New Antiepileptic Medications Expand Patients’ Options

VANCOUVER—None of the seven new antiepileptic drugs (AEDs) approved by the FDA during the past 10 years greatly increase the likelihood of seizure control, relative to previously existing therapies, according to an overview presented at the 68th Annual Meeting of the American Academy of Neurology. The broader array of choices is facilitating the individualization of therapy, however. Several of the newer agents are chemically related to previously existing AEDs, but all of the drugs have distinguishing features.

“We do have more options for the treatment of epilepsy,” confirmed Carl W. Bazil, MD, PhD, Director of the Comprehensive Epilepsy Center at Columbia University College of Physicians and Surgeons in New York City. “Although we do not yet have the perfect therapy, more are coming.”

In his evaluation of how newer agents fit into current clinical practice, Dr. Bazil indicated that relative efficacy among the newer agents has not been well defined in the absence of head-to-head trials. Treatment choice is instead based on their approved indications, side effect profiles, and half-lives.

Yet the emergence of more choices was characterized as a positive development. Since pregabalin received regulatory approval in 2005, the newer therapies have included lacosamide (2008), rufinamide (2009), clobazam (2010), ezogabine (2011), perampanel (2012), eslicarbazepine (2013), and brivaracetam (2016). Of these, Dr. Bazil focused primarily on the latter five and how they fit into routine care. Overall, these agents “have not been all that different” in terms of their associated rates of total seizure control or other meaningful end points.

This similarity does not suggest that these agents are interchangeable. The clinical profiles differ by characteristics such as dosing frequency, relative risk of somnolence and other common side effects, and the potential to ameliorate accompanying symptoms, such as anxiety. Moreover, due to differences in trial design and entry criteria, not all of the newer drugs have been granted the same indication, said Dr. Bazil.

Clobazam for Lennox-Gastaut Syndrome

Clobazam is a benzodiazepine receptor agonist that shares features with other benzodiazepines. One of the key features of this agent is a half-life that approaches 80 hours. This characteristic makes clobazam a “forgiving” drug for those who miss a dose, said Dr. Bazil.

Clobazam’s FDA-approved indication is for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome for individuals age 2 or older. Although this Schedule IV drug is not approved in the United States for partial onset seizures, it is widely used for this indication elsewhere, including in Europe and Canada. Clobazam, like other benzodiazepine-related agents, could have a favorable effect on anxiety or sleep problems, even though it is not indicated for these uses, said Dr. Bazil.

Relative to other commonly used AEDs, the rate of rash associated with clobazam has been relatively low, but dizziness and somnolence are sufficiently common that the once-daily dose should be taken before bedtime, according to Dr. Bazil. Relative to other benzodiazepines, clobazam appears to have a low potential for tolerance and dependence. Initial daily doses of 5 mg to 10 mg are standard, but lower doses should be considered in older patients or those with low body weight, said Dr. Bazil. Titration is performed on a weekly basis to a maximum recommended dose of 60 mg.

Perampanel Has a Long Half-Life

Perampanel, which is a noncompetitive AMPA-receptor inhibitor, has an even longer half-life of 100 hours. The drug’s FDA approval is for the adjunctive treatment of partial epilepsy and primary generalized tonic-clonic seizures in patients age 12 and older. Prudent initial dosing begins at 2 mg daily with a recommended maximum dose of 12 mg, according to Dr. Bazil. Due to its reliance on hepatic metabolism, a relatively slow upward titration of this Schedule III drug is appropriate in patients with impaired liver function, he added.

Dizziness and somnolence are commonly reported side effects for perampanel, as they are for most AEDs, and the drug also has a black box warning about its association with homicidal ideation, irritability and aggression. Yet the drug’s relative efficacy may compensate for these risks in selected patients. Even though researchers have not compared perampanel directly with another AED, the drug had an “impressive” seizure-free rate in a placebo-controlled trial, said Dr. Bazil. In this multicenter study of patients with drug-resistant, primary generalized tonic-clonic seizures, 30.9% of participants on perampanel, versus 12.3% of those on placebo, remained seizure-free during maintenance.

Ezogabine and Risk of Discoloration

Ezogabine, which is FDA-approved as adjunctive therapy for refractory partial epilepsy, is a K-channel opener. Due to a relatively short half-life of seven to 11 hours, thrice-daily dosing is required. In addition, bluish discoloration, primarily of the lips and fingertips, commonly occurs due to an interaction of a drug metabolite with sun exposure, according to Dr. Bazil. Concern that this drug may lead to retinal pigmentation means that eye examinations are recommended at baseline and every six months.

“Clinical use of ezogabine has been limited by the pigmentation and by tid dosing, which patients do not like,” Dr. Bazil said. Although the bluish color resolves over time, patients are likely to discontinue this Schedule V drug, which also is associated with dizziness and somnolence, before this occurs.

Eslicarbazepine, an Unscheduled Agent

Eslicarbazepine, a sodium channel blocker, has been approved as adjunctive and monotherapy for partial epilepsy. Although monotherapy trials with a placebo control are no longer considered ethical in patients with epilepsy, eslicarbazepine and lacosamide have been evaluated and found effective in trials in which other active agents were withdrawn over time to allow response on monotherapy to be monitored, Dr. Bazil explained.

Eslicarbazepine is also distinguished from other newer agents by the fact that it is not a scheduled agent. It is primarily metabolized by the liver and has a half-life of 13 to 20 hours. Due to its structural similarity to carbamazepine and oxcarbazepine, these agents should not be combined, said Dr. Bazil. Eslicarbazepine, like clobazam, also could interfere with the bioavailability of oral contraceptives.

“Eslicarbazepine is essentially a longer-acting carbamazepine, a drug with which we are all familiar,” said Dr. Bazil. Although eslicarbazepine also may cause the dizziness, somnolence, and nausea common to carbamazepine, its longer half-life has the potential to diminish peak effects to improve tolerability.

New and Emerging Therapies

Brivaracetam, which was approved for add-on therapy of refractory partial seizures for patients age 16 or older, “is structurally and functionally related to levetiracetam, but approximately 20 times more potent at the SV2A receptor,” said Dr. Bazil. As this recently approved drug is not yet widely used, its relative clinical utility within the context of other choices is not well established, but the side effects common to AEDs, such as dizziness and somnolence, have been relatively mild on this agent in the clinical trials.

Of treatment strategies on the horizon, Dr. Bazil drew attention to SAGE-547, an experimental agent now in a phase III study that has demonstrated uncommon efficacy for refractory status epilepticus, a condition for which there is a large unmet need for reliably effective treatments. In addition, researchers are conducting ongoing efforts to individualize therapy by identifying targetable underlying genetic mutations responsible for seizure activity.

Overall, the therapies approved during the past 10 years have expanded choice in a way that may increase the likelihood of providing a patient with adequate efficacy and acceptable tolerability. Although newer pharmacologic options have not yet generated a major leap in seizure control, coming therapies or strategies to better match existing therapies to the underlying seizure mechanism may yield greater rates of seizure freedom, said Dr. Bazil.

—Ted Bosworth

VANCOUVER—None of the seven new antiepileptic drugs (AEDs) approved by the FDA during the past 10 years greatly increase the likelihood of seizure control, relative to previously existing therapies, according to an overview presented at the 68th Annual Meeting of the American Academy of Neurology. The broader array of choices is facilitating the individualization of therapy, however. Several of the newer agents are chemically related to previously existing AEDs, but all of the drugs have distinguishing features.

“We do have more options for the treatment of epilepsy,” confirmed Carl W. Bazil, MD, PhD, Director of the Comprehensive Epilepsy Center at Columbia University College of Physicians and Surgeons in New York City. “Although we do not yet have the perfect therapy, more are coming.”

In his evaluation of how newer agents fit into current clinical practice, Dr. Bazil indicated that relative efficacy among the newer agents has not been well defined in the absence of head-to-head trials. Treatment choice is instead based on their approved indications, side effect profiles, and half-lives.

Yet the emergence of more choices was characterized as a positive development. Since pregabalin received regulatory approval in 2005, the newer therapies have included lacosamide (2008), rufinamide (2009), clobazam (2010), ezogabine (2011), perampanel (2012), eslicarbazepine (2013), and brivaracetam (2016). Of these, Dr. Bazil focused primarily on the latter five and how they fit into routine care. Overall, these agents “have not been all that different” in terms of their associated rates of total seizure control or other meaningful end points.

This similarity does not suggest that these agents are interchangeable. The clinical profiles differ by characteristics such as dosing frequency, relative risk of somnolence and other common side effects, and the potential to ameliorate accompanying symptoms, such as anxiety. Moreover, due to differences in trial design and entry criteria, not all of the newer drugs have been granted the same indication, said Dr. Bazil.

Clobazam for Lennox-Gastaut Syndrome

Clobazam is a benzodiazepine receptor agonist that shares features with other benzodiazepines. One of the key features of this agent is a half-life that approaches 80 hours. This characteristic makes clobazam a “forgiving” drug for those who miss a dose, said Dr. Bazil.

Clobazam’s FDA-approved indication is for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome for individuals age 2 or older. Although this Schedule IV drug is not approved in the United States for partial onset seizures, it is widely used for this indication elsewhere, including in Europe and Canada. Clobazam, like other benzodiazepine-related agents, could have a favorable effect on anxiety or sleep problems, even though it is not indicated for these uses, said Dr. Bazil.

Relative to other commonly used AEDs, the rate of rash associated with clobazam has been relatively low, but dizziness and somnolence are sufficiently common that the once-daily dose should be taken before bedtime, according to Dr. Bazil. Relative to other benzodiazepines, clobazam appears to have a low potential for tolerance and dependence. Initial daily doses of 5 mg to 10 mg are standard, but lower doses should be considered in older patients or those with low body weight, said Dr. Bazil. Titration is performed on a weekly basis to a maximum recommended dose of 60 mg.

Perampanel Has a Long Half-Life

Perampanel, which is a noncompetitive AMPA-receptor inhibitor, has an even longer half-life of 100 hours. The drug’s FDA approval is for the adjunctive treatment of partial epilepsy and primary generalized tonic-clonic seizures in patients age 12 and older. Prudent initial dosing begins at 2 mg daily with a recommended maximum dose of 12 mg, according to Dr. Bazil. Due to its reliance on hepatic metabolism, a relatively slow upward titration of this Schedule III drug is appropriate in patients with impaired liver function, he added.

Dizziness and somnolence are commonly reported side effects for perampanel, as they are for most AEDs, and the drug also has a black box warning about its association with homicidal ideation, irritability and aggression. Yet the drug’s relative efficacy may compensate for these risks in selected patients. Even though researchers have not compared perampanel directly with another AED, the drug had an “impressive” seizure-free rate in a placebo-controlled trial, said Dr. Bazil. In this multicenter study of patients with drug-resistant, primary generalized tonic-clonic seizures, 30.9% of participants on perampanel, versus 12.3% of those on placebo, remained seizure-free during maintenance.

Ezogabine and Risk of Discoloration

Ezogabine, which is FDA-approved as adjunctive therapy for refractory partial epilepsy, is a K-channel opener. Due to a relatively short half-life of seven to 11 hours, thrice-daily dosing is required. In addition, bluish discoloration, primarily of the lips and fingertips, commonly occurs due to an interaction of a drug metabolite with sun exposure, according to Dr. Bazil. Concern that this drug may lead to retinal pigmentation means that eye examinations are recommended at baseline and every six months.

“Clinical use of ezogabine has been limited by the pigmentation and by tid dosing, which patients do not like,” Dr. Bazil said. Although the bluish color resolves over time, patients are likely to discontinue this Schedule V drug, which also is associated with dizziness and somnolence, before this occurs.

Eslicarbazepine, an Unscheduled Agent

Eslicarbazepine, a sodium channel blocker, has been approved as adjunctive and monotherapy for partial epilepsy. Although monotherapy trials with a placebo control are no longer considered ethical in patients with epilepsy, eslicarbazepine and lacosamide have been evaluated and found effective in trials in which other active agents were withdrawn over time to allow response on monotherapy to be monitored, Dr. Bazil explained.

Eslicarbazepine is also distinguished from other newer agents by the fact that it is not a scheduled agent. It is primarily metabolized by the liver and has a half-life of 13 to 20 hours. Due to its structural similarity to carbamazepine and oxcarbazepine, these agents should not be combined, said Dr. Bazil. Eslicarbazepine, like clobazam, also could interfere with the bioavailability of oral contraceptives.

“Eslicarbazepine is essentially a longer-acting carbamazepine, a drug with which we are all familiar,” said Dr. Bazil. Although eslicarbazepine also may cause the dizziness, somnolence, and nausea common to carbamazepine, its longer half-life has the potential to diminish peak effects to improve tolerability.

New and Emerging Therapies

Brivaracetam, which was approved for add-on therapy of refractory partial seizures for patients age 16 or older, “is structurally and functionally related to levetiracetam, but approximately 20 times more potent at the SV2A receptor,” said Dr. Bazil. As this recently approved drug is not yet widely used, its relative clinical utility within the context of other choices is not well established, but the side effects common to AEDs, such as dizziness and somnolence, have been relatively mild on this agent in the clinical trials.

Of treatment strategies on the horizon, Dr. Bazil drew attention to SAGE-547, an experimental agent now in a phase III study that has demonstrated uncommon efficacy for refractory status epilepticus, a condition for which there is a large unmet need for reliably effective treatments. In addition, researchers are conducting ongoing efforts to individualize therapy by identifying targetable underlying genetic mutations responsible for seizure activity.

Overall, the therapies approved during the past 10 years have expanded choice in a way that may increase the likelihood of providing a patient with adequate efficacy and acceptable tolerability. Although newer pharmacologic options have not yet generated a major leap in seizure control, coming therapies or strategies to better match existing therapies to the underlying seizure mechanism may yield greater rates of seizure freedom, said Dr. Bazil.

—Ted Bosworth

VANCOUVER—None of the seven new antiepileptic drugs (AEDs) approved by the FDA during the past 10 years greatly increase the likelihood of seizure control, relative to previously existing therapies, according to an overview presented at the 68th Annual Meeting of the American Academy of Neurology. The broader array of choices is facilitating the individualization of therapy, however. Several of the newer agents are chemically related to previously existing AEDs, but all of the drugs have distinguishing features.

“We do have more options for the treatment of epilepsy,” confirmed Carl W. Bazil, MD, PhD, Director of the Comprehensive Epilepsy Center at Columbia University College of Physicians and Surgeons in New York City. “Although we do not yet have the perfect therapy, more are coming.”

In his evaluation of how newer agents fit into current clinical practice, Dr. Bazil indicated that relative efficacy among the newer agents has not been well defined in the absence of head-to-head trials. Treatment choice is instead based on their approved indications, side effect profiles, and half-lives.

Yet the emergence of more choices was characterized as a positive development. Since pregabalin received regulatory approval in 2005, the newer therapies have included lacosamide (2008), rufinamide (2009), clobazam (2010), ezogabine (2011), perampanel (2012), eslicarbazepine (2013), and brivaracetam (2016). Of these, Dr. Bazil focused primarily on the latter five and how they fit into routine care. Overall, these agents “have not been all that different” in terms of their associated rates of total seizure control or other meaningful end points.

This similarity does not suggest that these agents are interchangeable. The clinical profiles differ by characteristics such as dosing frequency, relative risk of somnolence and other common side effects, and the potential to ameliorate accompanying symptoms, such as anxiety. Moreover, due to differences in trial design and entry criteria, not all of the newer drugs have been granted the same indication, said Dr. Bazil.

Clobazam for Lennox-Gastaut Syndrome

Clobazam is a benzodiazepine receptor agonist that shares features with other benzodiazepines. One of the key features of this agent is a half-life that approaches 80 hours. This characteristic makes clobazam a “forgiving” drug for those who miss a dose, said Dr. Bazil.

Clobazam’s FDA-approved indication is for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome for individuals age 2 or older. Although this Schedule IV drug is not approved in the United States for partial onset seizures, it is widely used for this indication elsewhere, including in Europe and Canada. Clobazam, like other benzodiazepine-related agents, could have a favorable effect on anxiety or sleep problems, even though it is not indicated for these uses, said Dr. Bazil.

Relative to other commonly used AEDs, the rate of rash associated with clobazam has been relatively low, but dizziness and somnolence are sufficiently common that the once-daily dose should be taken before bedtime, according to Dr. Bazil. Relative to other benzodiazepines, clobazam appears to have a low potential for tolerance and dependence. Initial daily doses of 5 mg to 10 mg are standard, but lower doses should be considered in older patients or those with low body weight, said Dr. Bazil. Titration is performed on a weekly basis to a maximum recommended dose of 60 mg.

Perampanel Has a Long Half-Life

Perampanel, which is a noncompetitive AMPA-receptor inhibitor, has an even longer half-life of 100 hours. The drug’s FDA approval is for the adjunctive treatment of partial epilepsy and primary generalized tonic-clonic seizures in patients age 12 and older. Prudent initial dosing begins at 2 mg daily with a recommended maximum dose of 12 mg, according to Dr. Bazil. Due to its reliance on hepatic metabolism, a relatively slow upward titration of this Schedule III drug is appropriate in patients with impaired liver function, he added.

Dizziness and somnolence are commonly reported side effects for perampanel, as they are for most AEDs, and the drug also has a black box warning about its association with homicidal ideation, irritability and aggression. Yet the drug’s relative efficacy may compensate for these risks in selected patients. Even though researchers have not compared perampanel directly with another AED, the drug had an “impressive” seizure-free rate in a placebo-controlled trial, said Dr. Bazil. In this multicenter study of patients with drug-resistant, primary generalized tonic-clonic seizures, 30.9% of participants on perampanel, versus 12.3% of those on placebo, remained seizure-free during maintenance.

Ezogabine and Risk of Discoloration

Ezogabine, which is FDA-approved as adjunctive therapy for refractory partial epilepsy, is a K-channel opener. Due to a relatively short half-life of seven to 11 hours, thrice-daily dosing is required. In addition, bluish discoloration, primarily of the lips and fingertips, commonly occurs due to an interaction of a drug metabolite with sun exposure, according to Dr. Bazil. Concern that this drug may lead to retinal pigmentation means that eye examinations are recommended at baseline and every six months.

“Clinical use of ezogabine has been limited by the pigmentation and by tid dosing, which patients do not like,” Dr. Bazil said. Although the bluish color resolves over time, patients are likely to discontinue this Schedule V drug, which also is associated with dizziness and somnolence, before this occurs.

Eslicarbazepine, an Unscheduled Agent

Eslicarbazepine, a sodium channel blocker, has been approved as adjunctive and monotherapy for partial epilepsy. Although monotherapy trials with a placebo control are no longer considered ethical in patients with epilepsy, eslicarbazepine and lacosamide have been evaluated and found effective in trials in which other active agents were withdrawn over time to allow response on monotherapy to be monitored, Dr. Bazil explained.

Eslicarbazepine is also distinguished from other newer agents by the fact that it is not a scheduled agent. It is primarily metabolized by the liver and has a half-life of 13 to 20 hours. Due to its structural similarity to carbamazepine and oxcarbazepine, these agents should not be combined, said Dr. Bazil. Eslicarbazepine, like clobazam, also could interfere with the bioavailability of oral contraceptives.

“Eslicarbazepine is essentially a longer-acting carbamazepine, a drug with which we are all familiar,” said Dr. Bazil. Although eslicarbazepine also may cause the dizziness, somnolence, and nausea common to carbamazepine, its longer half-life has the potential to diminish peak effects to improve tolerability.

New and Emerging Therapies

Brivaracetam, which was approved for add-on therapy of refractory partial seizures for patients age 16 or older, “is structurally and functionally related to levetiracetam, but approximately 20 times more potent at the SV2A receptor,” said Dr. Bazil. As this recently approved drug is not yet widely used, its relative clinical utility within the context of other choices is not well established, but the side effects common to AEDs, such as dizziness and somnolence, have been relatively mild on this agent in the clinical trials.

Of treatment strategies on the horizon, Dr. Bazil drew attention to SAGE-547, an experimental agent now in a phase III study that has demonstrated uncommon efficacy for refractory status epilepticus, a condition for which there is a large unmet need for reliably effective treatments. In addition, researchers are conducting ongoing efforts to individualize therapy by identifying targetable underlying genetic mutations responsible for seizure activity.

Overall, the therapies approved during the past 10 years have expanded choice in a way that may increase the likelihood of providing a patient with adequate efficacy and acceptable tolerability. Although newer pharmacologic options have not yet generated a major leap in seizure control, coming therapies or strategies to better match existing therapies to the underlying seizure mechanism may yield greater rates of seizure freedom, said Dr. Bazil.

—Ted Bosworth