indicated groups — such as testing for HLA-B*15:02 in Asian patients being considered for carbamazepine. About once weekly, he must put a patient on a potentially higher-risk drug before test results are available. If after a thorough risk-benefit discussion, he and the patient agree that the higher-risk drug is warranted, Dr. Mani starts at a lower-than-labeled dose, with a slower titration schedule that typically extends the ramp-up period by 1 week.
Fortunately, Dr. Mani said that, in 20 years of practice, he has seen more misdiagnoses — involving rashes from poison ivy, viral infections, or allergies — than actual ASM-induced reactions. “That’s why the patient, family, and practitioner need to be open-minded about what could be causing the rash.”
Dr. Mani reported no relevant conflicts. The study authors reported no funding sources.
FROM CURRENT TREATMENT OPTIONS IN NEUROLOGY