Patients Taking Perampanel May Not Need Routine Laboratory Monitoring

WASHINGTON, DC—Patients taking perampanel may not require routine laboratory monitoring, according to data from three trials presented at the 67th Annual Meeting of the American Academy of Neurology. Those taking the adjunctive seizure treatment should, however, be monitored for suicidal thoughts and behavior.

Treatment-emergent adverse events (TEAEs) related to laboratory abnormalities occurred in small percentages of patients. “We didn’t see any clinically relevant changes in the mean data from all the laboratory tests,” said Timothy Welty, PharmD, Professor and Chair of the Department of Clinical Science at Drake University in Des Moines. “Data from the three pivotal trials would suggest that routine clinical laboratory monitoring is not necessary and that it should be left up to the judgment of the clinician treating each individual patient.”

Dr. Welty and his colleagues examined data from three phase III double-blind studies. The studies included patients over age 12 with drug-resistant partial seizures who were being treated with one to three concomitant antiepileptic drugs (AEDs). Following a six-week baseline period, subjects were randomized to 19 weeks of once-daily treatment, including a six-week titration period and a 13-week maintenance period, with placebo or 2, 4, 8, or 12 mg of perampanel. Clinical laboratory test results and TEAEs related to laboratory abnormalities that led to withdrawal of the drug, withholding treatment, reduction in dose, or additional concomitant therapy were reported by investigators using Medical Dictionary for Regulatory Activities (MedDRA) standardized terms.

The studies included 1,038 subjects receiving perampanel and 442 subjects receiving placebo. Mean clinical laboratory values were within normal ranges from baseline to the end of treatment. Mean changes in values were small, and no clear dose effect was demonstrated. At least one TEAE related to laboratory abnormalities occurred in 87 patients (8.4%) receiving perampanel and 21 patients (4.8%) receiving placebo. Hematology-related TEAEs occurred in 26 participants (2.5%) receiving perampanel and four participants (0.9%) receiving placebo. Hepatic TEAEs occurred in 13 participants (1.3%) receiving perampanel and three participants (0.7%) receiving placebo. TEAEs related to electrolytes occurred in 15 patients (1.4%) receiving perampanel and one patient (0.2%) receiving placebo. Renal-related TEAEs occurred in one subject (0.1%) receiving perampanel and one subject (0.2%) receiving placebo. Metabolic-related TEAEs occurred in 20 patients (1.9%) receiving perampanel and five patients (1.1%) receiving placebo. TEAEs related to other chemistry parameters occurred in 17 individuals (1.6%) receiving perampanel and seven individuals (1.6%) receiving placebo.

Five Laboratory-Related Discontinuations
There were no serious TEAEs (SAEs) related to laboratory abnormalities in the perampanel group. Discontinuations due to laboratory-related TEAEs occurred in five patients receiving perampanel. One of these patients discontinued because of thrombocytopenia. That patient entered the study with a low platelet count and continued to have problems throughout the study, Dr. Welty said. Another patient with abnormal creatine kinase started a strenuous exercise routine during the trial, which could explain his abnormal results. A third patient was coded as having hypokalemia, but when researchers examined the testing concentrations at baseline and at day 14, when the patient discontinued, the concentrations were within the normal range. The fourth patient had an altered serum sodium level, and the fifth patient had a decreased bicarbonate level.

The FDA approved perampanel in 2012 for the treatment of partial seizures. About 25,000 people have post-marketing experience with the drug so far, and there have been “no trends that have shown anything different than what was seen in the clinical trials,” Dr. Welty said.

Patients Should Be Monitored for Suicidal Thoughts
Patients taking perampanel or other AEDs should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and unusual mood or behavior changes, according to researchers who conducted a separate review of data related to suicidality events in the perampanel trials. The risk of suicidality based on the trial data appears to be low, said Alan B. Ettinger, MD, Professor of Clinical Neurology at the Albert Einstein College of Medicine in New York City.

Perampanel, like other AEDs, includes a class warning for increased risk for suicidal behavior or ideation. The FDA required these warnings after its 2008 finding that AEDs increase the risk of suicidal behavior or ideation. The FDA based its conclusion on a meta-analysis of 199 placebo-controlled trials of 11 AEDs. “Perampanel was not included in the original 11-AED meta-analysis, so it would be valuable to examine the available data regarding suicidality reported in premarketing trials,” said Dr. Ettinger. He and his colleagues reviewed instances of suicidal behavior or ideation in the perampanel clinical studies, which included patients with and without epilepsy and healthy volunteers. TEAEs were evaluated using MedDRA preferred terms. Suicidal behavior or ideation was determined retrospectively, based on adverse-event reporting.

Suicidality-related TEAEs in the phase III, double-blind, partial seizure population included suicidal ideation in two controls (0.5%) and in two patients (0.2%) receiving perampanel. Intentional drug overdose occurred in one patient (0.1%) receiving perampanel. Two events, suicidal ideation in a patient receiving perampanel (8 mg) and intentional drug overdose in another patient receiving perampanel (12 mg), were SAEs. All three patients who were taking perampanel and reported suicidality-related TEAEs discontinued the study. None of the patients receiving placebo discontinued because of suicidality-related TEAEs. There were no deaths reported in the phase III, double-blind, partial seizure studies.

Among 1,651 patients receiving perampanel from the broader, all-treated partial seizure population, 18 (1.1%) had suicidality-related TEAEs, compared with two (0.4%) of 510 patients receiving placebo. For this broader population, when accounting for duration of exposure to the study drug, the exposure-adjusted rate for TEAEs related to suicidality in perampanel-treated patients was similar to the rate for patients treated with placebo. Of the 18 patients receiving perampanel with suicidality-related TEAEs, 13 had SAEs and 11 discontinued. No deaths due to TEAEs were related to suicidality. Among the 2,717 patients without epilepsy treated with perampanel, suicidality-related TEAEs were observed in two patients with neuropathic pain and three with Parkinson’s disease. Four events were SAEs, and one led to discontinuation. Volunteers from phase I studies did not report any suicidality-related TEAEs.

The study was based on spontaneous reports of suicidality, rather than formal suicidality scales. Despite this limitation, the study is important for assessing “whether there is a signal in the data indicating a possible concern. Fortunately, the risk of suicidality based upon this data appears to be low,” he said. The studies were supported by Eisai, the developer of the drug.

—Jake Remaly

WASHINGTON, DC—Patients taking perampanel may not require routine laboratory monitoring, according to data from three trials presented at the 67th Annual Meeting of the American Academy of Neurology. Those taking the adjunctive seizure treatment should, however, be monitored for suicidal thoughts and behavior.

Treatment-emergent adverse events (TEAEs) related to laboratory abnormalities occurred in small percentages of patients. “We didn’t see any clinically relevant changes in the mean data from all the laboratory tests,” said Timothy Welty, PharmD, Professor and Chair of the Department of Clinical Science at Drake University in Des Moines. “Data from the three pivotal trials would suggest that routine clinical laboratory monitoring is not necessary and that it should be left up to the judgment of the clinician treating each individual patient.”

Dr. Welty and his colleagues examined data from three phase III double-blind studies. The studies included patients over age 12 with drug-resistant partial seizures who were being treated with one to three concomitant antiepileptic drugs (AEDs). Following a six-week baseline period, subjects were randomized to 19 weeks of once-daily treatment, including a six-week titration period and a 13-week maintenance period, with placebo or 2, 4, 8, or 12 mg of perampanel. Clinical laboratory test results and TEAEs related to laboratory abnormalities that led to withdrawal of the drug, withholding treatment, reduction in dose, or additional concomitant therapy were reported by investigators using Medical Dictionary for Regulatory Activities (MedDRA) standardized terms.

The studies included 1,038 subjects receiving perampanel and 442 subjects receiving placebo. Mean clinical laboratory values were within normal ranges from baseline to the end of treatment. Mean changes in values were small, and no clear dose effect was demonstrated. At least one TEAE related to laboratory abnormalities occurred in 87 patients (8.4%) receiving perampanel and 21 patients (4.8%) receiving placebo. Hematology-related TEAEs occurred in 26 participants (2.5%) receiving perampanel and four participants (0.9%) receiving placebo. Hepatic TEAEs occurred in 13 participants (1.3%) receiving perampanel and three participants (0.7%) receiving placebo. TEAEs related to electrolytes occurred in 15 patients (1.4%) receiving perampanel and one patient (0.2%) receiving placebo. Renal-related TEAEs occurred in one subject (0.1%) receiving perampanel and one subject (0.2%) receiving placebo. Metabolic-related TEAEs occurred in 20 patients (1.9%) receiving perampanel and five patients (1.1%) receiving placebo. TEAEs related to other chemistry parameters occurred in 17 individuals (1.6%) receiving perampanel and seven individuals (1.6%) receiving placebo.

Five Laboratory-Related Discontinuations
There were no serious TEAEs (SAEs) related to laboratory abnormalities in the perampanel group. Discontinuations due to laboratory-related TEAEs occurred in five patients receiving perampanel. One of these patients discontinued because of thrombocytopenia. That patient entered the study with a low platelet count and continued to have problems throughout the study, Dr. Welty said. Another patient with abnormal creatine kinase started a strenuous exercise routine during the trial, which could explain his abnormal results. A third patient was coded as having hypokalemia, but when researchers examined the testing concentrations at baseline and at day 14, when the patient discontinued, the concentrations were within the normal range. The fourth patient had an altered serum sodium level, and the fifth patient had a decreased bicarbonate level.

The FDA approved perampanel in 2012 for the treatment of partial seizures. About 25,000 people have post-marketing experience with the drug so far, and there have been “no trends that have shown anything different than what was seen in the clinical trials,” Dr. Welty said.

Patients Should Be Monitored for Suicidal Thoughts
Patients taking perampanel or other AEDs should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and unusual mood or behavior changes, according to researchers who conducted a separate review of data related to suicidality events in the perampanel trials. The risk of suicidality based on the trial data appears to be low, said Alan B. Ettinger, MD, Professor of Clinical Neurology at the Albert Einstein College of Medicine in New York City.

Perampanel, like other AEDs, includes a class warning for increased risk for suicidal behavior or ideation. The FDA required these warnings after its 2008 finding that AEDs increase the risk of suicidal behavior or ideation. The FDA based its conclusion on a meta-analysis of 199 placebo-controlled trials of 11 AEDs. “Perampanel was not included in the original 11-AED meta-analysis, so it would be valuable to examine the available data regarding suicidality reported in premarketing trials,” said Dr. Ettinger. He and his colleagues reviewed instances of suicidal behavior or ideation in the perampanel clinical studies, which included patients with and without epilepsy and healthy volunteers. TEAEs were evaluated using MedDRA preferred terms. Suicidal behavior or ideation was determined retrospectively, based on adverse-event reporting.

Suicidality-related TEAEs in the phase III, double-blind, partial seizure population included suicidal ideation in two controls (0.5%) and in two patients (0.2%) receiving perampanel. Intentional drug overdose occurred in one patient (0.1%) receiving perampanel. Two events, suicidal ideation in a patient receiving perampanel (8 mg) and intentional drug overdose in another patient receiving perampanel (12 mg), were SAEs. All three patients who were taking perampanel and reported suicidality-related TEAEs discontinued the study. None of the patients receiving placebo discontinued because of suicidality-related TEAEs. There were no deaths reported in the phase III, double-blind, partial seizure studies.

Among 1,651 patients receiving perampanel from the broader, all-treated partial seizure population, 18 (1.1%) had suicidality-related TEAEs, compared with two (0.4%) of 510 patients receiving placebo. For this broader population, when accounting for duration of exposure to the study drug, the exposure-adjusted rate for TEAEs related to suicidality in perampanel-treated patients was similar to the rate for patients treated with placebo. Of the 18 patients receiving perampanel with suicidality-related TEAEs, 13 had SAEs and 11 discontinued. No deaths due to TEAEs were related to suicidality. Among the 2,717 patients without epilepsy treated with perampanel, suicidality-related TEAEs were observed in two patients with neuropathic pain and three with Parkinson’s disease. Four events were SAEs, and one led to discontinuation. Volunteers from phase I studies did not report any suicidality-related TEAEs.

The study was based on spontaneous reports of suicidality, rather than formal suicidality scales. Despite this limitation, the study is important for assessing “whether there is a signal in the data indicating a possible concern. Fortunately, the risk of suicidality based upon this data appears to be low,” he said. The studies were supported by Eisai, the developer of the drug.

—Jake Remaly

WASHINGTON, DC—Patients taking perampanel may not require routine laboratory monitoring, according to data from three trials presented at the 67th Annual Meeting of the American Academy of Neurology. Those taking the adjunctive seizure treatment should, however, be monitored for suicidal thoughts and behavior.

Treatment-emergent adverse events (TEAEs) related to laboratory abnormalities occurred in small percentages of patients. “We didn’t see any clinically relevant changes in the mean data from all the laboratory tests,” said Timothy Welty, PharmD, Professor and Chair of the Department of Clinical Science at Drake University in Des Moines. “Data from the three pivotal trials would suggest that routine clinical laboratory monitoring is not necessary and that it should be left up to the judgment of the clinician treating each individual patient.”

Dr. Welty and his colleagues examined data from three phase III double-blind studies. The studies included patients over age 12 with drug-resistant partial seizures who were being treated with one to three concomitant antiepileptic drugs (AEDs). Following a six-week baseline period, subjects were randomized to 19 weeks of once-daily treatment, including a six-week titration period and a 13-week maintenance period, with placebo or 2, 4, 8, or 12 mg of perampanel. Clinical laboratory test results and TEAEs related to laboratory abnormalities that led to withdrawal of the drug, withholding treatment, reduction in dose, or additional concomitant therapy were reported by investigators using Medical Dictionary for Regulatory Activities (MedDRA) standardized terms.

The studies included 1,038 subjects receiving perampanel and 442 subjects receiving placebo. Mean clinical laboratory values were within normal ranges from baseline to the end of treatment. Mean changes in values were small, and no clear dose effect was demonstrated. At least one TEAE related to laboratory abnormalities occurred in 87 patients (8.4%) receiving perampanel and 21 patients (4.8%) receiving placebo. Hematology-related TEAEs occurred in 26 participants (2.5%) receiving perampanel and four participants (0.9%) receiving placebo. Hepatic TEAEs occurred in 13 participants (1.3%) receiving perampanel and three participants (0.7%) receiving placebo. TEAEs related to electrolytes occurred in 15 patients (1.4%) receiving perampanel and one patient (0.2%) receiving placebo. Renal-related TEAEs occurred in one subject (0.1%) receiving perampanel and one subject (0.2%) receiving placebo. Metabolic-related TEAEs occurred in 20 patients (1.9%) receiving perampanel and five patients (1.1%) receiving placebo. TEAEs related to other chemistry parameters occurred in 17 individuals (1.6%) receiving perampanel and seven individuals (1.6%) receiving placebo.

Five Laboratory-Related Discontinuations
There were no serious TEAEs (SAEs) related to laboratory abnormalities in the perampanel group. Discontinuations due to laboratory-related TEAEs occurred in five patients receiving perampanel. One of these patients discontinued because of thrombocytopenia. That patient entered the study with a low platelet count and continued to have problems throughout the study, Dr. Welty said. Another patient with abnormal creatine kinase started a strenuous exercise routine during the trial, which could explain his abnormal results. A third patient was coded as having hypokalemia, but when researchers examined the testing concentrations at baseline and at day 14, when the patient discontinued, the concentrations were within the normal range. The fourth patient had an altered serum sodium level, and the fifth patient had a decreased bicarbonate level.

The FDA approved perampanel in 2012 for the treatment of partial seizures. About 25,000 people have post-marketing experience with the drug so far, and there have been “no trends that have shown anything different than what was seen in the clinical trials,” Dr. Welty said.

Patients Should Be Monitored for Suicidal Thoughts
Patients taking perampanel or other AEDs should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and unusual mood or behavior changes, according to researchers who conducted a separate review of data related to suicidality events in the perampanel trials. The risk of suicidality based on the trial data appears to be low, said Alan B. Ettinger, MD, Professor of Clinical Neurology at the Albert Einstein College of Medicine in New York City.

Perampanel, like other AEDs, includes a class warning for increased risk for suicidal behavior or ideation. The FDA required these warnings after its 2008 finding that AEDs increase the risk of suicidal behavior or ideation. The FDA based its conclusion on a meta-analysis of 199 placebo-controlled trials of 11 AEDs. “Perampanel was not included in the original 11-AED meta-analysis, so it would be valuable to examine the available data regarding suicidality reported in premarketing trials,” said Dr. Ettinger. He and his colleagues reviewed instances of suicidal behavior or ideation in the perampanel clinical studies, which included patients with and without epilepsy and healthy volunteers. TEAEs were evaluated using MedDRA preferred terms. Suicidal behavior or ideation was determined retrospectively, based on adverse-event reporting.

Suicidality-related TEAEs in the phase III, double-blind, partial seizure population included suicidal ideation in two controls (0.5%) and in two patients (0.2%) receiving perampanel. Intentional drug overdose occurred in one patient (0.1%) receiving perampanel. Two events, suicidal ideation in a patient receiving perampanel (8 mg) and intentional drug overdose in another patient receiving perampanel (12 mg), were SAEs. All three patients who were taking perampanel and reported suicidality-related TEAEs discontinued the study. None of the patients receiving placebo discontinued because of suicidality-related TEAEs. There were no deaths reported in the phase III, double-blind, partial seizure studies.

Among 1,651 patients receiving perampanel from the broader, all-treated partial seizure population, 18 (1.1%) had suicidality-related TEAEs, compared with two (0.4%) of 510 patients receiving placebo. For this broader population, when accounting for duration of exposure to the study drug, the exposure-adjusted rate for TEAEs related to suicidality in perampanel-treated patients was similar to the rate for patients treated with placebo. Of the 18 patients receiving perampanel with suicidality-related TEAEs, 13 had SAEs and 11 discontinued. No deaths due to TEAEs were related to suicidality. Among the 2,717 patients without epilepsy treated with perampanel, suicidality-related TEAEs were observed in two patients with neuropathic pain and three with Parkinson’s disease. Four events were SAEs, and one led to discontinuation. Volunteers from phase I studies did not report any suicidality-related TEAEs.

The study was based on spontaneous reports of suicidality, rather than formal suicidality scales. Despite this limitation, the study is important for assessing “whether there is a signal in the data indicating a possible concern. Fortunately, the risk of suicidality based upon this data appears to be low,” he said. The studies were supported by Eisai, the developer of the drug.

—Jake Remaly